Anticancer Activity of Pyrazole via Different Biological Mechanisms

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Anticancer Activity of Pyrazole viaDifferent Biological MechanismsSimpal Chauhan a , Sarvesh Paliwal a & Rajani Chauhan aa Department of Pharmacy , Banasthali University , Tonk ,Rajasthan , IndiaPublished online: 29 Apr 2014.

To cite this article: Simpal Chauhan , Sarvesh Paliwal & Rajani Chauhan (2014) Anticancer Activityof Pyrazole via Different Biological Mechanisms, Synthetic Communications: An InternationalJournal for Rapid Communication of Synthetic Organic Chemistry, 44:10, 1333-1374, DOI:10.1080/00397911.2013.837186

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Synthetic Communications Reviews

ANTICANCER ACTIVITY OF PYRAZOLE VIA DIFFERENTBIOLOGICAL MECHANISMS

Simpal Chauhan, Sarvesh Paliwal, and Rajani ChauhanDepartment of Pharmacy, Banasthali University, Tonk, Rajasthan, India

GRAPHICAL ABSTRACT

Abstract In the past few years pyrazole derivatives have attracted increasing attention

because of their numerous potential pharmacological applications. Changes in their structure

have offered a high degree of diversity that has proven useful for the development of new

medicinal agents with improved potency and less toxicity. This review focuses on the recent

developments in pyrazole along with their structure–activity relationship (SAR), parti-

cularly for anticancer activity. The review covers SAR for active pyrazole molecules

such as cyclin dependent kinase (CDK) inhibitor (modulator), aurora kinase inhibitors

(modulator), break point cluster region-Abelson (BCR-ABL) tyrosine kinase inhibitors

(modulator), heat shock protein (HSP 90) inhibitors (modulator), polo-like kinase

inhibitors (modulator), cyclo-oxygenase (COX) and lypo-oxygenase (LOX) inhibitors

(modulator), epithelial growth factor receptor (EGFR) inhibitors (modulator), reticular

activating system–neuro endocrine tumor (Ras-Net) ETS-like transcription factor (Elk-3)

pathway inhibitors (modulator), and DNA binding agent.

Received August 19, 2013.

Address correspondence to Rajani Chauhan, Department of Pharmacy, Banasthali University,

Tonk, Rajasthan 304022, India. E-mail: [email protected]

Synthetic Communications1, 44: 1333–1374, 2014

Copyright # Taylor & Francis Group, LLC

ISSN: 0039-7911 print=1532-2432 online

DOI: 10.1080/00397911.2013.837186

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Keywords Enantiomers; imatinib-resistant mutations; lipoxygenases; promyelecytic;

resorcinylic; rofecoxib

INTRODUCTION

As the prognosis for treatment of many forms of cancer remains poor,improvements in treatment and prevention have led to a decrease in cancer deaths,but the number of new diagnoses continues to rise.[1] Several lines of evidence sup-port the view that chemotherapy has become one of the most significant treatmentmodalities in cancer management. Conventional cancer chemotherapy is seriouslylimited by tumor cells exhibiting multidrug resistance (MDR) [caused by the overexpression of integral membrane transporters, such as Pgp- and MDR-associatedproteins (MRPs), which decrease drug accumulation and cell death] and theirseverely toxic effects. There is a need for more efficient drugs to be developed.[2]

A literature survey revealed that N-substituted pyrazoles have been implemen-ted as antileukemic,[3,4] antitumor,[5,6] antiproliferative,[7,8] anti-angiogenic,[9,10] DNAinteracting,[11] proapoptotic,[12] autophagy,[13,14] and antitubulin[15] agents, besidestheir capability to exert remarkable anticancer effects through inhibition of differenttypes of enzymes, proteins, and receptor, which play important roles in cell divisionsuch as cyclin dependent kinase (CDK),[16–18] aurora kinase A=B=C,[19,20] heat shockprotein (HSP) 90,[21,22] selective polo-like kinase-1,[23] ETS-like transcription factorres-net (Elk-3),[24] break point cluster region–Abelson (BCR ABL) kinase,[25] epider-mal growth factor receptor (EGFR),[26] and tumor growth factor (TGF)-b type.[27]

In this respect the discovery of the natural antibiotic pyrazofurin, 4-hydroxy-3-b-D-ribofuranosyl-1H-pyrazoles-5-carboxamide, having a potent antitumor efficacyin some cancers, led to intensive investigation of many pyrazoles carrying differentfunctional groups for their anticancer activity.[28]

The first section of the review focuses on the recent development of pyrazolealong with its structure–activity relation (SAR).

In view of this, we have compiled a diverse series of compounds that have beenrecently synthesized by various research groups targeting many enzymes of cell cycleaurora kinase A=B=C, CDK, selective polo-like kinase-1, and many other new targets.

CDK INHIBITORS

The first CDK inhibitor introduced in clinical trials was flavopiridol(L868275)[29,30] for the treatment of chronic lymphocytic leukemia and 7-hydroxystaur-osporine (UCN-01).[31] A second generation of CDK inhibitors with greater selectivityhave also entered clinical trials, such as BMS-387032[32] and roscovitine (CYC-202),[33]

targeting mainly CDK2 but also CDK7 and 9, and PD0332991,[34] targeting CDK4 and6. Recently, several studies have suggested that CDKs and their cyclin partners canreplace and compensate for each other. For example, CDK1 is able to replace CDK2in the case of its absence or inhibition, which means that there in a need to develop akind of drug that targets more than one CDK for tumor growth suppression.[35]

In 2004 Pevarello et. al.[16] synthesized 3-aminopyrazole derivatives targetingcyclin-dependent kinases (CDK) and cyclins such as CDK2=cyclin A and CDK2=cyclin E. They synthesized compounds 1– 4 (Fig. 1a) in their first effort. The three

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nitrogens of the 3-aminopyrazole scaffold were essential for bonding with the hingeregion (Glu81–Leu83) of the kinase ATP pocket; a cyclopropyl substituent atposition 5 of the 3-aminopyrazole scaffold is much more effective than a methylor an other group. Halogen substituents on the 3-benzamido moieties givecompounds with increased potency. Compounds 5–9 (Fig. 1b) shows that a substituentat the p-position of the benzamido ring retained or favored potency compared to theunsubstituted compound 4. It has been observed that substitution at positions 2 and

Figure 1. (a) Initial hit compounds 1–4; (b) compounds 5–9; (c) compounds 10–18; (d) compounds 19–29; (e)

compound 30 and highly active compound N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(2-naphthyl)acetamid (31).

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3 on the benzamido moiety (10–18, Fig. 1c) (10–17) decrease the activity, while4-chloro substituted compound 18 retains activity. Replacement of cyclopropyl atthe 5-position on a series of 3-(4-bromobenzamido pyrazoles (5, 19–29) (Fig. 1b,d)confirmed that small cycloalkyl groups (5, 19, 20) were easy to tolerate while smalland large alkyl or cycloalkyl groups (21, 22, 26–29) were found to show a goodinhibitory effect. Compounds having phenylacetamide on 3-aminopyrazole 30 and31 (Fig. 1e) were most active. Compound 35 had poor physicochemical properties.

To improve the physiological properties of this lead compound, Pevarello et al.in 2005[17] synthesized a new series by introducing a methyl group in the a-positionof arylacetamido group at position 3 and changing the b-napthyl moiety with differ-ent 4-lactam-1-yl phenyl moiety of PNU-292137, showing that the methyl group(compounds 30–41) or a fluorine (compound 35) are fit for the activity and morehydrophilic (compounds 32–34, 36) or bulkier group (compound 37) are less potentagainst CDK2=cyclin A (Fig. 2a). Stereoselectivity indicates that S-enantiomers(compounds 33, 40) are more active than R-enantiomers (compounds 34, 41,Fig. 2a). It has low solubility in water and the plasma protein binding due to thenephthyl moiety is very high. Compound 44 (Fig. 2b) is as active as the parent leadagainst CDK2=cyclinA and more active than benzocondensed compounds 41 or 36(Fig. 2b). Increasing the lactam ring size upto a six-member ring (analog 35) is notsuitable for activity. In a series (compounds 52–63, Fig. 2c) only compound 55 withimidazolidinone is found to be most active in a biochemical assay but not in thecellular assay. In final set of compounds 64–66 (Fig. 2c), oxazolidine (35) is foundto be a potent CDK2 =cyclin A inhibitor and showed enhanced drug-like propertyover lead compound. Compound 44 has endowed with a tumor growth inhibition

Figure 2. (a) Compounds 1–10 (32–41); (b) compounds 11–20 (42–51); (c) compounds 21–32 (52–63); (d)

compounds 33–38 (64–69).


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(TGI) of more than 70% without significant toxicity in a human ovarian A2780xenograft model in nude mice.

Thirty-five 3,5-diamino-1H-pyrazole derivatives substituted with different ary-lazo groups at position 4 as shown in Fig. 3 were reported by Krystof and team.[18]

Activity of these compounds has been illustrated in Table 1.In compound 100, the position of the nitro affected the activity in the order

o>m> p, with 2 to 4-fold drop in potency between the different isomers (96–98).All compounds 102–104 having carboxylic acid drastically lose inhibitory activity.Compound 105 with a methylene group between the 2-OH and the phenyl groupled to decline in the activity.

Ibrahim and Ismail[36] synthesized pyrazolo[3,4-d]pyrimidine scaffold, a newclass of highly selective inhibitors of cyclin dependent kinases.

Alessio et al.[37] synthesized derivatives of benzodipyrazoles, a tetrahydro-benzodipyrazole derivative bearing a sulfamidophenyl moiety (compound 113).

Brasco et al.[38] identified a novel series of pyrazolo[4,3-h]quinazoline-3-carboxamides as CDK inhibitors.

Figure 3. (a) Compounds 1–7 (70–76); (b) compounds 8–17 (77–86), which did not display antiprolifirative

activity; (c) compounds 87–90.


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Traquandi et al.[39] explored the compounds with the objective of obtainingmulti-CDKs inhibitors.

Noskova et al. synthesized 1,5-diaryl-3-(3,4,5-trimethoxyphenyl)-1H-pyrazolo[4,3-e][1,2,4]triazines derivatives (192, Fig. 8a) and some of them displayed cytotoxi-city against A549 lung carcinoma cell lines.[40] In an extension of this study, Guckyet al.[41] studied the cytotoxicity in compounds synthesized in 2010.

The best potency and selectivity profile was demonstrated by compound 225,wherein the 4-(dimethylamino) piperidine moiety was speculated to make a favor-able polar interaction with Thr 107 of CDK4=6 and an unfavorable electrostatic

Table 1. CDK2=inhibitory activity studied by Krystof et al.[18]

Compound Activity

72–75, 70 Increased activity

71 Decreased activity

87, 89 Steady activity

77–86 No activity, due to p-substitution on arylazo group (Fig. 3b)

90–93 Reduced and insignificant, due to bulkiness

95–105 Active (Fig. 3c)

99, 101 Highly active, at very low concentrations

100 Half potent to compounds 99, 101

101 Most potent, also reduces the frequency of S-phase cells

of cancer cell line HT-29 in antiproliferation assays

Figure 4. (a) Compounds 106 and 107; (b) compounds 108–111; (c) compound 112.


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Table 2. Results on the basis of docking study

Compounds Activity

106, 107 Initial hit for docking (Fig. 4a)

108–112 Maximum fit to the receptor, working at positions 1, 4,

and 6 in pyrazolo [3,4-d] pyrimidine moiety (Fig. 4b and 4c)

107b Not highest biological activity, highest docking

108a Most active, could be new potential candidate for the

development of anticancer drugs

Figure 5. (a) Compounds 115a–g; (b) compounds 115h–k; (c) compounds 114, 116, 117, 118, and 119; (d)

compound 113 and the most potent compound 120 (4,4-gem-dimethyl benzodipyrazole).


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Table 3. Activity on CDK2=Cyc A and to an ATP competitive inhibitor

Compound Activity

113 Pyrazole ring A, carboxamido and sulfamido group are essential requirement for

binding of the ligand to the adenine phosphate and ribose region of the ATP pocket

respectively. Poor cell permeability due to several NH bonds (Fig. 5d)

115a–e Reduces the CDK2 inhibition, increases antiproliferative activity in both TH-BDP and

DH-BDP, Fig. 5a

115h, 115i, 115j,

115k

Order of activity: 115k> 115j> 115h> 115i (Fig. 5b)

115f,d,g, 117d Order of activity: 115f,d,g> 117d (Fig. 5a)

114j,d,i Less active then corresponding amides (Fig. 5c)

116f,d,g, 118g Acid and ketone retain activity (Fig. 5c)

119f Most promising agent, activity comparable to amide with higher solubility (Fig. 5c)

Figure 6. (a) Hit compounds 121 and 122 of benzapyrazole series; (b) compounds 123–127 with R1

modifiction; (c) compounds 127–131; (d) compounds 132–147.


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repulsion with Lys89 in CDK1=2. Trifluoromethyl group at C1 on pyrazole ring(compound 226) showed an 8-fold decrease in CDK4 potency as compared to 225;this loss was less dramatic than that observed in methyl substituted derivative.Compounds 225 and 226 were considered the most active compound of this series.Substituted pyridinylamine side-chain at pyrimidine C-2 position was favorablefor both potency and selectivity, and an isopropyl-substituted pyrazole at C3afforded further improvements in potency. An additional substitution of the

Table 4. CDK inhibitors synthesized by Brasca et al.[38]

Compound Activity

121 Potent inhibitor, antiproliferation activity against A2780 human ovarian carcinoma

122 Potent inhibitor, more soluble than 121 (Fig. 6a)

123–125 Inhibitor, methyl, cyclopropyl, and hydroxyethyl derivative (Fig. 6b)

126–127 Decrease activity, bulkier residues (Fig. 6b)

121–125 No improvement in terms of selectivity vs the Aurora kinase A and cellular antiproliferative

activity was achieved. Moving from primary amide (121) to secondary amide (125)

128, 129 Potent enzyme inhibitors, improvement in antiproliferative activity with increased solubility

in neutral buffer, selectivity due to dimethyl moiety

130, 131 Potent enzyme inhibitors, improvement in antiproliferative activity with decreased solubility

in neutral buffer (Fig. 6d)

132 Highly active against CDK2 and potency in A2780 cells assay

133, 134 Good activity against CDK2=cyclinA, antiproliferative activity with good solubility, binding

affinity in same manner as in compound 122. Selectivity due to dimethyl moiety, high

stability to human CYP4203A41, acceptable plasma protein binding and good solubility,

better pharmacokinetic properties, dose-dependent inhibition of A2780 tumor growth up

to 91%, effect on cell progression and DNA synthesis in 134. Compound 134 is highly

potent, orally available, and underwent phase I and II clinical trials (Fig. 6d, Table 5)

135 Retain same activity

136, 137 Less active, less soluble

138–140 Good activity as CDK2=cyclin A, selectivity against Aurora A (Fig. 6d)

143, 145 Comparable activity to CDK2=cyclin A

Table 5. Compound numbers with their substituents

Compound R1 R2 R3

132 H H H

133 H 4-Methyl piprazin-1-yl H

134 CH3 4-Methyl piprazin-1-yl H

135 CH3 H 4-Methylpiprazin-1-yl

136 CH3 Morpholin-4-yl H

137 CH3 H morpholin-4-yl

138 CH3 1-Methylpipradin-4-yloxyl H

139 CH3 H 1-Methylpipradin-4-yloxyl

140 CH3 4-Methylpiprazin-1-ylmethyl H

141 CH3 H 4-Methylpiprazin-1-ylmethyl

142 CH3 Morpholin-4-ylmethyl H

143 CH3 H Morpholin-4-ylmethyl

144 CH3 Dimethyl amino H

145 CH3 H Dimethyl amino

146 CH3 Dimethyl aminomethyl H

147 CH3 H Dimethylaminomethyl


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Table 6. Activity profile: CDK2=CyA

Compound Activity remarks

148 Moderate antiproliferative activity in A2780 human ovarian carcinoma cells, very low

solubility, significant selectivity on a panel of 35 serine-threonine and tyrosine

kinases

148–158 Good activity, also inhibits activity of enzyme aurora-A, activity due to R3

substitution as this is similar to structure of CDK and aurora A (Fig. 7a)

149–152 Good selectivity over aurora A, poor solubility

159–161, 164 Good selectivity over aurora A, solubility increased (Fig. 7b)

165 Increases the activity due to methyl at R1 (Fig. 7c)

163 Less active against CDK2=CycA, improved antiproliferative activity against A2780

human ovarian carcinoma with excellent selectivity

166–168 Decreased activity due to bulky R1 (Fig. 7c)

169–171, 174, 175 Significant activity, bulkier group at R2, modulate the solubility but critical to

selectivity (Fig. 7d)

178, 180, 182, 184,

186

Less potent due to secondary methyl amide (Table 7)

177, 179, 181, 183,

185

Less potent due to primary amide functionality (Table 7)

187–191 Good activity

179, 181, 189 Potent inhibitors of CDK2=CyA, CDK2=CyE, CDK1=CyB, and CDK5=p25 inhibit

CDK4=CyD1 (lower potency), high metabolic stability, good plasma protein

binding, good solubility, good permeability, low clearance, suitable volume of

distribution, high oral bioavailability (most potent), selective multi-CDK inhibitor

in the series in compound 189

189 Dose-dependent inhibition of A2780 tumor growth

Table 7. Different substituents for 177–191

Compound R3 R1

177 NH2

178 NHCH3

179 NH2

180 NHCH3

181 NH2

(Continued )


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pyrazole with chlorine was found to augment potency and selectivity in bothenzymatic and cellular assay. A trifluoromethyl group at C-l on the pyrazole ringdecreases potency against CDK4.

AURORA KINASE INHIBITORS

Aurora kinases are a family of mitotic serine=threonine kinases conserved fromyeast to humans, and they have received significant recent attention as new targetsfor anticancer therapy.[43]

1,4,5,6-Tetrahydropyrrolo[3,4-c]pyrazole bicycle derivative, a versatile scaffold,has been designed to target the ATP pocket of protein kinases.[44] Compound 227

was assumed to be a versatile scaffold designed to target ATP pocket of protein

Table 7. Continued

Compound R3 R1

182 NHCH3

183 NH2

184 NHCH3

185 NH2

186 NHCH3

187 NH2

189 NHCH3

190 NH2

191 NHCH3


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kinases but needs SAR investigation. In addition to this, a synthetic optimization studybased on the lead anticancer compound N-(2,6-diethylphenyl)-3-[4-(4-methyl-piperazin-1-yl)-benzoylamino]-4,6-dihydro-1H-pyrrolo[3,4-c]pyrazole-5-carboxamide (227) was

Figure 7. (a) Compounds 149–158; (b) compounds 159–164; (c) compounds 165–168; (d) compounds

169–176; (e) compounds 177–191.


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undertaken by Soncini et al.[45] in an attempt to discover a new class of aurora kinaseinhibitor characterized by a urea substituent at position 5, which led to formation of228 (PHA-680632), 229, and 230 (Fig. 10a).

BCR-ABL TYROSINE KINASE INHIBITORS

Imatinib was the first reported drug in this category. It was approved by the U.S.Food and Drug Administration in 2001 and became frontline therapy for early-phaseCML, but it causes drug resistance.[50] Followed by a number of second-generationtherapeutic inhibitors with increased potency and ability to inhibit the majority ofimatinib resistant mutations.[51] BCR-ABL plays critical roles in the pathogenesis ofCML, thus representing potential therapeutic targets revealed from several clinical studies.

Recently, Xiaomei et al.[52] reported 1H-pyrazolo[3,4-b]pyridine derivativeGZD824, hoping to overcome the problem induced with imatinib. Many derivativesof compound 279 were synthesized with different substituents R1 and R2. Cyclopro-pyl, phenyl, and methoxy groups were not favorable at the R1 position, althoughmethyl substituted compound at R1 displayed comparable activity to the H substi-tuted compound. In it was found that a methyl group at the R2 position was criticalfor activity against BCR-ABL when the CH3 group was replaced by hydrogen (smallmolecule) compound that displayed almost equal potency to methyl-substitutedderivative, but when this group was replaced by a relatively large group such ascyclopropyl, ethyl decreases inhibitory activity. Compounds with H at R1 and methylat R2 displayed potential antiproliferation of Bcr-Abl-positive K562 and Ku812human CML cells with IC50 in nM, in addition to good oral bioavailability, a consi-derable half-life, and excellent in vivo antitumor efficacy (Fig. 12a).

A series of pyrazolo[3,4-d]pyrimidines derivatives were synthesized by Manettiet al.[53] (Fig. 12b), changing substituents at R1 and R2 positions and investigatingtheir affinity toward Abl enzyme in a cell free assay and their antiproliferativeactivity in cellular assays on human leukemia cell lines.

HSP 90 INHIBITORS

The molecular chaperone heat shock protein 90 has emerged as the most widelyacknowledged molecular target. Geldanamycin (naturally occurring) derivativesuch as 17-allylamino-17-demethoxy-geldanamycin (17-AAG) was the first HSP90

Figure 8. Compounds 192 and 193.


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ATPase inhibitor which entered clinical trial.[54,55] However, synthetic smallmolecule HSP90 inhibitors also have potential advantage.

Cheung et al.[21] synthesized 13 potent resorcinylic pyrazole analogs andassayed for activity against yeast Hsp90 ATPase using a malachite green assay.

Brough and coworkers[56] designed 3-(5-chloro-2,4-dihydroxyphenyl)-pyrazole-4-carboxamide as a novel inhibitor of HSP90 accessing an extra interaction with theHSP90 via PHe 138, which gave a significant increase in binding potency compared to

Figure 9. (a) Compounds 194–199; (b) compounds 200–203; (c) compounds 204–206; (d) compounds

207–213; (e) compounds 214–226.


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other analogs that do not make this interaction. This has been done by altering the 4-position of pyrazole. All compounds were tested for binding at ATP binding site usinga fluroscencepolarization assay and forHCT116 human colon cancer cell in vitro.Avail-able data showed that most of them inhibit binding of probe substrate in the low micro-molar range, except for tertiary amide derivative 301a and heteroaryl compounds 301band 301c. Compounds 301d and 301e (Fig. 12f) were most potent at low concentrations.

Polo-Like Kinase Inhibitors

The polo-like kinase (Plk1-4) family plays an important role in regulating cellcycle progression. Schoffski mentioned that almost 80% of cancer cases of differentorgans express high level of PLk transcript.[57] Among the four Plka isoforms,polo-like kinase 1 (Plk1) was recognized as a fundamental regulator of mitotic entry,chromosome segregation, centrosome duplication, bipolar spindle formation, tran-sition from metaphase to anaphase, and execution of cytokinesis. It plays importantroles in cell mitotis and therefore overexpansion of this kinase has been recognized asattractive therapeutic target in cancer.[58–61]

Plk1 is often overexpressed in a majority of carcinomas such as non-small-celllung cancer, prostate cancer, ovarian carcinoma, breast cancer, human melanomacells, carcinomas of the head and neck, and bladder cancer.[62–68]

Beria et al.[23] identified a novel series of ATP-competitors, 4,5-dihydro-1H-pyra-zolo[4,3-h]quinazoline derivatives, as a new class of orally and selective polo-like kinase1 inhibitors. In vitro antiproliferative activity was evaluated in a broad panel of cell lines.Structure-activity relationships for these compounds have been summarized in Table 18.

Table 9. Activity study of 4-(pyrazole-4yl)-pyrimidines derivatives developed by Cho et al.[42]

Compound Activity

195 Promising hit for lead optimization due to competitively and reversibly binding to the ATP

binding site of CDK4 and selective against other non-CDK (Fig. 9a)

197 Activity due to isopropyl substitution

196 Less activity than 197

199 Selective to CDK4 over CDK1 and CDK2, slight improvement in CDK4 binding affinity

200–203 Decrease in potency (Fig. 9b)

204 Improved selectivity profile over 199 (Fig. 9c)

207–213 Selectivity for CDK4 due to pyrazole substituted, change in size diminishes activity (Fig. 9d)

219–222 Slight loss in CDK1=2 activity due to bulky group

214–226 Improve solubility and potency (Fig. 9e)

Table 8. Cytotoxic study of 1,5-diaryl-3-(3,4,5-trihydroxyphenyl)-1H-pyrazolo[4,3-e][1,2,4]triazines

Compound Cytotoxicity

192 Against A549 lung carcinoma cell lines[40] (Fig. 8a)

193e, 193h Highest cytotoxicity, in case of drug-resistant subclones of CEM and K562 cell

lines, activity decrease due to increased expression of multidrug-resistance genes

193b, 193i Most active due to hydroxylated phenyl at n1 position

193e, 193h Increases cytotoxic activity due to hydrophobic group


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Figure 10. (a) Compounds 228, 229, 230, and 231; (b) compounds 232, 233, and 234; (c) compounds

235–247; (d) compounds 248, 249, 250, and 251; (e) compounds 252–253.


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COX AND LOX INHIBITORS

Barbey et al.[69] synthesized methoxytetrahydropyran derivative as dualcyclooxygenase-2=5-lipoxygenase inhibitor and identified it as an anticancer agent.Pommery et al.[70] synthesized structurally related diaminopyrazole derivatives303a–s (Fig. 13a, b) and evaluated their cyclooxygenase-2 (COX-2) and lipoxy-genases (LOXs) inhibitory activity and antiproliferative activity against two humanprostate carcinoma cell lines, LNCaP and PC-3, by a immunoassay taking celecoxiband rofecoxib as reference drugs.

EGFR INHIBITORS

The epidermal growth factor receptor (EGFR) is responsible for regular cellgrowth. The EGFR is transmembrane receptor that transits signal from one cellto another to tell either to grow and multiply or to die. In cancer cells EGFR doesnot work properly; dysregulation in the function of this receptor sends wronginformation or too many signals to the cell. This makes EGFR a target for cancertreatment. Among many growth receptors it was the first novel proposed targetfor anticancer therapy. A critical review on the EGFR antagonist has been publishedby Fortunato.[71]

Lv et al.[72] synthesized pyrazole derivative containing thiourea, 3(3, 4-dimethylphenyl)-5(4-methoxyphenyl)-4,5dihydro-1H-pyrazole-1-carbothiamide 304, 305, 306a–j

(Fig. 13c) as nonurea compounds and studied EGFR inhibitor activity.

Table 10. 1,4,5,6-Tetrahydropyrrolo[3,4-c]pyrazole bicycle derivatives to target the ATP pocket of

protein kinases

Compound Activity

227 Potent inhibitor of aurora kinases (IC50¼ 27 nm, 135 nm, and 120nm versus Aurora-A, -B,

and -C, respectively, tested on human colon cancer cell line HCT-116 with IC50¼ 0.05mmFancelli et al.[44] >25-fold selectivity for aurora-A enzyme over 19 out of the 20 kinases

evaluated.

228–230 Soncini,[45] urea substituent at position 5 of compounds 227, 228 demonstrated high in vitro

antiproliferative activity

231 231d: Highest activity, additional effect against ABL, RET, TRKA, FGFRI-fantastic

antiproliferative activity against HCT-116, MCF-7, and hela (IC50¼ 28–140 nm). 231e:

Decreases activity, Fancelli et al.[46] modified compound 229

232–234 Mortlock et al.[47] inhibition of histone-H3 phosphorylation. 232–233: Increases the

physicochemical properties of the compounds, hydrogen bond donor in pyrazole ring

increases the binding affinity to the protein backbone of aurora kinase. Substitution on

acitanilide and quinazoline C-7 side chain

235–247 235, 236: Prolinol side chains highly active, short carbon chain reduces potency, 235–236:

highly active, short carbon chain reduces activity, noncyclic amine are more active than

cyclic amine. Three carbon spacers, most favorable, 2,3-difluorophenyl groups have greater

potency than 3-fluorophenyl group, c-6 methoxy group with a proton generally reduced

potency

248–251 Phosphate prodrug of 235, 246, 252, and 253 respectively, freely soluble in 0.3m tris buffer at

pH 9 at a concentration of 25mg=ml.


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RAS-NET (ELK-3) PATHWAY INHIBITORS

Phosphorylation and activation of net (Elk-3=SAP-2=Erp) is a transcriptionfactor that occurs through Ras-extracellular signal-regulated kinase signaling

Table 11. Substrate for 235–241

Compound R X

235 2,3-di-F

236 2,3-di-F

237 2,3-di-F

238 2,3-di-F

239 2,3-di-F

240 3-F

241 3-F

242 3-F

243 3-F

244 3-F

245 2,3-di-F

246 2,3-di-F

247 2,3-di-F


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Table 12. Pentacyclic aurora kinase inhibitor, active compound against aurora kinase due to their lactam

portion (Rawson et al.[48])

Compound Activity

256–260 Five-membered ring reduces potency compared to six-membered ring, but seven-membered

ring showed increased cellular and enzymatic potency, substitution on pyrazole at

position-5: hydrophilic or sterically demanding groups decreases activity: lipophilic methyl

substitution increase potency, varying the length of hydrocarbon bridge joining pyrazole to

indole, N-alkylation of lactam portion had little effect on enzymatic potency and N-ethyl

analog effect on oral PK properties

265 Excellent in vitro cellular activity, in vivo: HCT-116 mouse xenograft model: lesser effect at

1mg=kg dose, merging all substituents responsible for increased activity

Table 13. Pthalazinone pyrazoles derivatives with aurora-A inhibitors activity[49]

Compound Activity

266–278 Potency with excellentselectivityover aurora-B, R2 methylene group and R1 hydrogen lead to

decrease in activity separately. Compounds 267, 269, 278 showed highest inhibitory

activities tested against aurora-A by ELISA assay. Aminopyrazole moiety was found

essential for interaction between compound and the hing region of enzyme aurora kinase

A (Glu-211, Alu-213, and Pro-214).

Figure 11. (a) Compound 254 and 255; (b) compounds 256–260; (c) compounds 261–264; (d) compound

265; (e) pthalazinone and its derivatives 267–278.


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Figure 12. (a) Structure of 1H-pyrazolo[3,4-b]pyridine analogs; (b) compounds 279–289; (c) compounds

290a–h; (d) compounds 291–292; (e) compounds 4–8 and 293–300; (f) compound 301; (g) compound

302 with highest activity.


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Figure 12 Continued.

Table 14. ABL tyrosine kinase activity (Manetti et al.[53])

Compound Activity

279–289 R1 and R2 positions were found responsible for interaction with

HR P and HRI region of Abl

280, 289 Halogen substituent at o-phenyl ring of R1 increases binding affinity toward Abl

283, 284 Reduced affinity for Abl, o- and m-Cl substitution at R1 respectively

285 Best biological profile, antiproliferation, and affinity toward Abl

279 Four times better affinity but less antiproliferation

Table 15. Resorcinylic pyrazole analog activity overview

Compound Activity

290 Most potent

290a–f Reduce the activity, 5-fold increase in IC50, methylation of the hydroxyl group, para to the

pyrazole, ethyl group in 290 replaced by hydrogen or propyl chain 9,8

291–292 Retained activity


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pathway, which is also responsible in wound healing, angiogenesis,[73] and tumorgrowth.[74] It makes ras-net (Elk-3) a well-known target for development of cancertherapy.[75]

ANTIANGIOGENIC, CYTOTOXIC, AND ANTIPROLIFERATIVE AGENT

This section gives details about agents that show anticancer activity bynonreceptor binding mechanism.

Franchini et al.[76] synthesized N-aryl pyrazole, which showed remarkablepotential in nanomedicine applications against malignant gliomas. 1-(4-Chlorophenyl)-4-hydroxy-3-substituted-1H-pyrazoles were announced by the U.S.National Cancer Institute (NCI) to have pronounced anticancer activity.[77,78] Onthe basis of this compound Riyadh and coworkers[79] synthesized several novelenaminone-based compounds containing N-arylpyrazoles. All of them (311, 312,314) (Fig. 14a) were selected for cytotoxic effect against human breast cell line(MCF-7) and liver carcinoma cell line (HEPG2) by SRB assay.

Rostam et al.[80] introduced a new series of 1-(4-chlorophenyl)-4-hydroxy-1H-pyrazol-3-carbonyl derivatives linked to nitrogenous heterocyclic ring. A carbonylbridge, comprising essentially 1-(4-chlorophenyl)-4-hydroxy-1H-pyrazol-3-carbonylcounterpart, was found to be an essential pharmacophore for anticancer activity.

Table 16. Structurally related compound 290 having Hsp90 inhibition (Dymock[22])

Compound Activity

293–295 Did not show significant effect on the binding site

296–300 Improved potency in the inhibition of growth of HCT116 cells

Table 17. ATP-competitor 4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline derivatives[23]

Compound Activity remark

302 Potent cell growth inhibitor in vitro, methyl group as the best residue at the position 1 of

4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline in terms of biochemical and cellular activity.

Primary amide at 3-position of pyrazole: essential for better enzyme binding. Replacement

of this group with ethyl ester, carboxylic acid, secondary amides, simple methyl amide

decreased Plk1. Methoxy group at 8-anilino residue (2-methoxy at phenyl ring): essential

for enzyme selectivity toward aurora-A and CDK-2=A. Methylpiprazine moiety at

5-position of aniline residue: essential for enhanced potency and solubility of compound.

Table 18. Diaminopyrazole derivatives activity[70]

Compound Cyclooxygenase-2 (COX-2) and lipoxygenases (LOXs) inhibitory activity

303a–s Compound 303a, 303h, combination of standard diaryl heterocyclic methyl sulfone or

aminosulfonyl and the 4-methoxytetrahydropyran: most potent inhibitor

303a,

303k–j

Complete loss of LOX inhibition

303b–j Reduce activity

303h Retention of activity and highest activity, block cell cycle I in sub-G1 phase


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Introductionof carbonyl group inpyrazolidin-3,5-dione (319) in theplaceofmethylgroup (314), resulted in a two-fold increase in inhibition activity. Incorporation of a pyra-zole moiety in a tricyclic ring system as in the naphthopyrazole (320) showed the greatestgrowth inhibition against all tested tumor cell lines. Substitution of the second pyrazolemoiety with two adjacent highly active functionalities (cyano and amino) led to

Figure 13. (a) Compounds 303a–j; (b) compounds 303k–s; (c) compounds C1–C30 (304, 305, 306a–j);

(d) active derivatives of 3-piperazinylcarbonyl-pyrazole.


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a potentially active analog 321. Replacement of cyano group in compound 321 witha ethoxycarbonyl functionality as in structure analog 323 led to a complete abolishmentof activity.

Bondgor et al.[81] synthesized 15 derivatives of 3,5-diaryl and evaluatedtheir anticancer activity against five cancer cell lines (breast, prostate, lung, colon,and promyelecytic leukemia cell line). Compounds 324a and 324b (Fig. 14c) amongthe series exhibited promising in vitro anticancer activity. Compounds 324a and 324b

contain Cl and Br substituents, which suggests that halogen substituent improvesanticancer activity of the compound.

Christodoulou et al.[82] synthesized trisubstituted pyrazole derivatives (Fig. 15a)and their particle immuno-fluorescence (PIFA)-mediated conversion to fused pyra-zole[4, 3-c]quinoline ring system. Compound 325d proved to be the most potentinhibitor of endothelial cell proliferation, whereas 325a did not inhibit endothelialcell proliferation. Replacement of their aldehyde group with an alkylated ester327a–e resulted in a slight improvement of their antiproliferative activities. On thecontrary, 328a–e rendered the compounds inactive. The presence of two hydroxylgroups in meta and para positions of B-phenyl moiety increased their antiprolifera-tive activities. On the other hand, ring closure of compound 325 to producehydroxypyrazoloquinolin-4-ones 326 potentate the cytostatic effect of the compound326a and hydroxypyrazoloquinolin-4-one 327b, the most potent inhibitor of endo-thelial cell migration.

Compound 325a did not show significant antiangiogenic effect, and compounds325d and 325e induced an inflammatory response in the CAM. All compounds of 326series significantly inhibited blood vessel formation in the CAM, compound 326b being

Table 19. Epidermal growth factor receptor (EGFR) inhibitors

Compound Activity

304e Excellent activity

304a–j Better activity than 305a–j, 304e and 304f best among these

304h–j Less activity than those substituted at 4-position (304a–g)

304d–f Electron-donating group at 4-position at ring B was more potent than electron-withdrawing

group 304a–c,g

Table 21. Activity study of N-arylpyrazoles derivatives human breast cell line (MCF-7), liver carcinoma

cell line (HEPG2)[79]

Compound Activity

311 Same as 5-fluorouracil against breast cancer cells

311–313 Higher activity against liver carcinoma cell line than 5-flurouracil

Table 20. 3-Piperazinylcarbonyl-pyrazole as ras-net (Elk-3) pathway inhibitors (Wasylyk et al.[75])

Compound Activity

307

(XRP44X)

Inhibits net phosphorylation of COOH terminal domain activated by ras-erk signaling,

which further induces fibroblast growth factor 2 (FGF-2). Inhibited luciferase more

efficiently than its regioisomer 308 (XRP45X), 309 (XRP57X), 310 (XRP58X)


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Figure 14. (a) Most active compounds of this series; (b) compounds with highest activity; (c) compounds

324a and 324b.

Table 22. N-Arylpyrazoles[79]

Compound Activity

311 Same as 5-fluorouracil against breast cancer cell

311–313 Higher activity against liver carcinoma cell line than 5-flurouracil


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the most potent one. Compound 326b bearing the fused pyrazolo[4,3-c]-quinolinestructural motif emerged as a promising lead compound, with inhibitory activity againstendothelial and tumor cell proliferation in vitro and angiogenesis in vivo.

Figure 15. (a) Active compounds of series (5,8-dihydroxy-2-(4-hydroxyphenyl-2H-pyrazolo[4,3-c]-quinoline-

4-one); (b) compounds 329a–h; (c) compounds 330a–h; (d) compounds 331 and 332.


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Raju et al.[83] synthesized a series of 5-amino pyrazole derivatives 329a–h

(Fig. 15b). Compound 329a exhibited the greatest tumor inhibitory effect with 77%ILS. Compound 329a with the bioactive nitro, cyclopropoxy, and methoxy groupsat ortho, para, and meta positions at rings A and B showed potent in vivo antitumorand antiangiogenic activity against mouse tumor. Electron-withdrawing groups suchas dinitro, difluoro, and dichloro at para and meta position as in cases of 329a, 329e,and 329g showed relatively significant activity, whereas 329c,d,f,h having electron-withdrawing groups such as o,m-chloro and p,o-fluoro showed moderate activity.Electron-withdrawing efficiency increases antitumor activity. Compound 329b with-out substituent on the phenyl ring of aryl isothiocyanates showed poor activity.

The benzimidazole and pyrazole nucleus were important in numerous naturaland synthetic compounds and in medicinal chemistry. They have antiproliferativeactivity.[84] Klirajan et al.[85] synthesized benzamidazoles (Fig. 15c). Compounds330b,g demonstrate significant activity when compared with standard drugs againsthuman breast cancer.

Congiu et al.[86] synthesized a series of 3,5-diaryl-4,5-dihydropyrazole and their1-acetylated derivatives, bearing 3,4,5-trimethoxyphenyl moiety combined with avariety of substituted phenyl rings. 5-(3,4,5-Trimethoxyphenyl) pyrazolines 331

and 332 (Fig. 15d) were found to possess potent antiproliferative activity againstSR and MDA-MB-435. Introduction of a hydroxyacetyl group at N-1 of inactive5-(3,4,5-trimethoxyphenyl) pyrazolines results in a clear in vitro activating effect.Compound 331 (IC50¼ 5.16 mM) showed inhibition of tubulin polymerizationcomparable to that of CA-4 (IC50¼ 4.92 mM).

After reporting 333(YC-1) (Fig. 16a) and its high potential as a new anticancerdrug candidate,[87,88] Chou et al.[89] synthesized 1-benzyl-3-(5-hydroxymethyl-2-furyl)selenolo[3,2-c]pyrazole derivatives. Compounds 334, 335, 337, and 338

(Fig. 16a) demonstrated significant cytotoxicity. These four compounds have thesame common structure as 333 (Fig. 16a). Among them, compounds 335 and 338

with -CH2-link (n¼ 1) exhibited relatively greater cytotoxicity than those without-CH2- link (n¼ 0) (336, 337). Between two compounds with n¼ 1, the one withR-H showed greater cytotoxicity than the other with R-CH3 (338). Among them,cytotoxicity of compound 335 was greatest, which was comparable with 333

(YC-1) and much greater than that of fluro[3,2-c]pyrazole (334) and thieno[3,2-c]pyrazole (339), about 20–100 times more potent than the MID values against NCI-H226 and 100 times more than MID against renal cancer cell line.

In 2010 some potent furochromen imidazole derivatives were reported withgood anticancer activity,[90] which Magd-El-Din[91] synthesized more derivatives ofwith the pyrazole nucleus. Compound 340b was most potent one compared withstandard drug DXR. Compounds 340a, 340c, 341, 342, 343, and 344 (Fig. 16b)showed varying activity in the order 344> 341> 342> 340c> 343> 340a.

Wang et al.[92] investigated in vitro anticancer activity of pyrazolone. Compound345was most potent compound. The 4 position of the pyrazole moiety was responsiblefor anticancer activity. Compounds 346 and 347 have more cytotoxic effect than 348.In fact compounds 348 and 349 (R4¼methylaminoformylhydrazide)-propylidene)were found inactive in this series. Among 3-phenyl substituted derivatives 350

and 351, compounds containing p-nitrobenzoylhydrazide)-ethidine at the 4 position(351) displayed greater potency than 2-hydroxylbenzylidenehydrazine derivative 350.


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Carraro[93] synthesized pyrazolo[3,4-d]pyrimidines analogs. The most activecompounds belonged to subclasses 352 and 3520, bearing both an alkylthio substituentat C6 and a chlorophenylethyl side chain at N1. However, the styryl derivative bearinga morpholino ring at C4 (354b) was found to be more active than the Congenercompounds 352b and 3520b. A butyl chain was found as the optimal substituent withinthe ethylthio subclass, while only the phenylethyl chain led to a better result amongthe thiomethyl derivatives 352. Both the deletion of the thioalkyl chain at C6and the transformation of the chlorine atom of the N1 chlorophenylethyl side chainwith the corresponding hydroxy group led to 353 with lower or insignificant activity.

Compounds 362a and 3520c showed a proapoptic effect toward 8701-BCcomparable to that reference and 352d.

Figure 16. (a) 1-Benzyl-3-(5-hydroxymethyl-2-furyl)selenolo[3,2-c]pyrazoles; (b) furochromen pyrazole

derivatives.


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Dhanya et al.[94] synthesized 3-substituted-6-(3-substituted-1H-pyrazol-4-yl)[1,2,4]triazolo [3,4-B][1,2,4]thiaziazole as illustrated in Fig. 18a. Replacement ofan active molecule or of a hydrogen atom by alkyl, halogens, etc., modified

Figure 17. (a) Pyrazolone derivatives; (b) 1,4,6-trisubstituted pyrazolo[3,4-d]pyrimidines.


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compound 355h and 355f and showed remarkable antineoplastic activity. Increase inlipophilicity was attributed to methyl groups. Presence of fluoro-substituents andaromatic naphthalene rings were responsible for enhanced antineoplastic characterof the respective compounds.

Figure 18. (a) 3-Substituted-6-(3-substituted-1H-pyrazol-4-yl)[1,2,4] triazolo[3,4-B][1,2,4]thiaziazole; (b)

phenyl derivative of 1,4-dihydrobenzothiopyrono[4,3-C]pyrazole; (c) indeno[1,2-c]pyrazole derivatives;

(d) platinum and palladium complex of pyrazole.


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Via et al.[95] recently reported a phenyl derivative of 1,4-dihydrobenzothiopyrono[4,3-C]pyrazole. The compounds containing methoxy substituent at position 7 anda suspended phenyl p-chlorophenyl or p-methoxyphenyl at the 1-position of pyrazolering displayed significant antiproliferative activity (356b–d, Fig. 18b). On the otherhand, compounds without a phenyl moiety did not show antiproliferative activity(356a, 357b–d, Fig. 18b). Replacement of methoxy group at 7-position by chlorineeliminates the biological activity.

Medina et al.[96] investigated antitumor activity of indeno[1,2-c]pyrazolefused-ring system linked to other heterocycles, which encouraged Al-Saadi et al.[97]

to synthesize some fused pyrazole and pyrazoline derivatives. Compounds 360,

361a,b, 362a,b, and 364a (Fig. 18c) passed primary 3-cell line in vitro antitumorscreening. Compound 362a proved to be the most active antitumor agent. Pyrazolinederivative 359 was totally inactive, while its corresponding pyrazole analog 360

showed considerable antitumor activity against most of the tested subpanel tumorcell lines. Dihydrosulfonylurea derivative 361a (R1¼ cyclohexyl) and 361b

(R1¼ phenyl) did not show significant improvement in anticancer activity. On thecontrary, pyrazolesulfonyl urea 362a (R1¼ cyclohexyl) proved to be highly activeanalog of this series. Replacing cyclohexyl moiety in 362a with a phenyl one as in362b resulted about 2-fold decrease in activity (GI50¼ 16.2 and TGI¼ 53.7). Thiouraderivatives 363a,b were inactive. Cyclized products 364a showed some moderateantitumor activity.

Discovery of cisplatin as an anticancer drug[98] has provided the basis for thedesign of a wider range of metal-containing compounds with improved therapeuticprofiles. However, cisplatin use is very limited in regular exercise because of its sideeffects and the development of drug-resistant tumors. Hence there is a need forimproved platinum-derived drugs to overcome these limitations. In this respectKeter et al.[99] evaluate the potential anticancer properties of a series of pyrazolepalladium(II) and platinum(II) complexes, [(3,5-R2pz)2 PdCl2] [R=H (365),R=CH3(366)], and [(3,5-R2pz)2PtCl2] fR=H (367), R=CH3 (368)] (Fig. 18d).

Platinum complexes were shown to be considerably more active thanpalladium complexes. Complex 367 demonstrated the greatest cytotoxic and proa-poptotic activity, significantly greater than that of cisplatin. It has been shown thatbulkiness of pyrazole ligand increases activity and at least one NH moiety was foundnecessary for hydrogen bonding with DNA. It was concluded that small size of NHgroup, rather than its hydrogen bonding ability, was also responsible for betteractivity exhibited by platinum compounds comparable to multiple NH protoncarrier ligands. Cytotoxic activity of complex 367 (LD50¼ 20 mM) was three timeshigher than that of cisplatin.

Pyrimidinyl pyrazole analoge has been prepared and investigated for antican-cer activity.[100] A large number of structurally related congeners of pyrimidinylpyrazole have been made by changing the length of the carbon chain at the4-position and replacing the position of substitution at phenyl ring (Fig. 19a). In2002 Natto et al.[101] focused on the piprazine moiety and synthesized a new seriesof compounds replacing piprazine with pypirazinyl (Fig. 20b) or pipridinyl groups.Compounds 370a,e,f,j,l with a halogen atom at 3 or 5 position of benzene showed thegreatest activity, and bromine-substituted 370b and fluorine substituted at 2 position(370d) showed moderate activity. It has been shown that hydrogen-substituted


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compounds (371) were more active than CN, CH3, CF3, and NO2 substituted compound(370e,g,i). Pyperidinyl series (373a–l) displayed weak activity similar to compound372. Compounds 370a,e did not showed any side effect such as muscle relaxationor decrease of body temperature, observed with 372.

Later, Natto et al.[102] synthesized a series of pyrimidinyl pyrazoles, replacingpyrimidine and pyrazole moieties of A, B, and E with some heteroaryl moietiesand introduced various substituents to the phenyl ring. Compounds 375a–j showedsimilar activity to pyrimidin-2-yl derivative and it has been suggested that pyrimidin-2-yl and 3-chloropyridin-2-yl on ring were essential for potent activity. Methyl groupat 5-position of pyrazole was important for cytotoxicity and replacement of pyrazoleby imidazole or pyrole decreases activity. Among Compounds 377a–e bearing CN orCl group at the 3-position of phenyl, 377b,e showed increased or the same potencycompared with 374c. It has been investigated whether CN group at the 3-positionincreases the solubility of the compound. Iodo-substituted 377a was a weak analog,and on the other hand trifluromethyl (377d) was moderately active.

Figure 19. (a) Pyrimidinyl pyrazole derivatives; (b) compounds 370a–l, 371, and 372.


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Compounds 375g, 377b, 377c, and 377e showed strong in vitro cytotoxicactivity. Compound 377b showed superior effect at MTD than 374b, 374c, and5-FU on oral administration whereas 375g, 377c, and 377e were moderately active.These compounds displayed potent antitumor activity without causing undesirableeffects as observed in compounds 374b, 374c, and 374d (Fig. 20).

Abadi et al.[103] synthesized 1,3,4-trisubstituted pyrazole derivatives. Antitumorproperties of these compounds depend on the placement of the chlorine group at thepyrazole moiety. Compounds 380 and 381 bearing the 2-chlorobenzohydrazidemethylene substituent at the 4 position of the pyrazole ring were the only activecandidate in this series and benzohydrazide derivatives 378 and 379 were inactive.Compound 400 proved to be the most active derivative in every experiment. Inaddition, compounds 380, 382, 383, 384, 385, and 386 (Fig. 21a) were tested fortheir antiangiogenic properties by testing their ability to inhibit human umbilical veinendothelial cell (HUVEC) proliferation, cord formation, and migration in response tochemo attractant. Compound 380 was active in the 60 cell-line antitumor assayand against HUVEC proliferation but 382 showed significant antiangiogenic profile

Figure 20. (a) Compounds 374 and 375; (b) compounds 376 and 377.


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at noncytotoxic doses with HUVEC proliferation inhibition and was superior to thereference drug celecoxib.

DNA BINDING AGENTS

In 1994 Sessa et al.[104] synthesized tallimustine and investigated its antipro-liferative activity. It shows drug-like activity in primary studies. It displayedstrong activity against a series of several tumors but due to brutal myelotoxicity ithas withdrawn from phase 2 clinical trials.

Baraldi et al.[105] synthesized a series of cinnamoyl nitrogen mustard pyrazoleanalogs of tallimustine (388–392, Fig. 21b) in which amidino moiety was replaced bybasic (compounds 388–389) or nonbasic groups (compounds 390–392). Thesecompounds were first tested in vitro against L1210 murine leukemia cells.Compound 388 and N,N-dimethylamidine 387 (Fig. 21b) were equally active while

Figure 21. (a) 1,3,4-Trisubstituted pyrazoles; (b) cinnamoyl nitrogen mustard pyrazole analogs of

tallimustine.


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Figure 22. N-5,2-Di(a-aminoalkyl)-2,6-dihydropyrazolo[3,4,5-kl]acridine-5-carboxamides.


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imidazoline derivative 389 was less potent than 388 but more potent than 392. Thisindicated that a basic moiety was not required for activity. Among the pyrazolicderivative compound 388 displayed the greatest activity.

Early in 1997 Antonini et al.[106] discovered acridine derivatives (N-4)-x)]-1-aninoalkyl)-x-aminoalkyl)amino]acridione, which were potential antitumor agents.Antonini et al. in 2001[107] synthesized and investigated cytotoxicity of N-5,2-di(x-aminoalkyl)-2,6-dihydropyrazolo[3,4,5-kl]acridine-5-carboxamides (Figs. 22a and22b) and verified DNA binding of an additional pyrazole ring. Two highly DNA-affineand potent cytotoxic compounds 393d and 393e were identified against two anticancerdrugs mitoxantrone and doxorubicin. Except for 393a–c, all compounds possess goodantiproliferative activity. Compound 393d was more potent than both reference drugsfollowed by 393e (31 nM), which was comparable with doxorubicin. Pyrazole ring leadsto an increase in in vitro activity and DNA-binding ability. The most favorable distancebetween N atoms was 2-methylene groups; increasing the length decreases the activity asshown in 393f vs 393g, 393 h vs 393i, 393f vs 393a, and 393h vs 393e. Compounds 393j–kdisplayed lower cytotoxicity because of the unique substituent on the nitrogen of thecarboxamide side chain. Absence of substituent at terminal nitrogen 393l does not affectthe activity. Bulky substituents at terminal nitrogen (compounds 393m,o) did notdecrease cytotoxicity. Dimethyl group was the best substituent on terminal nitrogenof both side chains. Nitro group at the 9-position gives the best activity (393d,e).Replacement of nitro by amino group drastically decreases activity. Replacement ofhalogen by OH decreases potency of compounds. Among all compound (393d,e) wereinvestigated as new leads in antitumor drugs therapies.

Sugaya et al.[107] synthesized 7-substituted 6H-pyrazolo-[4,5,1-de]-acridin-6-ones (Fig. 23) with aminoalkyl-amino and hydroxyalkyl-amino groups in sidechain at C2 and C5 position, introducing a substituent at the 7-position. It wasfound that 7-hydroxypyrazoloacridones showed greater antiproliferative activity

Figure 22. Continued.


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than unsubstituted or 7-methoxy substituted compounds (394a vs 395, 396). Com-pound bearing CH2NH(CH2)nOH at C2 and NH(CH2)mNRR0 at C5 possess superioractivity than adriamycin at lower doses, increasing the number of methylene in the sidechain at C2 and C5 position decreases activity. Compounds 394b, 394c, 394d, and 394e

were also more effective than adriamycin with nearly the same dose. 7-Hydroxy andaminoalkyl-amino and hydroxyalkyl-amino groups in the side chain were importantfor their activity. Compound 394b was found most active in all aspects.

Capps et al.[108] prepared 2-aminoalkyl-5-nitropyrazolo[3,4,5-kl]acridines (Fig. 24).9-Hydroxy, 9-alkoxy, and 9-acyloxy analogs (397b–j) presented in vitro activity againstL1210 and human colon line HCT-8. Pyrazoloacridines 397awere potent DNAbinders,measuring displacement of ethidium from calf thymus DNA and showed selectivityagainst colon carcinoma 38 and pancreatic carcinoma relative to leukemia.

Figure 23. 7-Substituted 6H-pyrazolo-[4,5,1-de] acridin-6-ones.


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CONCLUSION

Study discloses that pyrazoles with substituents in the 3-position that areelectron releasing, or more accurately with an amine group at the 3-position and arylor alkyl group, possess good activity with or without subsistuent at the N1-position.

Figure 24. 2-(Aminoalkyl)-5-nitropyrazolo[3,4,5-kl]acridines.


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Lipophilic substituent at the 4-position of the pyrazole ring with a methylenechain was found favorable for binding at different protein kinases, which play crucialroles in cancer drug treatment. Despite the synthesis and testing of untold numbersof pyrazole analogs, it is clear that we still do not have an ideal set of congeners toproperly define the structure–activity relationship although many different biologicaltests have been devised to assess their activity. Even if pyrazole derivatives haveachieved significant clinical benefit for many solid tumors, their effectiveness hasbeen limited by toxic side effects. This drug discovery story has taught us thatpyrazole compounds could have an important role in chemotherapy.

In summary, the science of the pyrazole has reached a sophisticated level.Therefore, it is anticipated that future research about pyrazole will be focused mainlyon improving its capability to be used as a new drug candidate for cancer treatment.

NOMENCLATURE

BCR-Abl breakpoint cluster region–Abelson

CDK cyclin dependent kinase

CML chronic myelogenous leukemia

CNS central nervous syntem

COX cyclo-oxygenase and

EGFR Epidermal growth factor receptor

GI50 median growth inhibition

HSP heat shock protein

IC50 half-maximal inhibitory concentration

ID 50 median infective dose

LC50 median lethal concentration

LOX lipo-oxygenase

MDR multidrug-resistant

MG-MID mean graph midpoint

MTT 3-(4,5-dimethythiazol-2-yl)-2,5-diphenyl tetrazolium bromide

PGs prostaglandins

SAR structure–activity relationship

TGI tumor growth inhibition=total growth concentration

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Documents

Anticancer Activity of Pyrazole via Different Biological Mechanisms