Upload
weiming
View
219
Download
4
Embed Size (px)
Citation preview
1. Introduction
2. Simple DKPs and their activities
3. DKP derivatives and their
activities
4. Expert opinion
Review
Developments around thebioactive diketopiperazines: apatent reviewYi Wang, Pei Wang, Hongguang Ma & Weiming Zhu†
Ocean University of China, School of Medicine and Pharmacy, Key Laboratory of Marine Drugs,
Ministry of Education of China, Qingdao, People’s Republic of China
Introduction: 2,5-Diketopiperazines (DKPs) are cyclic dipeptides from two
amino acids with or without further structural modifications in DKP nucleus.
These DKPs demonstrated attractive bioactive diversity and potential in
drug discovery.
Areas covered: This review summarized those bioactive DKPs in patents, and
provided the analysis of the structure types (N-substitution, secondary cycliza-
tion, isopentenylation, S-substitution, dehydrogenation, and dimerization)
and bioactivities including anti-tumor, neuroprotective, immune and meta-
bolic regulatory, oxytocin inhibitory and anti-inflammatory effects, antibiotic
activity, PAF inhibition, inhibition of plasminogen activator and T-cell
mediated immunity, and insecticidal activity, etc.
Expert opinion: Though DKPs did not show very complicated chemical
structures, their rigid structure, chiral nature and varied side chains led to
their various medicinal applications.
Keywords: 2,5-diketopiperazines, bioactivities, chemical structure, patents
Expert Opin. Ther. Patents [Early Online]
1. Introduction
2,5-Diketopiperazines (DKPs) are cyclic dipeptides from two amino acids with orwithout further structural modifications in DKP nucleus. Their basic structureincludes a six-membered piperazine nucleus formed from the double condensationsbetween two amino acids. In recent years, DKPs have attracted attention in the fieldof drug discovery because of their rigid structure, chiral nature and varied sidechains. Both natural and synthetic DKPs inhibit phosphodiesterase-5, plasminogenactivator, and oxytocin receptor (OXTR) and have neuroprotective, anti-oxidative,anti-hyperglycemic, anti-inflammatory, anti-tumor, anti-viral, anti-fungal and anti-bacterial activities and affinity for quorum-sensing signaling. These compounds andtheir bioactivities have been reviewed in the past 10 years [1-10]. Herein, we present areview of attractive DKPs published in patents before August 2012. There are about150 global patents on DKPs and their derivatives after considering filings with thesame content in different languages from the China, European and Japan PatentOffice and SciFinder Scholar. These patents can be classified into four categories:DKPs and their bioactivities, manufacture of DKPs, application of DKPs in drugdelivery systems and other aspects of DKPs. This review will focus on the patentedDKPs and their bioactivities including their drug uses. Structures of 2,5-DKPsinclude simple DKPs and DKP derivatives.
2. Simple DKPs and their activities
Simple DKPs are used herein to indicate those 2,5-DKPs resulting from the doublecondensations between two amino acids including rare amino acids without any
10.1517/13543776.2013.828036 © 2013 Informa UK, Ltd. ISSN 1354-3776, e-ISSN 1744-7674 1All rights reserved: reproduction in whole or in part not permitted
Exp
ert O
pin.
The
r. P
aten
ts D
ownl
oade
d fr
om in
form
ahea
lthca
re.c
om b
y Q
ueen
's U
nive
rsity
on
09/0
5/13
For
pers
onal
use
onl
y.
further modifications in DKP nucleus. This type of DKPs hascentral nervous system (CNS) activity including anti-depressantand neuroprotection properties, they are also immunoregulatory,anti-bacterial and can act as a PAF antagonist.The first examples of these simple patented DKPs are the
immunoregulatory cyclo-(L-Gln-L-Lys), cyclo-(L-Gln-L-Orn),cyclo-(L-Asn-L-Lys), cyclo-(L-Asn-L-Orn), cyclo-(D-Gln-D-Lys),cyclo-(D-Gln-D-Orn), cyclo-(D-Asn-D-Lys), cyclo-(D-Asn-D-Orn), cyclo-(D-Gln-L-Lys), cyclo-(L-Gln-D-Lys), cyclo-(L-Asn-D-Lys), cyclo-(L-Gln-D-Orn) and cyclo-(D-Asn-L-Orn)disclosed by Ortho Pharma. Corp. in 1981 [11,12]. The hydro-chloride of cyclo-(L-Gln-L-Lys) showed enhancement of thecytotoxic lymphocyte precursor unit (CLP-U) in vitro inmurine C57BL/6 spleen cells on optimal stimulation at con-centrations ranging from 0.1 to 10 pg/ml and suboptimalstimulation at concentrations from 0.1 pg/ml to 10 ng/ml.Cyclo-(L-Pro-L-Tyr) (Maculosin) was obtained by the fer-
mentation of Alternaria alternate. As a host-specific phyto-toxin for spotted knapweed, maculosin was disclosed byResearch and Development Institure, Inc. at Montana stateUniversity in 1990 [13]. Maculosin was applied to knapweedleaves and hypocotyls and exhibited lesion inductive abilitiesat concentrations of 10-3, 10-4 and 10-5 M. However, onwhole and intact knapweed plants, it was inactive. Theselectivity and specificity tests showed that maculosin was ahost-specific herbicide.Fujisawa Pharmaceutical Co. Ltd disclosed DKPs that con-
tained one or all of a N-methylindole, naphthene, anthraceneand pyridine nuclei, and a S-containing chain as the plateletactivating factor (PAF) antagonist in 1990 [14]. Takingcyclo-(D-NMeTrp-D-Leu) (1), (3R,6R)-3-(2-methylthioethyl)-6-(1S-naphthalenylethyl)piperazine-2,5-dione (2) and (3R,6R)-3-(1R-(1-methyl-1H-indol-3-yl)ethyl) -6-(2-pyridinylmethyl)piperazine-2,5-dione (3), as examples, they exhibited antago-nism against PAF-induced platelet aggregation with IC50 val-ues of 1.04, 0.061 and 0.16 µg/ml, respectively. Whenadministered intravenously at a dosage of 10, 3 and 10 mg/kg, compounds 1 -- 3 showed 75, 51 and 72% inhibition ofPAF-induced hypotension in rats, respectively. Compounds1 -- 3 also showed 30, 40 and 35% inhibition of PAF-induced increases of vascular permeability in mice when
administered intra-dermally at a dosage of 10, 10 and 1 mg/kg,respectively.
Five immunosuppressive DKPs (4-8) were synthesizedfrom the condensation between 1-aminocyclopentanoic acidwith Ala, Leu, Phe, Met and 4-benzyloxy Phe by Snow BrandMilk Prod. Co., Ltd in 1991 [15]. After intraperitoneal admin-istration of 14.1, 17.4, 20.0, 16.0 and 28.4 mg/kg for18 days, compounds 4-8 showed 7, 20, 52, 29 and 15% inhi-bition in a rat allergic encephalomyelitis hind leg model,respectively.
3,6-Bis(aziridin-1-ylmethyl)-2,5-DKPs (9, 10) were syn-thesized and found to be the effective and safe anti-neoplastic agents for human MX-1 breast carcinoma byKanebo Ltd in 1993 [16]. The meso-9 (3S,6R or 3R,6S) showed183% of the life-prolonging rate compared with saline controlgroup and had a therapeutic index of 13 for P388-bearingCDF1 mice after 30 days with intra-peritoneal injection threetimes on the first, fifth and ninth day at dosage of 2.5 mg/kg/dose, while the corresponding data for dl-10 (3S,6S + 3R,6R)were 194% (life-prolonging rate) and 22 (therapeutic index),respectively, at 1.25 mg/kg/dose. Both compounds showed100% of tumor inhibitory rate at 1.25 mg/kg for colon26-bearing CDF1 mice after 14 days with the same patternof administration. In addition, compounds 9 and 10 exhib-ited 98 and 73% of tumor inhibitory rates for MX-1 bearingBALB/c mice after 20 days with intra-peritoneal injectiontwice on the fourth day at dosage of 2.5 and 1.25 mg/kg,respectively.
Cyclo-(L-His-L-Pro) was found to act on the CNS to inhibitappetite in rats by the University of Maryland in 1995 [17]. Itreduced appetite after intra-cerebroventricular administrationto animals at a dosage of 20 mg/kg/day for 24 day. When itwas given orally to rats at a dosage of 1 -- 2 mg/kg/day for14 -- 18 days, 8.1% inhibition of weight gain was observedwithout nausea, vomiting, illness and weight loss. Cyclo-(L-His-L-Pro) was also disclosed to be useful for attenuating thedesire for alcohol in a mammal by Prasad in 2002 [18]. Thepatent indicated that it can reduce the desire of the alcohol-experienced mice for alcohol without decreasing consumptionof food and water. Compared with the control group, cyclo-(L-His-L-Pro) showed 25.6, 30.8 and 48.7% inhibition of etha-nol preference in experimental mice at 2.9, 14 and 27 µg/day,respectively.
Four DKPs (11-14) containing an arginine residue wereshown to inhibit chitinase and used as an anti-mycotic agentin 1996 [19]. All these compounds showed inhibition of Serra-tia marcescens. Cyclo-(L-Arg-Gly) (11) can inhibit the morpho-logical change of Candida albicans IFO 1060 from the yeast-form to the filamentous-form, and thus may be useful as atherapeutic agent for candidiasis.
Nineteen DKPs, cyclo-(Gly-Gly), cyclo-(Pro-Gly), cyclo-(Pro-Ala), cyclo-(Pro-Ile), cyclo-(Pro-Leu), cyclo-(Pro-Ser),cyclo-(Pro-Glu), cyclo-(Pro-Gln), cyclo-(Pro-Cys), cyclo-(Pro-Met), cyclo-(Pro-Phe), cyclo-(Pro-Tyr), cyclo-(Pro-His), cyclo-(Pro-Trp), cyclo-(cis-Hyp-Ile), cyclo-(trans-Hyp-Ile), cyclo-(O-
Article highlights.
. The chemical structures of DKPs from the world patentswere analyzed.
. The bioactivities of DKPs from the world patentswere discussed.
. Some important pharmaceutical uses of patents’ DKPswere disclosed.
. Expert opinions were demonstrated on thepatents’ DKPs.
This box summarizes key points contained in the article.
Y. Wang et al.
2 Expert Opin. Ther. Patents (2013) 23(11)
Exp
ert O
pin.
The
r. P
aten
ts D
ownl
oade
d fr
om in
form
ahea
lthca
re.c
om b
y Q
ueen
's U
nive
rsity
on
09/0
5/13
For
pers
onal
use
onl
y.
MeHyp-Ile), cyclo-(O-AcHyp-Ile) and cyclo-(O-BnHyp-Ile),were synthesized and patented for their anti-inflammatoryeffects by Teika Seiyaku in 2000 [20]. The invention showedthat cyclo-(Pro-Ile), cyclo-(Pro-Leu), cyclo-(Pro-Trp), cyclo-(cis-Hyp-Ile), cyclo-(trans-Hyp-Ile), cyclo-(O-MeHyp-Ile),cyclo-(O-AcHyp-Ile) and cyclo-(O-BnHyp-Ile), exhibited24 -- 39% inhibition of TPA (12-O-tetradecanoylphorbol-13-acetate) induced ear edema in mice at 0.5 mg/ear. TheseDKPs could be used for treatment of inflammatory diseasessuch as myalgia, arthritis, rheumatism and allergic dermatitis.
DKPs containing carboxyl, ester and amide group chainssuch as cyclo-(Asp-Ala) and cyclo-(Asn-Ala) were shown toinhibit the effects of PAF and to inhibit the productionand/or release of interleukin 8 (IL-8) regardless of whether itwas induced by PAF in 2002 [21]. PAF is a potent inflamma-tory phospholipid mediator involved in pathological immuneand inflammatory responses. IL-8 is a proinflammatorycytokine, a potent chemoattractant and activator of T-lym-phocytes, neutrophils and eosinophils. For example, cyclo-(Asp-Ala) showed inhibition of the PAF-induced secretionof IL-8 in normal human bronchial epithelial 6122 cells. Itwas proposed that this type of DKP could be used to treat dis-eases or conditions mediated by PAF such as acute respiratorydistress syndrome, cardiovascular disease and inflammation.
Dmi Biosciences, Inc. claimed a series of DKPs for treatingT-cell mediated diseases in 2004 [22,23]. Low-dose cyclo-(Asp-Ala) and cyclo-(Glu-Ala) could be rapidly absorbed into theblood from the gastrointestinal track of the rat without othersignificant metabolites, suggesting oral administration as anadequate therapeutic utilization. Cyclo-(Asp-Ala) and cyclo-(Met-Arg) can inhibit the production of human T-lymphocytecytokines (IL-8, IL-16 and interferon-gamma), and tumornecrosis factor alpha (TNF-a). At the same time, these twoDKPs can selectively affect antigen-specific T-cells in vitro byactivation of cytokine transcriptional factor (ERK1/2) andinhibition of release of pre-formed cytokines. These DKPscan cross the blood--brain barrier, suggesting their potentialuse in the treatment of nervous system disorders.
Special DKPs containing a proline residue (15-27) wereprepared and proposed as neuroprotective agents in2007 [24]. Compound 16 showed significant neuroprotectionand cognitive enhancement of mice in beam-walking andwater maze experiments. Compounds 16-18 could improvemotor function of fluid-percussion induced traumatic braininjury rats at 14 days post-injury. In the same experimentwith compounds 16-18, compound 28, a sulfur-substitutedDKP derivative, showed the most significant recovery effect.
Three DKPs within a 4-hydroxyproline (4-Hyp) moiety,cyclo-(L-Phe-L-4R-Hyp) (29), cyclo-(L-Leu-L-4R-Hyp) (30)and cyclo-(L-Ala-L-4R-Hyp) (31), were isolated from the fer-mentation broth of Alternaria alternate and were claimed tobe active against the pathogen fungus Plasmopara viticolabut non-toxic for the vine plant in 2008 [25].
In an effort to identify anti-cancer and anti-viral therapeu-tics, Dmi Biosciences, Inc. protected a DKP, methyl 2-(1,1¢-
biphenyl-4-yl)-2-(3,6-dioxopiperazin-1-yl)acetate (32) as aninhibitor of cell proliferation, angiogenesis, the productionand release of matrix metalloproteinase-9 (MMP-9) which isbelieved to play a critical role in tumor invasion and metasta-sis, and inhibition of the activation of serine/threonine kinaseAkt in 2009 [26]. Compound 32 showed 78.7 and 13.4%inhibition of proliferation of STTG (Grade 4) astrocytomacells and AU565 breast cancer cells, respectively, at 50 µM.However, it did not inhibit the proliferation of human umbil-ical vein endothelial cells and metastatic astrocytomaU-118 cells at 50 µM. This compound could inhibit thesecretion of MMP-9 from BT001 glioma cells better thanSTTG cells. It also showed inhibition of the phosphorylationof Akt in AU565 breast cancer cells andWM-266-4 metastaticmelanoma cells.
Suntory Holdings Ltd patented an effective and safe anti-depressant and learning motivation improver, comprising ofa DKP as the active ingredient, in 2011 [27]. The inventionshowed that cyclo-(L-His-L-Pro), cyclo-(L-Trp-L-Pro) andcyclo-(L-Phe-L-Phe) and cyclo-(L-Trp-L-Trp), cyclo-(L-Trp-L-Leu) and cyclo-(L-Trp-L-Val) inhibited serotonin transporterbinding and norepinephrine transporter binding with IC50
values of 580, 1060 and 2.4 µg/ml, and 55, 420 and2100 µg/ml, respectively. In addition, cyclo-(L-Phe-L-Phe)improved the learning motivation of mice in the MorrisWater Maze experiment when administered orally at0.02 mg/kg or more, while the linear dipeptide (L-Phe-L-Phe) did not show the effect at 20 mg/kg, suggesting thatthe cyclic dipeptide structure was required. Furthermore,cyclo-(L-Phe-L-Phe) did not show toxicity in mice when orallyadministered at a single dose of 2 g/kg or repeated for 28 days.
Dmi Acquisition Corp. disclosed that cyclo-(L-Asp-L-Ala)could suppress the appetite, reduce weight and blood lipidlevels and inhibit adipogenesis in animals, indicating its usein the treatment of metabolic syndrome such as obesity andnon-alcoholic steatohepatitis in 2012 [28]. Oral administrationof this DKP to human volunteers led to the decrease ofappetite, blood cholesterol, triglycerides, LDL and HDL.In vitro, cyclo-(L-Asp-L-Ala) could inhibit adipogenesis in sub-cutaneous preadipocytes at low dose (25 µM) but promotedadipogenesis at high dose (100 µM).
Cyclo-(Asp-Ala), cyclo-(Met-Arg) and cyclo-(Tyr-Glu) werefound to inhibit vascular hyperpermeability, and modulatethe cytoskeleton of endothelial cells in 2012 [29]. In the elec-tric cell-substrate impedance sensing assay, cyclo-(Asp-Ala),cyclo-(Met-Arg) and cyclo-(Tyr-Glu) showed high transendo-thelial electrical resistance of human retinal endothelial cells(RECs) at 0.5 -- 100 µM (dose-dependent), 50 and 100 µM,and 100 µM, respectively. In addition, cyclo-(Asp-Ala) strength-ened the protective effects of sphingosine-1 phosphate, whichplays an important role in the formation and maintenance ofthe vascular endothelium of RECs. This compound also showedinhibition of the thrombin-induced activation of Rho A (Rashomolog gene family, member A), a small GTP-binding pro-tein associated with the endothelial cell cytoskeleton.
Developments around the bioactive DKPs
Expert Opin. Ther. Patents (2013) 23 (11) 3
Exp
ert O
pin.
The
r. P
aten
ts D
ownl
oade
d fr
om in
form
ahea
lthca
re.c
om b
y Q
ueen
's U
nive
rsity
on
09/0
5/13
For
pers
onal
use
onl
y.
3. DKP derivatives and their activities
DKP derivatives discussed herein are those 2,5-DKPs withstructural modifications such as secondary cyclization, sulfur-substitution, N-modification and dehydrogenation in DKPnucleus, isopentenylation in aromatic rings, and dimerization.
3.1 N-modificationThe nitrogen atoms of 2,5-DKPs were modified by substitu-tion of hydrogen atoms with halogens, an alkyl group, aro-matic group and other substituents.In 1972, N,N ¢-disubstituted DKPs (33 -- 37) were synthe-
sized and protected for their anti-plant pathogens activitieswith 63 -- 99% effectiveness against Phytopthora infestans,Xanthomonas vesicatoria, Piricularia oryzae and Erysiphecichoracearum on tomato, rice and cucumber plants at100 -- 1000 ppm [30]. Compounds 33 -- 37 were also activeagainst the nematode, Panagrelli redivivi, with 100% killingrate at 25 -- 125 ppm. The invention suggested that DKPsdisubstituted at the N,N ¢- positions by --Cl, --Br, --HgAc,--HgOCOCF3 and --HgCl could be used to protect plantsfrom attack by pathogenic fungi and nematodes.Some N,N ¢-disubstituted DKPs containing an imidazole
(38 -- 41) or pyridine (42) moiety were found to inhibitfarnesyl-protein transferase (FPTase) and the farnesylation ofthe oncogene protein Ras by Merck & Co., Inc. USA in1997 [31]. DKP derivatives 39 and 41 exhibited in vitro inhib-itory activity against human FPTase with IC50 values< 50 µM. Because FPTase inhibitors could inhibit theproliferation of vascular smooth muscle cells and the growthof Ras-dependent tumors, this type of DKP derivative couldbe used in the prevention and therapy of arteriosclerosis,and diabetic disturbance of blood vessels and tumors.Three N-substituted DKPs dimeric derivatives (43 -- 45)
formed by linkage of two proline-containing DKP moietiesand 1,4-phenylenedimethyl were synthesized in 1997. Thesecompounds showed hemo-regulatory activities and may beuseful to stimulate hematopoiesis and to prevent and treatbacterial, viral and fungal infections [32].A total of 135 DKP derivatives (46 -- 180) containing the
Cys moiety were synthesized and disclosed to be collagenase-1 and/or stromelysin-1 inhibitors by Affymax TechnologiesN.V. in 1999 [33]. Compounds 58 and 59 showed inhibitionof collagenase-1 with IC50 values < 2 µM. Collagenase-1 andstromelysin-1 are metalloproteases that are involved in thebreakdown of the extracellular matrix during several diseaseprocesses such as arthritis, articular cartilage damage, invasionof metastatic tumors, coronary thrombosis, glomerular dis-ease, ulceration of the cornea, periodontal diseases, degenera-tive aortic disease, and ovulation processes among others.Thus, this type of DKP derivative could be used for the treat-ment of diseases involved in tissue breakdown such asrheumatoid arthritis.Twenty-three N-substituted DKPs (181 -- 203) were syn-
thesized and found to inhibit fructose-1,6-bisphosphatase
(FBPase) by Ontogen Corp. in 1999 [34]. Among them, com-pounds 181 -- 183 showed comparable anti-FBPase activitywith IC50 values of 0.37, 2.1 and 8 µM, respectively, com-pared with the controls adenosine monophosphate (IC50
1.4 ± 0.5 µM) and fructose 2,6-bisphosphate (IC50 2.9 ±0.9 µM). The results showed that the nucleus contained in181 is the active center for inhibition of FBPase. FBPasecontrols the conversion of fructose-1,6-bisphosphate intofructose-6-phosphate, the key rate-limiting step in the gluco-neogenesis pathway. The inhibition of FBPase could decreaseblood glucose levels, indicating the use of these compounds inthe treatment or management of type 2 diabetes.
A group of N-substituted DKPs (204 -- 209) were synthe-sized by Novoscience Pharma, Inc. as selective inhibitors ofcoagulation in 2001 [35]. Among them, cycloargatroban(207) showed selective inhibition for serine proteases (throm-bin and trypsin) over fibrinolytic enzymes (urokinase, plasminand tissue plasminogen activator). Compared with argatroban(US Patent No. 4, 258, 192 [36] and 4, 201, 863 [37]), thesmall molecule thrombin inhibitor cycloargatroban retainedhigh thrombin inhibition activity (2.1-fold lower than arga-troban) and achieved higher selectivity for thrombin thantrypsin (12-fold higher than argatroban), but showed no sig-nificant inhibition of fibrinolytic enzymes (similar to argatro-ban). This higher selectivity was also suggested by the slightreduction of cycloargatroban over the prolonged activatedpartial thromboplastin time.
Forty-five N-substituted DKPs derivatives (210 -- 254)were synthesized and all showed anti-inflammation and anti-cancer activities by Celltech R & D, Inc. USA in 2002 [38].In addition, these compounds contained an acylamino chainin position 4 of the L-Pro nucleus. These DKPs derivativescould inhibit the expression of NF-kB and the cell apoptosisinduced by TNF-a, binding of TNF-a to TNFR, and bind-ing of IL-8 or GRO-a to CXCR1 or CXCR2. Compounds210 -- 213 were the most active. The IC50 values of 210and 212 against CXCR2, 211 and 213 against NF-kB, and213 against the apoptosis of A549 cells were 15, 25, 4,30 and 8 µM, respectively.
Glaxo Group Ltd claimed a series of synthetic N-substi-tuted 2,5-DKPs as oxytocin antagonists with pharmaceuticalformulations for administration including parenteral formula-tion, capsule and tablet from 2003 to 2009 [39-45]. Two hun-dred and twenty-seven DKP derivatives (255 -- 491) formedfrom (R)-2-amino-2-(2,3-dihydro-1H-inden-2-yl)acetic acidand N-substituted D-Leu and its carboxylic acid derivativeswere synthesized [39,45]. These DKP derivatives all exhibitedpotent and selective antagonist activity toward the OXTRin vitro with pKi (Ki calculated as IC50/5) values in the rangeof 8.5 to 10.8 in oxytocin binding assays with no adverse tox-icological effects observed. Further improved derivatives 492and 493 were invented. Both compounds are potent OXTRantagonists with pKi values of 9.0 and 8.2, respectively. Afteroral administration to rats at doses of 30 mg/kg for 7 days,compound 492 did not show adverse toxicological effects [40].
Y. Wang et al.
4 Expert Opin. Ther. Patents (2013) 23(11)
Exp
ert O
pin.
The
r. P
aten
ts D
ownl
oade
d fr
om in
form
ahea
lthca
re.c
om b
y Q
ueen
's U
nive
rsity
on
09/0
5/13
For
pers
onal
use
onl
y.
Eight DKP amides (494 -- 501) derived from (R)-2-amino-2-(2,3-dihydro-1H-inden-2-yl)acetic acid and N-substitutedD-allo-Ile were synthesized and all displayed OXTR antago-nistic activity with pKi values ranging from 8.8 to10.5 [41,42]. A total of 9 DKP amides (502 -- 510) derived
from (R)-2-amino-2-(2,3-dihydro-1H-inden-2-yl)acetic acidand N-substituted (R)-2-amino-3-ethylpentanoic acid wereprepared and all showed antagonist affinities toward thehuman oxytocin-1 receptor in a FLIPR assay with fpKi valesranging from 8.2 to > 9.4 [43]. More than two hundreds of
HN
NH
O
O1
N HN
NH
O
O2
S
H
HN
NH
O
O
R
HN
NH
O
O
3
NN
H
4 – 8
4: R = Me,5: R = i-Bu6: R = PhCH27: R = MeSCH2CH28: R = p-PhCH2OC6H4CH2 N
H
HNO
O
N
N
9 meso
NH
HNO
O
N
N
+ enantiomer10 dl
HN
NHNH
H2N
NH
O
O
11
HN
N
O
O
HN
NH
15
HN
NNH
H2N
NH
O
O
H12: S-13: R-
HN
NHNH
H2N
NH O
O14
HN
N
O
O16
H
HN
NH
O
O32
H3CO O
N
N
O
O
33: R = Cl; 34: R = Br35: R = HgAc; 36: R = HgOCOCF337: R = HgCl
R
R
N
N
O
O
N
N
CN
n
38: n = 0, R = Cl39: n = 0, R = H41: n = 1, R = H
R
HN
N
O
O17
H
HN
N
O
OH
18 – 27
HN
N
O
OH
OH HN
N
O
OH
OHHN
N
O
OH
OH
29 30 31
R
N
N
O
O
N
N
CN
ClN
N
O
O
CN
ClN
434240
NH HNN
O
N
O
N N
O
OOH
H
HOO
OH
CMe3
OH
CMe3 O
OH
N
O
-O
NN S
NH2
HN NHNH
R′
NHN
HS
18
19
20
21
22
R R R
23: R′ = Me; 24: R′= SH
25
26
R
-S-CMe3
27
NH2
S
NHO
HN
N
O
O CONH2
S
S
HN
N
O
O28
+
Developments around the bioactive DKPs
Expert Opin. Ther. Patents (2013) 23 (11) 5
Exp
ert O
pin.
The
r. P
aten
ts D
ownl
oade
d fr
om in
form
ahea
lthca
re.c
om b
y Q
ueen
's U
nive
rsity
on
09/0
5/13
For
pers
onal
use
onl
y.
DKP derivatives from (R)-2-amino-2-(2,3-dihydro-1H-inden-2-yl)acetic acid and N-arylmethyl substituted (R)-2-amino-3-ethylpentanoic acid (511 -- 724), D-Leu(725 -- 793), D-Val (794 -- 797) and other amino acids
(798 -- 803) were also prepared [44]. These compoundsshowed antagonist affinity toward human oxytocin-1 receptorin a FLIPR assay with fpKi values greater than 8.2. Thus,these DKP derivatives are potentially useful in the treatment
N N
O
O H
NN
O
O
HN
N
OH
N
N
OH
44 45
HN
N
O
O
R2HS
R1
13
5 N
NH
O
O
HS
R1
13
5R2
163 – 18060 – 162
R1, R2 = alkyl, aryl
HN
N
O
O
HS 13
5
46: 3R, 4S; 47: 3S, 4R;48: 3R, 4R; 49: 3S, 4S;
HN
N
O
O
HS 13
5
50: R = p-CH3OC6H4-
51: R =N
R
HN
N
O
O
HS 13
5
R
NO2
52: R = p-CH3OC6H4-53: R = CH3CH2CH2-
54: R =N
HN
N
O
O C6H5
13
5OCH3
HN
N
O
O
HS 13
5
55
56
HN
N
O
O
HS
HNO
58
NO2
EtHN
N
O
O
HS 13
5
57
HN
N
O
O
HS
NHO
OCH3
59
N
NH
O
O
O
NH
R2
R1
SH
N
N
O
O
R1
H
O
R2
HN
R1 R2 R3
182183184185186187
p-NCC6H4-p-NCC6H4-p-H2NCOC6H4-p-C6H5OC6H4-p-NCC6H4-
p-HOC6H4CH2CH2-m-HOC6H4CH2CH2-p-FC6H4CH2CH2-p-HOCOC6H4CH2-p-RCOC6H4CH2-
186 R = 187 R =ON N
199200201
-CH2(CH2)3CO2Hp-HOCOC6H4-p-HOC6H4CH2-
C6H5O-C6H5O--NO2
N
N
O
OH
O
NH
CN
OH
181
OH
R1 R2
R3
188189190191192
i-Pri-Pr
p-O2NC6H4-p-NCC6H4-p-NCC6H4-n-Pr
p-HOC6H4CH2CH2-p-HOC6H4CH2CH2-p-HOC6H4CH2CH2-p-HOC6H4CH2CH2-p-HOCOC6H4CH2-
193194195196197
n-pentyln-Pri-BuEtH
p-HOC6H4CH2CH2-p-HOC6H4CH2CH2-p-HOC6H4CH2CH2-p-HOC6H4CH2CH2-p-HOC6H4CH2CH2-
198 Me p-CH3C6H4- p-HOC6H4CH2CH2-
OH
N
NH
O
O
O
NH
OC6H5
NO2
CO2H 202
207 – 209
N
N
O
OH
O
NH
CN
203
OH
N
N
O
O
HNH2N
SR2
H
O
O
NH
H
R1
Y. Wang et al.
6 Expert Opin. Ther. Patents (2013) 23(11)
Exp
ert O
pin.
The
r. P
aten
ts D
ownl
oade
d fr
om in
form
ahea
lthca
re.c
om b
y Q
ueen
's U
nive
rsity
on
09/0
5/13
For
pers
onal
use
onl
y.
or prevention of oxytocin-mediated diseases such as pretermlabor, dysmenorrhea, endometriosis, benign prostatic hyper-plasia and sexual dysfunction. Among them, retosiban(GSK221149A) (492) was in Phase II clinical trials for thetreatment of preterm labor. As an oral drug, retosiban showed
nanomolar affinity (Ki = 0.65 nM) for the human OXTR, andgood solubility (> 0.22 mg/ml), low protein binding (< 80%),good Cyp450 profile with no significant inhibition(IC50 > 100 µM) and low predicted CNS penetration [46].Epelsiban (GSK557296) (496) showed good antagonist
NNH
N
O
O
SH
HNH2N
205: n = 0; 206: n = 1
H
O
O
n
N
N
O
O
SH
H
O
O
O2N
204N
NH
207: R1 = Me, R2 = N
208: R1 = Me, R2 =
209: R1 = H, R2 =
N
N
O
O
NHR1
O
H
R2 OHN
OR3
214 – 254: R1 = alkyl, alkyloxyl; R2 = alkyloxyl, alkylamino; R3 = H, 2,4,6-trimethoxybenzyl
N
N
O
O
NHR1
O
H
R2 O
HN
O
OCH3
OCH3H3CO
210: R2 = -CH2CO2H; R1 =
211: R2 = -CH2CO2CH2CH = CH2; R1 =
212: R2 = -CH2CO2CH3; R1 =
O
N
N
N
O
O
NH
O
H
N O
H2N
O
213
N HN
N
O
O
R21
3
5
255 – 491: R1 = Aromatic groups; R2 = -OH, -OR, -NRR′
R1
O
HN
N
O
O
N1
3
5 OHR
NN
500: R = H;501: R = Me
HN
N
O
O
R21
3
5
R1
OH
N494
495 ibid -NMe2
496 ibid ON
N497
499 ibid ON
R1 R2 R1 R2
HN
N
O
O
N1
3
5 O
ON
O
H
492: S-;493: R-
498 ibid -NMe2
-NHMe -NHMe
494 – 499
HN
N
O
O
R21
3
5
R1
ON
502
503
504 ON
N
505
506
507
-NMe2
ON
R1 R2R1 R2
O
N
508
509
ON
NN
510
R1 R2
-NHMe -NHMe -NHMe
502 – 510
HN
N
O
O
R13
5HN
N
O
O
R13
5 HN
N
O
O
R13
5
R = aromatic groups in 511 – 797
511 – 724 725 – 793 794 – 797
HN
N
O
O
13
5
SO
803
O
Developments around the bioactive DKPs
Expert Opin. Ther. Patents (2013) 23 (11) 7
Exp
ert O
pin.
The
r. P
aten
ts D
ownl
oade
d fr
om in
form
ahea
lthca
re.c
om b
y Q
ueen
's U
nive
rsity
on
09/0
5/13
For
pers
onal
use
onl
y.
activity at the human OXTR with > 31,000-fold selectivityover all three human vasopressin receptors hV1aR, hV2Rand hV1bR. Compound 496 had good oral exposure andbioavailability in the cynomolgus monkey. The result of
genotoxic trial was negative and a satisfactory safetyprofile was observed in the 7-day oral toxicity test in femalerats. This compound had been completed Phase I clinicaltrial [47].
HN
N
O
O
R13
5
SO
O
NO
O
801: R =
802: R =
HN
N
O
O
13
5R
798: R = cyclohexyl;799: R = cyclopropyl;800: R = dicyclopropylmethyl
N
NH
O
O
OH
N
O
HO
O 804
HN
NH
O
O
O
OH
OH
OH
H2CHO
805
N
NH
NH
HO
OH
H
H
N
N
NH
HO
OH
H
H
N
N
NH
HO
OH
H
H
H
N
NH
N
HO
OH
H
H
N
N
N
HO
OH
H
H
806 807 808 809 810
N
N
NH
HO
O
OR1
OR2
811: R1R2 = CH2812: R1 = R2 = H813: R1 = Me, R2 = H814: R1 = Me, R2 =
OHO
HOOH
HO2C
O
N
N
NH
HO
O
R3
R1
R2
135
67
911
12
815 : OCH2O cis-
816 : OCH2O (R,R)-OCH2O (R,R)-OCH2O (R,R)-OCH2O (R,R)-
817: i-Pr818: Me819: H 820: n-Bu H Me cis-
821 : H OCH3 (R,R)-822 : Me Cl OCH3 (R,R)-
R1 R2 R3
N
N
N
NH
HO
O
135
67
911
12
R
823: R = cis-
824: R = cis-
O
S Br
N
N
NH
HO
O
5 3
131211
97
6
OO
14 1
4
H
825: 14aS-; 826: 14aR-
N
N
NH
H
R2
O
O
R1135
67
911
12
R1 = Me, i-Pr, n-Bu,
R2 =
X
N
X
(X = O, NH, NBn, CH2, CH2CH2)
X(X= O, S)
S X
S
Br
(X = Br, H)
N
O
N
833 – 854: cis-, (6R,12aR):
H
N
N
NH
HO
O
R1
R2
R3
135
67
911
12
N
N
NH
HO
O
R1
R2
R3
135
67
911
12
R4
R1 R2 R3 R4
829: Bu H H3CO F cis-830: CH2CF3 H H3CO F cis-831: Me OCH2O F cis-832: Me OCH2O Me cis-
827: 3S-; 828: 3R-
N
N
NH
HO
O
135
67
911
12
OO
R1 = H, Me, Et, i-Pr, n-Bu,
-CH2Ph, -CH2CF3,
N N
OO
OCH3
OCH3
OCH3
OCH3
N
X (X = O, S)
-H2CC CH
R2 = H, Me, H3CO, HO, ClR2R3 = OCH2O,
R3 = H, Me, Et, i-Pr, H3CO, HO, EtO, NO2, CF3, CN, NH2, NMe2, AcNH; MeSO2NH, -CO2Me
855 – 930:cis-, trans-, (6R,12aR)
Y. Wang et al.
8 Expert Opin. Ther. Patents (2013) 23(11)
Exp
ert O
pin.
The
r. P
aten
ts D
ownl
oade
d fr
om in
form
ahea
lthca
re.c
om b
y Q
ueen
's U
nive
rsity
on
09/0
5/13
For
pers
onal
use
onl
y.
Aplaviroc (APL; GW873140) (804) was an antagonist ofchemokine co-receptor 5 (CCR5) that was being developedfor treatment of patients with human immunodeficiency virus(HIV) infection/AIDS by Ono Pharmaceutical Co. Ltd [48].In vitro, APL exhibited high-affinity binding to human
CCR5 and had potent activity against a broad panel of labo-ratory and clinical HIV type 1 (HIV-1) isolates includingdrug-resistant HIV-1 variants [49]. The results from preclinicaltoxicology studies were consistent with further clinical devel-opment, while changes in alanine aminotransferase (ALT)
N
N
NH
HO
O
5 3
131211
76
14 1
4
H
934: 5aS,12R, 14aS;935: 5aS,12S, 14aS;936: 5aR,12R, 14aS;937: 5aR,12S, 14aS;938: 5aS,12R, 14aR;939: 5aS,12S, 14aR;940: 5aR,12R, 14aR;941: 5aR,12S, 14aR;
N
N
OH
OOH
N
H3CO
OO
H
O
931
N
N
OH
OOH
N
H3COOH
932
N
N
OH
OH
N
H3CO
933: R = H;967: R = -CH2CH=CMe2
N
N
NH
HO
O
6 3
14132
87
15 1
H
942: 6aS,13R, 15aS;943: 6aS,13S, 15aS;944: 6aR,13R, 15aS;945: 6aR,13S, 15aS;946: 6aS,13R, 15aR;947: 6aS,13S, 15aR;948: 6aR,13R, 15aR;949: 6aR,13S, 15aR;
5
N
N
OH
OH
NH
950: 12R; 951: 12S
N
N
OH
OH
R
NH
952: R = H; 953: R = Me
N
N
OH
OH
R
NH
954: R = -CH2(CH2)3CH2Ph, 12R;955: R = -CH2(CH2)3CH2Ph, 12S;
956: R = , 12R; 957: R = , 12S;
958: R = -CH = CMe2, 12S;959: R =n-C9H19, 12S;960: R = -CH2CH2CH2NH2, 12R;961: R = -CH2CH2CH2NH2, 12S;962: R = -CH2CH2CH2NHAc, 12R;963: R = -CH2CH2CH2NHAc, 12S;964: R = -CH2CH2CH2NHCOCH2CH2CH3, 12S;965: R = -CH2CH2CH2NHCOCH2CH2CO2H, 12S;
966 R = , 12S;
ONH
O
NH
HN
O
R
N
NH
O
O
969
N
NH
O
O
968
NH
HN
NHO
O
972
NH
HNO
OO
NH
HNO
O
O
973 974
HN
NH
O
O
O
O
R1
HN
NH
O
O
O
O
N(CH3)2
R1 = N(CH3)2, N(CH2CH3)2, N(CH2CH2)2, N(CH2CH2)2CH2, N(CH2CH2)2CHCH3, N(CH2CH2)2O, N(CH2CH2)2NCH3
982975-981
HN
N
O
O
NH
H
HR
970: R = OCH3; 971: R = H
Developments around the bioactive DKPs
Expert Opin. Ther. Patents (2013) 23 (11) 9
Exp
ert O
pin.
The
r. P
aten
ts D
ownl
oade
d fr
om in
form
ahea
lthca
re.c
om b
y Q
ueen
's U
nive
rsity
on
09/0
5/13
For
pers
onal
use
onl
y.
and bilirubin levels were observed in long-term studies withrats treated with extremely high doses of APL (500 mg/kg ofbody weight/day), no adverse effects were observed in mon-keys treated with doses up to 2000 mg/kg/day [50]. In healthyhuman subjects, APL exhibited dose-proportional pharmaco-kinetics (PKs) in the 200- to 800-mg twice-daily dose rangeand had a half-life of approximately 3 h [51]. ProgenicsPharmaceutical, Inc. disclosed the methods that inhibitHIV-I infection by the usage of CCR5 antagonists includingAPL [52]. In 2005, a case of severe hepatic cytolysis was
reported as a serious adverse event (SAE) in Phase III clinicaltrials. Thus, London-based pharmaceutical GlaxoSmithKline(GSK) stopped clinical trials of APL.
3.2 Secondary cyclizationSecondary cyclization is often observed in the N-substituted2,5-DKPs derivatives across the patent literature.
Bicyclomycin (805), a marketed drug, was firstly obtainedand identified from the fermentation broth of Streptomycessapporonensis ATCC 21532 in 1972 [53,113]. A series of
NH
HN
NH
OCH3
O
ONH
HN
NHO
O
NH
HN
NHO
O
983 984 985
NH
H3CO
N
HN
OO
988
N
N
NH
O
OO
H
R1
R2
NO
N
OH
O
NH
O
1001
989–1000
989 R1 = β-H R2 = α-OH990 R1 = α-OH R2 = β-H991 R1 = β-H R2 = α-OCH3992 R1 =α-OCH3 R2 = α-H993 R1 = β-H R2 = α-OCH2CH3994 R1 = α-OCH2CH3 R2 = β-H995 R1 = β-H R2 = α-OCOCH3996 R1 = α-OCOCH3 R2 = β-H997 R1 = β-H R2 = α-Succinyloxyl 998 R1 = α-Succinyloxyl R2 = β-H999 R1 = β-H R2 = α-Linoleoyloxyl1000 R1 = α-Linoleoyloxyl R2 = β-H
HNNH
NHN
O
O1004
HNNH
NHN
O
O
HNNH
NHN
O
O1005 1006
N
N
H
OH
H3CS
SCH3
O
O
1010
O
N N
OOAc O
OAcO
SS
O
N N
OAc O
O
SS
AcOO
N N
OAc O
O
SS
10111012 1013
OH
HNNH
NHN
O
O1007
HN
NH
O
O1008
N
N
O
O
SCH3
H3CS
H
1009
N
N
HNH
OHO
O
S
S
NH
N
N
HO O
OH
S
SS1014
HO
O
O
OHH
OH
OH
H
NH
N
N
NH
H
O
O
HR
H
986: R = CH3; 987: R = H
HN
NH
O
O
XS
N
1002: X = O; 1003: X = S
Y. Wang et al.
10 Expert Opin. Ther. Patents (2013) 23(11)
Exp
ert O
pin.
The
r. P
aten
ts D
ownl
oade
d fr
om in
form
ahea
lthca
re.c
om b
y Q
ueen
's U
nive
rsity
on
09/0
5/13
For
pers
onal
use
onl
y.
bicyclomycin derivations were synthesized by Fujisawa Phar-maceutical Co. Ltd [54]. As an inhibitor of Rho that is aRecA-type ATPase and a transcription termination factorin Escherichia coli, bicyclomycin showed abroad inhibitionspectrum of Gram-negative and -positive bacteria, and lowtoxicity. Drug 805 was used for treatment of diarrhea inhumans and bacterial diarrhea in calves and pigs [55,56]. Bicy-clomycin was also used in animal feed composition and themethod for promotion of the animal growth was disclaimedby Fujisawa Pharmaceutical Co. Ltd [57].
Drimentines A-E (806 -- 810) with secondary cyclizationwere obtained from the fermentation broth of the actinomy-cete strain MST-8651 in 1998 [58]. Compounds 806 -- 810showed inhibition against murine myeloma NS-1 cells,among which 808 and 809 were the most active with63 and 77% inhibition at 12.5 µg/ml, respectively.
N-substituted tetracyclic 2,5-DKP derivatives (811 -- 814)were synthesized and found to be potent and selective inhibi-tors of cyclic guanosine 3¢,5¢-monophosphate specific phos-phodiesterase (cGMP-specific PDE), in particular PDE5, byLilly Icos Llc Corp. in 2001 [59]. Compounds 812 and 813exhibited in vitro inhibition of recombinant humanPDE5 with IC50 values of 45 and 230 nM, respectively.Icos Corp. disclosed the manufacture of 116 N-substitutedtetracyclic DKP derivatives (815 -- 930) in 1999 [60]. Thesecompounds were also effective inhibitors of cGMP specificPDE enzymes (IC50 < 500 nM, EC50 < 5 µM) in which com-pounds 815 -- 825 had IC50/EC50 values of 10/0.5,20/0.5, < 10/0.15, 2/0.2, 10/0.2, 30/0.35, 10/0.4, 10/<0.1, < 10/0.5, 20/0.8 and < 10/0.4, respectively. In addition,compounds 816 -- 823 displayed antihypertensive effects onconscious spontaneously hypertensive rats in vivo with AUC(Area Under the Curve) values of 111, 171, 135, 136, 95,77, 117 and 99 mmHg h, respectively, after oral administra-tion for 5 h. PDEs can catalyze the hydrolysis of cyclic nucleo-tides and PDE5 provides vasodilating, relaxing and diureticeffects. These results suggested that these tetracyclic DKPderivatives could be used for the treatment of cardiovasculardisorders and erectile dysfunction. Tadalafil (811) showed atleast 9000 times more selective for PDE5 than most of theother families of PDEs. This drug was approved for the treat-ment of male erectile dysfunction by FDA in 2003 (Cialis�
Eli Lilly and Co., Indianapolis, IN, USA). The half-life oftadalafil is 17.5 h, aproximately fourfold longer than 4 h ofsildenafil (viagra), which led to once-daily dosing enough toa longer therapeutic window, and its PKs are linear withrespect to dose and time and are not affected by fatty mealsor alcohol consumption [61].
In order to overcome the multiple drug resistance (MDR)of anticancer drugs, fumitremorgins A--C (931 -- 933) wereprepared from the fermentation broth of Aspergillus fumigatusand the analogues (934 -- 967) were synthesized by WyethHoldings Corp. in 2003 [62]. These compounds reversedthe non P-gp and multiple drug resistance protein (MRP) medi-ated MDR. Fumitremorgin C (FTC) showed the best reversal
activity and the lowest toxicity against S1-M1-3.2 cells(a mitoxantrone-selected MDR human colon carcinomacell line) with IC50 and LD20 values of 0.3 and > 80 µM,respectively. FTC (5 µM) could re-sensitize S1-M1-3.2 cellsto mitoxantrone, doxorubicin and topotecan with reversalsof 93-, 26- and 24-fold, respectively. FTC (5 µM) couldalso reverse resistance of MCF-7/mtx (a mitoxantrone-selected MDR human breast cell line) to mitoxantrone anddoxorubicin, MCF-7/AdrVp (an adriamycin- and verapa-mil-resistant human breast cell line) to mitoxantrone anddoxorubicin, and HL-60/AR (an anthracycline-resistanthuman leukemia cell line) to mitoxantrone, doxorubicinand paclitaxel, with reversals of 114/3, 5000/100 and3.3-/2.8-/2.6-fold, respectively. The synthetic analogues935, 943, 955, 959 and 967 also showed significant re-sensitization of S1-M1-3.2 cells to mitoxantrone butwere highly toxic with IC50/LD20 values of 1.0/35.0,1.5/25.0, 0.3/7.5, 0.25/7.0 and 2.0/20 µM, respectively.The results showed that the methoxylation in the L-Trpnucleus, the 12S-configuration and the 12-substitutionby a longer alkyl chain with or without aromatic groupscould significantly increase the sensitivity of MDR cells tochemotherapeutic drugs.
Cyclo-(G-2AllylP) (968) and cyclo-(cyclopentG-2MeP)(969) were disclosed as potential neuroprotective agents byNeuren Pharmaceuticals Ltd in 2005 [63]. Concentrations of100 pM to 10 nM of 968 and 100 pM to100 µM of 969significantly decreased or prevented glutamate-induced neu-rotoxicity in cerebellar explants of rats. Compound 968(2 -- 100 ng) significantly reduced the neural damage in thebrain region of rats caused by hypoxic-ischemic injury. Theseresults showed the two compounds can be used to inhibitneuronal degeneration or cell death in the nervous system.
3.3 IsopentenylationExcept for N-modification and secondary cyclization, isopen-tenyl modification of DKPs in aromatic nucleus was alwaysfound in the patents. And the isopentenylation of DKPs isalways accompanied with dehydrogenation of DKP nucleus.
Tryprostatins A (970) and B (971) were identified fromthe metabolites of Aspergillus fumigatus BM939 by RikagakuKenkyuzyo in 1997, and showed cytotoxic activities againstthe cancer cell lines K562 and HL-60 with MICs of 50 µg/mland 16 µg/ml, 16 µg/ml and 5 µg/ml, respectively [64]. Trypros-tatin A showed cell cycle arrest at the M phase as an inhibitor ofMAP-dependent microtubule assembly, but tryprostatin Bshowed no cell-cycle specific inhibition [65]. In 2004, tryprosta-tin A was disclosed to be a potential reversing agent for multi-drug-resistance, in particular breast cancer resistance proteinmediated drug-resistance and at the same time, was shownnot to be cytotoxic in different drug-sensitive and drug-resistantgastric (below 10 µM) and breast cancer cell lines (below50 µM) [66].
Chrysogenazine (972), with an isopentenyl disubstitutedindole and a DKP ring, was isolated from the broth of the
Developments around the bioactive DKPs
Expert Opin. Ther. Patents (2013) 23 (11) 11
Exp
ert O
pin.
The
r. P
aten
ts D
ownl
oade
d fr
om in
form
ahea
lthca
re.c
om b
y Q
ueen
's U
nive
rsity
on
09/0
5/13
For
pers
onal
use
onl
y.
mangrove-associated fungus Penicillium chrysogenum in2005 [67]. This compound showed anti-bacterial propertiesagainst the human pathogen Vibrio cholera MCM B-322equal with streptomycin (10 µg/disc) on agar platedpetri dishes.Two DKPs derivatives PJ147 (973) and PJ157 (974) dis-
closed by Shenyang Pharmaceutical of the University ofChina were isolated from an acetone extract of mycelium ofthe marine fungi Gliocladium sp. YUP08 in 2007 [68]. Thesetwo geometric isomers both contained a geranyloxy groupside chain. Both showed cytotoxicity against A549, HL-60,BEL-7402, A375-S2 and Hela cell lines with IC50 valuesbelow 5 µM except for 973 against BEL-7402 that had anIC50 value of 9.69 µM. Compound 973 was synthesized formass production in 2008 [69].Two series of synthetic isomers of DKPs were disclosed by
SPU of China in 2011 [70]. The compounds 975 -- 981showed cytotoxic activities against A549 and HL-60(IC50s < 5 µM) and BEL7402 (IC50 ~ 10 µM) cell lines.Compound 982 showed cytotoxic activities against A549and HL-60 (IC50 < 5 µM) and BEL7402 (IC50 9.7 µM)cell lines.Three DKPs (983 -- 985) containing an isopentenyl di- or
tri-substituted indole moiety were disclosed to be obtainedthrough the fermentation of fungus Eurotium cristatum bythe Institute of Oceanology, Chinese Academy of Sciencesin 2012 [71,72]. These DKPs showed good insecticidal activityagainst Artemia salina with LD50s of 19.8, 27.1 and 19.4 µg/ml respectively. They were found to be degraded in the envi-ronment and safe to natural enemies of pests andbeneficial microorganisms.
3.4 Isopentenyl-modification and secondary
cyclizationSecondary cyclizations of patent 2,5-DKPs are often accom-panied by isopentenylation in aromatic ring.N-Methyl epi-amauromine (986), epi-amauromine (987)
and cycloechinulin (988) were isolated from the fungus A.ochraceu by US Agriculture and other applicants in
1993 [73]. Insecticidal activities of 986 and 987 toward theneonate larvae of H. zea gave 17.1 and 30% reduction ofweight gain, respectively, and insecticidal activities of 988on adult of C. hemipterus provided 33.3% reduction ofweight gain.
Two DKP derivatives (989 and 990) and their syntheticanalogues (991 -- 1000) were disclosed by the Academy ofMilitary Medical Science of China in 2011 [74]. Compounds989 and 990 showed 34.8 and 88.2% inhibitions againstK562 cell lines at 100 µg/ml, and 31.0 and 60.2% inhibitionsat 50 µg/ml, respectively. The methylated and acetylated com-pounds 989 and 990 also showed 30 -- 50% inhibitionagainst K562 between at 50 µg/ml. Cell morphology observa-tion suggested that cell division was inhibited by compound936 and apoptosis was initiated by compound 990.
Compound 1001 containing a bicyclo[2.2.2]diazoctanering was identified from the metabolites of the mangrove fun-gus, A. taichungensis ZHN-7-07 by The Ocean University ofChina in 2011 [75]. This compound showed inhibitory effectson A549 and HL-60 cell lines with IC50 values of 1 - 10 µM.
3.5 Other modificationsDehydrogenation, sulfur-substitution and dimerization arealso evident in patented 2,5-DKP derivatives.
More than 200 synthetic DKP derivatives containingdehydro-amino acid moieties were manufactured as inhibitorsof plasminogen activator by Xenova Ltd in 1995 [76,77]. Com-pounds 1002 and 1003 inhibited the production of plasminfrom plasminogen with IC50 values of 4.5 and 3.0 µM,respectively.
Phenylahistin was a natural DKP derivative produced byAspergillis ustus NSC-F037 and NSC-F038. The enantiomer(--)(1004) could arrest the cell cycle of P388 at G2/M phaseand affect the proliferation, mitosis and microtubule structureof A549 cells. In vivo, (--)-phenylahistin also showed inhibi-tion of mouse leukemia and Lewis lung carcinoma [78,79].Some dehydro-derivatives were obtained through enzymereaction by Nippon Steel Corp. in 2001 [78]. (Z,Z)-Dehydro-phenylahistin (1005) inhibited cell division of Scaphechinusmirabilis and Temnopleurus toreumaticus with MICs of0.0061 µg/ml, and Hemicentrotus pulcherrimus with an MICof 0.00038 µg/ml. (Z,Z)-Tetradehydro-CFH (1006) inhib-ited cell division of S. mirabilis, T. toreumaticus and H. pul-cherrimus with MICs of 1.6, 1.6 and 0.78 µg/ml which were15-fold better than CFH (cyclo-(Phe-His)). These results sug-gested that dehydro-derivatives had potential anti-tumoreffects as well as being a cell division inhibitor. Plinabulin(NPI-2358) (1007) was an analogue of (--)-phenylahistin. Itshowed potent in vitro anti-tumor activity against various can-cer cell lines and multidrug-resistant cell lines, which effectedby interacting at the colchicine binding site on microtubules.In preclinical trials for breast, sarcoma, colon and prostatecancers, plinabulin demonstrated potent and selective tumorvascular disrupting activities [80]. As a vascular disruptingagent, it was in Phase II clinical trials for the treatment of
B: 90%
d: 23%
c: 3%b: 18%
a: 46%
A: 10%
Figure 1. The structural categories of the patents’ DKPs.
A. Simple DKPs and B. DKPs derivatives (a. N-substitution, b.
secondary cyclization, c. isopentenylation, d. others includ-
ing dehydrogenation, S-substitution and dimerization).
Y. Wang et al.
12 Expert Opin. Ther. Patents (2013) 23(11)
Exp
ert O
pin.
The
r. P
aten
ts D
ownl
oade
d fr
om in
form
ahea
lthca
re.c
om b
y Q
ueen
's U
nive
rsity
on
09/0
5/13
For
pers
onal
use
onl
y.
Table 1. The patents’ DKPs and their bioactivities.
Bioactivities Refs. Compound No. Remark
Anti-tumor activities [16] 9 -- 10 Tumor inhibition[26] 32 Inhibition of MMP-9 and Akt[38] 210 -- 254 Inhibition of NF-kB and TNF-a induced cell
apoptosis[58] 806 -- 810 Cytotoxicities against murine myeloma NS-1
cells[62] 931 -- 967 Against multiple-drug resistance[64-66] 970, 971 Cytotoxicities[68,69] 973, 974 Cytotoxicities[70] 975 -- 982 Cytotoxicities[74] 989 -- 1000 Cytotoxicities[75] 1001 Cytotoxicities[78-81] 1004 -- 1007 Plinabulin (1007): a tumor vascular disrupting
agent; in Phase II trial[83] 1009 Cytotoxicities[84] 1010 Cytotoxicities[85] 1011 -- 1013 Cytotoxicities[86] 1014 Cytotoxicities
CNS activities [17,18] cyclo-(L-His-L-Pro) Inhibition of appetite and desire for alcohol[24] 15 -- 28 Neuroprotection and cognitive enhancement;
28 is most active[27] cyclo-(L-His-L-Pro), cyclo-(L-Trp-L-Pro),
cyclo-(L-Phe-L-Phe), cyclo-(L-Trp-L-Trp),cyclo-(L-Trp-L-Leu), cyclo-(L-Trp-L-Val)
Anti-depressant and learning motivationimprover
[63] 968, 969 NeuroprotectionOxytocin inhibitor [39-45] 255 -- 803 Retosiban (492) in Phase II trial; epelsiban
(496) in Phase I trialAntibiotic activity [19] 11 -- 14 Chitinase inhibition
[25] 29 -- 31 Inhibition of pathogen fungus[30] 33 -- 37 Pesticidal activities against pathogenic fungi
and nematodes[32] 43 -- 45 Hemo-regulatory activities[67] 972 Anti-bacterial properties[13] cyclo-(L-Pro-L-Tyr) Maculosin: a marketed herbicide[48-52] 804 Aplaviroc: anti-HIV; stopped in Phase III
clinical trials[53-57,113] 805 Bicyclomycin: a marketed drug for the
treatment of human diarrhea and bacterialdiarrhea in calves and pigs
Immunoregulatory activity [11,12] cyclo-(L-Gln-L-Lys), cyclo-(L-Gln-L-Orn),cyclo-(L-Asn-L-Lys), cyclo-(L-Asn-L-Orn),cyclo-(D-Gln-D-Lys), cyclo-(D-Gln-D-Orn),cyclo-(D-Asn-D-Lys), cyclo-(D-Asn-D-Orn),cyclo-(D-Gln-L-Lys), cyclo-(L-Gln-D-Lys),cyclo-(L-Asn-D-Lys), cyclo-(L-Gln-D-Orn),cyclo-(D-Asn-L-Orn) and hydrochlorideof cyclo-(L-Gln-L-Lys)
[15] 4 -- 8Insecticidal activity [71,72] 983 -- 985
[73] 986 -- 988Anti-coagulant effect [35] 204 -- 209 207 is most active.T-cell mediated diseases [22,23] cyclo-(Met-Arg), cyclo-(Asp-Ala) and
cyclo-(Glu-Ala)PAF inhibitor [14] 1 -- 3
[21] cyclo-(Asp-Ala), cyclo-(Asn-Ala)Anti-inflammatory effect [20] cyclo-(Pro-Ile), cyclo-(Pro-Leu),
cyclo-(Pro-Trp), cyclo-(cis-Hyp-Ile),cyclo-(trans-Hyp-Ile), cyclo-(O-MeHyp-Ile), cyclo-(O-AcHyp-Ile) and cyclo-(O-BnHyp-Ile)
Developments around the bioactive DKPs
Expert Opin. Ther. Patents (2013) 23 (11) 13
Exp
ert O
pin.
The
r. P
aten
ts D
ownl
oade
d fr
om in
form
ahea
lthca
re.c
om b
y Q
ueen
's U
nive
rsity
on
09/0
5/13
For
pers
onal
use
onl
y.
advanced or metastatic non-small cell lung cancer combinedwith docetaxel or carboplatin [81].DKP derivative 1008 from Penicillium sp. F70614 could
be used as a a-glucosidase inhibitor for the treatment andprevention of diabetes and obesity [82].A thiomethyl substituted DKP (1009) was claimed to be
purified from the ethyl acetate extract of the soil fungusPaoularia sp. A4-Z-1 by Xiamen University of China in2005 [83]. Compound 1009 showed cytotoxic effects on thehuman nasopharyngeal carcinoma KB cell line with an IC50
value of 120 µg/ml.Bisdethiobis(methylthio)gliotoxin (1010) was obtained
from an ethyl acetate extract of the marine fungus A. fumigatusin 2011 by Shenyang Pharmaceutical University [84]. Thiscompound showed cytotoxicity against the human leukemiacell line U937 and the prostate cancer cell line PC-3 withGI50 values of 0.5 and 15.9 µM, respectively.Three DKP derivatives with disulfide bonds, acetylaranotin
(1011), acetylapoaranotin (1012) and dehydrodeoxyapoara-notin (1013), were isolated from marine-derived fungus,Aspergillus sp. KMD 901 by The Korea Institute of Scienceand Technology, disclosed in 2011 [85]. These compoundsdisplayed cytotoxicity against several human cancer cell lines.The DKP dimer 1014 with multi-sulfur bonds was
obtained from an Antarctic fungus, Oidiodendron truncatumGW3-13, by the Ocean University of China in 2012 [86].This compound could inhibit the proliferation of A549,HL-60 and BEL-7402 cell lines with IC50 values below1 µM. Compound 1014 also showed 100% inhibitory effectson hypoxia inducible factor (HIF-1) in the human breastcancer cell line T47D at 0.01 µM.
4. Expert opinion
Based on the above descriptions, patented DKPs include sim-ple DKPs (direct condensations between two amino acids)and DKP derivatives (modified DKPs). Modified DKPs canbe further classified as N-substituted, secondary cyclized,
isopentenylated, dehydrogenated, S-substituted and dimer-ized DKPs. (Figure 1) Apart from isopentenylation occurs inaromatic nucleus, N- and S- substitutions, secondary cycliza-tion and dehydrogenation always occur in DKP nucleus. Sec-ondary cyclization is always accompanied with N-substitutionor isopentenylation that is always accompanied with dehydro-genation, which constitutes the three major modificationsnormally found in the patents’ DKPs.
The bioactive DKPs disclosed in patents can be obtainedfrom natural resources and artificial synthesis. Approximately3 and 97% of patented DKPs come from natural sources andartificial synthesis which included in 23 and 79% publishedpatents, respectively. Though synthesized DKPs occupied aconsiderable number, most of these compounds receivedinspiration from natural DKPs. The natural DKPs mainlycame from microorganisms, specifically from filamentousfungi. At the same time, with an increasing number of inves-tigations into the structures and bioactivities of natural DKPs,synthetic chemists are attracted to design and synthesizeDPKs and, therefore, many DKPs have been synthesizedand protected in patents [87-100].
The DKPs disclosed in patents demonstrate attractive bio-active diversity for drug discovery (Table 1), including anti-tumor, neuroprotective, immune and metabolic regulatory,oxytocin inhibitory and anti-inflammatory effects, antibioticactivity, PAF inhibition, inhibition of plasminogen activatorand T-cell mediated immunity, and insecticidal activity(Figure 2). The biological activities analysis revealed thatoxytocin inhibitory, plasminogen activator inhibitor, anti-tumor and platelet aggregation inhibitor activities constitutedabout 85% of the described biological activities of patentsDKPs, among which cytotoxicity or anti-tumor is the largest(Figure 3). Detailed analysis of the indicated cytotoxic activityrevealed that cell cycle inhibition, FPTase inhibition, metallo-proteinase inhibition and inhibitory effects on the multidrug-resistant protein were involved in antitumor activities.
Compared with DKP derivatives, simple DKPs demon-strated more bioactive diversity although they occupied
Table 1. The patents’ DKPs and their bioactivities (continued).
Bioactivities Refs. Compound No. Remark
[38] 210 -- 254 Inhibition of TNF-a and IL-8Plasminogen activatorinhibitor
[76,77] 1002, 1003
PDE5 inhibitor [59-61] 811 -- 930 Tadalafil (811): a marketed drug for thetreatment of male erectile dysfunction
Metabolic regulation [28] cyclo-(L-Asp-L-Ala)Vascular hyperpermeabilityinhibitor
[29] cyclo-(Asp-Ala), cyclo-(Met-Arg) andcyclo-(Tyr-Glu)
FTase inhibitor [31] 38 -- 42Collagenase-1 andstromelysin-1 inhibitor
[33] 46 -- 180 58 and 59 are most active
FBPase inhibitor [34] 181 -- 203a-glucosidase inhibitor [82] 1008
Y. Wang et al.
14 Expert Opin. Ther. Patents (2013) 23(11)
Exp
ert O
pin.
The
r. P
aten
ts D
ownl
oade
d fr
om in
form
ahea
lthca
re.c
om b
y Q
ueen
's U
nive
rsity
on
09/0
5/13
For
pers
onal
use
onl
y.
a) Anti-tumor activities
b) Antibiotic activity
c) Oxytocin inhibitor
d) CNS activities
e) Immunoregulatory activity
f) Insecticidal activity
g) T-cell mediated diseases
h) PAF inhibitor
i) Anti-inflammatory effect
j) Plasminogen activator inhibitor
k) PDE5 inhibitor
l) Anticoagulant effect
m) Metabolic regulation
n) Vascular hyperpermeability inhibitor
o) FTase inhibitor
p) Collagenase-1 and stromelysin-1 inhibitor
q) FBPase inhibitor
r) μ-glucosidase inhibitor
r: 2%q: 2%p: 2%o: 2%
n: 2%
m: 2%
l: 2%
k: 3%
j: 3%
i: 3%
h: 3%
g: 3%
f: 5%
e: 5%
d: 8%
c: 11%
b: 16%
a: 30%
Figure 2. The bioactivities of DKP patents based on patents’ numbers.
a) Oxytocin inhibitor
b) Plasminogen activator inhibitor
c) Anti-tumor activities
d) PDE5 inhibitor
e) Anti-inflammatory effect
f) FBPase inhibitor
g) CNS activities
h) PAF inhibitor
i) Insecticidal activity
j) Antibiotic activity
k) Immunoregulatory activity
l) FTase inhibitor
m) T-cell mediated diseases
n) Vascular hyperpermeability inhibitor
o) Collagenase-1 and stromelysin-1 inhibitor
p) Anticoagulant effect
q) Metabolic regulation
r) μ-glucosidase inhibitor
l – r: < 1%k: 1%j: 1%
i: 2%h: 2%
g: 2%f: 2%
e: 4%
d: 10%
c: 10%
b: 19%
a: 46%
Figure 3. The bioactivities of patents’ DKPs based on compounds numbers.
Developments around the bioactive DKPs
Expert Opin. Ther. Patents (2013) 23 (11) 15
Exp
ert O
pin.
The
r. P
aten
ts D
ownl
oade
d fr
om in
form
ahea
lthca
re.c
om b
y Q
ueen
's U
nive
rsity
on
09/0
5/13
For
pers
onal
use
onl
y.
relatively small numbers. This might attribute to the change-able chiral and rigid skeleton that allows these compoundsto easily bind to different receptors. Multi-modification inthe DKP nucleus and aromatic ring enriched the biodiver-sities, specifically for anti-tumor. Nearly 30% patents num-bers of bioactive DKPs related to anti-tumor activities(Figure 2). Though DKPs were disclosed to inhibit cell pro-liferation in large proportion, deep investigation includingother wider biological screenings such as anti-influenza Avirus [101], the mechanism and the druggability needs to befurther investigated.In addition to their pharmaceutical use, simple DKPs and
their derivatives were synthesized and developed for use indrug delivery systems [102-112], especially by the MannkindCorp., USA [102-110]. It is known that the effectiveness ofdrug delivery is closely related to the drug’s efficiency. Therigid six-membered ring skeleton makes DKPs stable at lowpH and helps them to disintegrate in the blood or small
intestine. All these characteristics support the use of DKPsas microparticles and microspheres in drug delivery systems.
Simple chemical structures but broad bioactivities of DKPsinspire a great deal of interest in pursuing comprehensivepharmacological studies of natural or artificial DKPs. Futurechemical and biological studies will undoubtedly result inmuch more clinical applications of simple DKPs andtheir derivatives.
Declaration of interest
This work was supported by a grant from 863 Program ofChina (No. 2013AA092901), from 973 program of China(No. 2010CB833804), and from the Special Fund for MarineScientific Research in the Public Interest of China (No.2010418022-3). The authors state no conflict of interestand have received no payment in preparation ofthis manuscript.
Bibliography
1. Borthwick AD. 2,5-diketopiperazines:
synthesis, reactions, medicinal chemistry,
and bioactive natural products. Chem Rev
2012;112:3641-716
2. Cornacchia C, Cacciatore I,
Baldassarre L, et al.
2,5-Diketopiperazines as neuroprotective
agents. Mini Rev Med Chem
2012;12:2-12
3. Eriko I, Yoshitaka H, Mikiko S.
Epipolythiodiketopiperazine alkaloids:
total syntheses and biological activities.
J Chem 2011;51:420-33
4. Minelli A, Bellezza I, Grottelli S, et al.
Focus on cyclo-(His-Pro): history and
perspectives as antioxidant peptide.
Amino Acids 2008;35:283-9
5. Martins MB, Carvalho I.
Diketopiperazines: biological activity and
synthesis. Tetrahedron 2007;63:9923-32
6. Huang R, Zhou X, Xu T, et al.
Diketopiperazines from marine
organisms. Chem Biodivers
2010;7:2809-29
7. Fischer PM. Diketopiperazines in peptide
and combinatorial chemistry. J Pept Sci
2003;9:9-35
8. Dinsmore JC, Beshore DC. Recent
advances in the synthesis of
diketopiperazaines. Tetrahedron
2002;58:3297-312
9. Guo XC, Zheng L, Zhou WH, et al.
Research advance on diketopiperazines
produced by marine microorganism.
Microbiology 2009;36:1596-603
10. Lin H, Wang D. Progress in the
synthesis of diketopiperazines.
Acta Pharm Sin 2003;38:395-400
11. Ortho Pharmarceutical Corperation.
Immunoregulatory diketopiperazine
compounds. US4289759; 1981
12. Ortho Pharmarceutical Corperation.
Immunoregulatory diketopiperazine
compounds. US4331595; 1982
13. Development Institure, Inc. at Montana
State University. Method of inducing
chlorosis in a knapweed plant.
US4929270; 1990
14. Fujisawa Pharmaceutical Co., Ltd.
Piperazine compound as PAF-antagonist.
US4940709; 1990
15. Snow Brand Milk Prod. Co., Ltd. New
diketopiperazine derivative and
immunosuppressive agent containing the
same as active ingredient. JP3176478;
1991
16. Kanebo Ltd. Anti-neoplastic agent.
JP5163148; 1993
17. The University of Maryland at
Baltimore. Histidyl-proline
diketopiperazine (cyclo-(His-Pro)), a
CNS-active pharmacologic agent.
US5418218; 1995
18. Prasad C. Histidyl-proline
diketopiperazine and method of use.
WO0201956; 2002
19. Kaiyo Bio Technol Kenkyusho: KK,
Shizuoka Prefecture. Chitinase inhibitor.
JP8277203; 1996
20. Teika Seiyaku. Remedy for
inflammatiory disease containing
diketopiperazine derivative.
JP2000327575; 2000
21. Dmi Biosciences, Inc. Method of using
diketopiperazines and composition
containing them. WO200211676; 2002
22. Dmi Biosciences, Inc. Treatment of
T-cell-mediated diseases.
WO2004103304; 2004
23. Dmi Biosciences, Inc. Treatment of
T-cell-mediated diseases. CN101279094;
2008
24. Georgetown University. Cyclic dipeptides
and azetidinone compounds and their
use in treating CNS injury and
neurodegenerative disorders.
US20070161640; 2007
25. Universita Deglistudi di Udine.
Antifungal compositions containing the
endophyte fungus Alternaria alrernata
and/or its metabolites, as antagonist
agents of Plasmopara viticola.
WO2008007251; 2008
26. Dmi Biosciences, Inc. Therapeutic
Methods and compounds.
WO2009146320; 2009
27. Suntory Holdings Ltd and Cerebos
Pacific Ltd. Leaning motivation
improvers. WO2011077760; 2011
28. Dmi Acquisition Corp. Treatment of
diseases. US2012172294; 2012
29. Dmi Acquisition Corp. Treatment of
diseases. US2012058934; 2012
Y. Wang et al.
16 Expert Opin. Ther. Patents (2013) 23(11)
Exp
ert O
pin.
The
r. P
aten
ts D
ownl
oade
d fr
om in
form
ahea
lthca
re.c
om b
y Q
ueen
's U
nive
rsity
on
09/0
5/13
For
pers
onal
use
onl
y.
30. Allied Chem Corp. Method of
combation nematods employing N,N¢-disubstituted-2,5-diketopiperazaines.
US3692908; 1972
31. Merck & Co., Inc., USA. Inhibitors of
farnesyl-protein transferase.
WO9736888; 1997
32. Smithkline Beecham Corp.
Hemoregulatory compounds.
WO9718214; 1997
33. Affymax Technologies NV.
Collagenase-1 and
stromelysin-1 inhibitors, pharmaceutical
compositions comprising same and
methods of their use. US5932579; 1999
34. Ontogen Corp. Piperazines as inhibitors
of fructose-1,6-bisphosphatase (FBPase).
WO9947549; 1999
35. Novoscience Pharma, Inc.
Diketopiperazine derivatives to inhibit
thrombin. WO0140224; 2001
36. Mitsubishi Chemical Industries, Ltd.
N2-Arylsulfonyl-L-argininamides and the
pharmaceutically acceptable salts thereof.
US4258192; 1981
37. Mitsubishi Chemical Industries, Ltd.
N2-Arylsulfonyl-L-argininamides and the
pharmaceutically acceptable salts thereof.
US4201863; 1980
38. Celltech R & D, Inc., USA.
Pharmaceutical uses and synthesis of
diketopiperazine. US20020187984; 2002
39. Glaxo Group Ltd. Substituted
diketopiperazines for the treatment of
benign prostatic hyperplasia.
WO2005000311; 2005
40. Glaxo Group Ltd. Substituted
diketopiperazines and their use as
oxytocin antagonists. WO2005000840;
2005
41. Glaxo Group Ltd. Novel compounds.
WO2006000399; 2006
42. Glaxo Group Ltd. Substituted
diketopiperazines as oxytocin antagonists.
WO2006000400; 2006
43. Glaxo Group Ltd. Substituted
diketopiperazines as oxytocin antagonists.
WO2006000759; 2006
44. Glaxo Group Ltd. 1,6-disubstituted-
(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-
2,5-piperazinedione derivatives as
oxytocin receptor antagonists for the
treatment of pre-term labor,
dysmenorrhea and endometriosis.
WO2006067462; 2006
45. Glaxo Group Ltd. Substituted
diketopiperazines as oxytocin antagonists.
WO03053443; 2003
46. Borthwick AD, Liddle J. The design of
orally bioavailable 2,5-diketopiperazine
oxytocin antagonists: from concept to
clinical candidate for premature labor.
Med Res Rev 2011;31:576-604
47. Borthwick AD, Liddle J, Davies DE,
et al. Pyridyl-2,5-diketopiperazines as
potent, selective, and orally bioavailable
oxytocin antagonists: synthesis,
pharmacokinetics, and in vivo potency.
J Med Chem 2012;55:783-96
48. Ono Pharmaceutical Co., Ltd.
Triazaspiro[5.5]undecane derivatives and
drugs containing the same as the active
ingredient. WO02074770; 2002
49. Maeda K, Nakata H, Koh Y, et al.
Spirodiketopiperazine-based
CCR5 inhibitor which preserves CC-
chemokine/CCR5 interactions and exerts
potent activity against R5 Human
immunodeficiency virus type 1 in vitro.
J Virol 2004;78:8654-62
50. Nichols WG, Steel HM, Bonny T, et al.
Hepatotoxicity observed in clinical trials
of aplaviroc (GW873140).
Antimicrob Agents Chemother
2008;52:858-65
51. Adkison KK. Pharmacokinetics and
short-term safety of 873140, a novel
CCR5 antagonist, in healthy adult
subjects. Antimicrob Agents Chemother
2005;49:2802-6
52. Progenics Pharmaceuticals, Inc. Methods
of inhibiting infection by diverse
subtypes of drug-resistant HIV-1. WO
2009134401; 2009
53. Miyoshi T, Miyairi N, Aoki H, et al.
Bicyclomycin, a new antibiotic. I.
Taxonomy, isolation, and
characterization. J Antibiot
1972;25:569-75
54. Fujisawa Pharmaceutical Co., Ltd.
Bicyclomycin derivatives. US4215043;
1976
55. Williams RM, Durham CA.
Bicyclomycin: synthetic, mechanistic, and
biological studies. Chem Rev
1988;88:511-40
56. Kohn H, Widger WC. The molecular
basis for the mode of action of
bicyclomycin. Drug Targets
Infect Disord 2005;5:273-95
57. Fujisawa Pharmaceutical Co., Ltd.
Bicyclomycin as an animal growth
promotion. US4209518; 1978
58. Novartis Animal Health Australasia PTY
Ltd and Microbial Screening
Technologies PTY Ltd. Terpenylated
diketopiperazines (drimentines).
WO9809968; 1998
59. Lilly Icos Llc. Tetracyclic
diketopiperazine compounds as PDEV
inhibitors. WO0194347; 2001
60. Icos Corp. Tetracyclic derivatives, process
of preparation and use. US5859006; 1999
61. Coward RM, Carson CC. Tadalafil in
the treatment of erectile dysfunction.
Ther Clin Risk Manag 2008;4:1315-30
62. Wyeth Holdings Corp. Reversal of
multidrug resistance in human colon
carcinoma cells. US6537964; 2003
63. Neuren Pharmaceuticals Ltd.
Neuroprotective bicyclic compounds and
methods for their use. WO2005023815;
2005
64. Rikagaku Kenkyuzyo. Triprostatins
manufacture with Aspergillus.
JP09059275; 1997
65. Takeo U, Masuo K, Cui CB, et al.
Tryprostatin A, a specific and novel
inhibitor of microtubule assembly.
Biochem J 1998;333:543-8
66. Huboldt-Universitat Zu Berlin. Uses of
tryprostatin for the reversal of cancer
drug resistance. WO2004087162; 2004
67. Council of Scientific and Industrial
Research. Chrysogenazine obtained from
fungus Penicillium chrysogenum having
antibacterial activity. WO2005063740;
2005
68. Shenyang Pharmaceutical University.
Antineoplastic active substance of
diketopiperazine PJ147and PJ157.
CN101041640; 2007
69. Shenyang Pharmaceutical University.
Method for synthesizing antitumor
compound of diketopiperazine PJ147.
CN101255139; 2008
70. Shenyang Pharmaceutical University. New
diketone piperazidine-like derivative and
application thereof. CN101935306; 2011
71. Institute of Oceanology Chinese
Academy of Sciences. The application of
an indolyl diketopiperazine compound.
CN102669110; 2012
72. Institute of Oceanology Chinese
Academy of Sciences. An indolyl
diketopiperazine-like derivative, its
Developments around the bioactive DKPs
Expert Opin. Ther. Patents (2013) 23 (11) 17
Exp
ert O
pin.
The
r. P
aten
ts D
ownl
oade
d fr
om in
form
ahea
lthca
re.c
om b
y Q
ueen
's U
nive
rsity
on
09/0
5/13
For
pers
onal
use
onl
y.
preparation method and application.
CN102675293; 2012
73. The United States of America as
represented by the Secretary of
Agriculture, University of Iowa Research
Foundation and Biotechnology Research
and Development Corpor.
N-Methylepiamauromine epiamauromine
and cycloechinulin antiinsectan
metabolites. WO9301718; 1993
74. Institute of Pharmacology and
Toxicology of Academy of Military
Medical Sciences. Diketopiperazine
compound as well as composition,
preparation method and application
thereof. CN102020649; 2011
75. Ocean University of China.
A tryptophan- and proline-derived indole
diketopiperazine alkaloid, its preparation
method and application. CN102268005;
2011
76. Xenova Ltd Pharmaceutical.
Diketopiperazine compounds.
WO9404512; 1994
77. Xenova Ltd Pharmaceutical.
Diketopiperazine compounds.
WO9532190; 1995
78. Nippon Steel Corp. Cell division
inhibitors and process for producing the
same. WO2001053290; 2001
79. Nereus Pharmaceuticals, Inc.
Phenylahistin and the phenylahistin
analogs, a new class of anti-tumor
compounds. US6358957; 2002
80. Nicholson B, Kenneth GL, Millera BR.
NPI-2358 is a tubulin-depolymerizing
agent: in-vitro evidence for activity as a
tumor vascular-disrupting agent.
Anti Cancer Drugs 2006;17:25-30
81. Mayer AM, Glaser KB, Cuevas C, et al.
The odyssey of marine pharmaceuticals:
a current pipeline perspective.
Trends Pharmacol Sci 2010;31:255-65
82. Korea Research Institute of Bioscience
and Biotechnology. Penicillium sp.
F70614(KCTC 8918P) and an
a-glucosidase inhibitor.KR20010025876; 2001
83. Xiamen University. Manufacture of
diketopiperazine derivative by
fermentation of Papularia. CN1667126;
2004
84. Shenyang Pharmaceutical University.
Manufcature of antitumoric
thiopiperazinedione derivative with
Aspergillus fumigates. CN102051394;
2011
85. Korea Institute of Science and
Technology. Aspergillus sp. KMD 901,
diketopiperazines isolated from the strain,
and composition containing
diketopiperazines for preventing or
treating cancer. KR2011045763; 2011
86. Ocean University of China. Polysulfide
bond-containing piperazidine compound
isolated from Oidiodendron truncatum
and antitumor application thereof.
CN101812079; 2010
87. Mannkind Corp. Formation of
N-protected 3,6-bis(4-aminoalkyl)-2,5,
diketopiperazines. WO2012109256;
2012
88. Qing Y. Synthetic methods of 3,6-bis(4-
bisfumaroyl aminobutyl)-
2,5-diketopiperazine and salt substitute
thereof. CN101851213; 2010
89. Nanjing University of Technology.
Method for preparing high-purity
diketopiperazine cyclopeptide.
CN102146065; 2011
90. Temple University of the
Commonwealth System of Higher
Education. Acylation of hindered amines
and functional bis-peptides obtained
thereby. US2011184171; 2011
91. Indiana University Research and
Technology Corp. Ester-based peptide
prodrugs. US20110065633; 2011
92. Mannkind Corp. Catalysis of
diketopiperazine synthesis.
US2006041133; 2006
93. Toyohashi University of Technology.
Method of synthesis for cyclic peptides
utilizing high temperature and high
pressure water. JP2003252896; 2003
94. DMI Biosciences, Inc. Method of
synthesizing diketopiperazines.
WO0212201; 2002
95. Degussa A.G. Production of known and
new 2,5-diketopiperazine derivatives
useful for the synthesis of bioactive
compounds, e.g. cyclo(Lys-Lys).
DE20001019879;2001
96. Affymax Technologies N.V. UK. Method
for synthesis of diketopiperazine and
diketomorpholine derivatives.
US5817751; 1998
97. Affymax Technologies N.V. UK. Method
for the synthesis of diketopiperazines.
WO9600391; 1996
98. Mitsui Toatsu Chem, Inc. Preparation of
3,6-bis[(4-hydroxyphenyl)methyl]-2,5-
diketopiperazine. JP06321916; 1994
99. Ajinomoto Co., Inc. Process for
preparing diketopiperazine derivatives.
JP04234374; 1992
100. Monsanto Co. The compound 1,4-
diisopropyl-2,5-diketopiperazine.
EP0216744; 1987
101. Wang P, Xi L, Liu P, et al.
Diketopiperazine derivatives from the
marine-derived actinomycete
Streptomyces sp. FXJ7.328. Mar Drugs
2013;11:1035-49
102. Mannkind Corp. Dry powder drug
delivery system and methods.
WO2011163272; 2011
103. Mannkind Corp. Val (8)
glp-1 composition and method for
treating functional dyspepsia and/or
irritable bowel syndrome.
WO2011017554; 2011
104. Mannkind Corp. Diketopiperazine
microparticles with defined specific
surface areas. WO2010144789; 2010
105. Mannkind Corp. An improved dry
powder drug delivery system.
WO2010102148; 2010
106. Mannkind Corp. Glucagon-like peptide
1 (GLP-1) pharmaceutical formulations.
US2008260838; 2008
107. Mannkind Corp. Method for improving
the pharmaceutic properties of
microparticles comprising
diketopiperazine and an active agent.
US2007196503; 2007
108. Mannkind Corp. Method of drug
formulation based on increasing the
affinity of crystalline microparticle
surfaces for active agents.
US2007059373; 2007
109. Mannkind Corp. Diketopiperazine salts
for drug delivery and related methods.
US20060040953; 2006
110. Mannkind Corp. Cell transport
compositions and uses thereof.
WO2004012672; 2004
111. Pharmaceutical Discovery Corp.
Compositions for treatment or
prevention of bioterrorism.
WO03061578; 2003
112. Emisphere Techinologies, Inc.
Diketopiperazine-based delivery systems.
WO9609813; 1996
113. Kamiya T, Maeno S, Hashimoto M,
Mine Y. Bicyclomycina, new antibiotic.
II. Structurale lucidation and acyl
derivatives. J Antibiot 1972;25:576-81
Y. Wang et al.
18 Expert Opin. Ther. Patents (2013) 23(11)
Exp
ert O
pin.
The
r. P
aten
ts D
ownl
oade
d fr
om in
form
ahea
lthca
re.c
om b
y Q
ueen
's U
nive
rsity
on
09/0
5/13
For
pers
onal
use
onl
y.
AffiliationYi Wang, Pei Wang, Hongguang Ma &
Weiming Zhu†
†Author for correspondence
Ocean University of China,
School of Medicine and Pharmacy,
Key Laboratory of Marine Drugs,
Ministry of Education of China,
Qingdao 266003,
People’s Republic of China
Tel: +86 532 82031268;
Fax: +86 532 82031268;
E-mail: [email protected]
Developments around the bioactive DKPs
Expert Opin. Ther. Patents (2013) 23 (11) 19
Exp
ert O
pin.
The
r. P
aten
ts D
ownl
oade
d fr
om in
form
ahea
lthca
re.c
om b
y Q
ueen
's U
nive
rsity
on
09/0
5/13
For
pers
onal
use
onl
y.