Cytotoxic Anticancer Candidates from Natural Resources

Curr. Med. Chem. - Anti-Cancer Agents, 2002, 2, 485-537 485

1568-0118/02 $35.00+.00 © 2002 Bentham Science Publishers Ltd.

Cytotoxic Anticancer Candidates from Natural Resources

Jinwoong Kim* and Eun Jung Park

College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742,Korea

Abstract: Natural products have been regarded as important sources that could produce potential chemotherapeuticagents. Over 50% of anticancer drugs approved by United States Food and Drug Administration since 1960 wereoriginated from the natural resources, especially from terrestrial plants. Based on cytotoxicity bioassay, over 400compounds have been isolated from plants, marine organisms and microorganisms from the period of 1996 to 2000.Recently, interest of natural product research has slowly moved to marine organisms. As a result, almost 50% of reportedcytotoxic compounds were isolated from marine organisms such as sponges and corals. Also, traditional cytotoxiccompounds of acetogenins, alkaloids and terpene skeletons have been reported continuously. In this review, we willpresent the cytotoxic compounds obtained from natural sources from 1996 to 2000, and the structures and cytotoxicactivity of natural compounds isolated from territorial, marine and microorganism resources.

BACKGROUND

Since the nitrogen mustard has been used for ananticancer agent in 1940s, FDA approved 87 anticancerdrugs for clinical trial through 1994. Among them, 62% ofanticancer drugs were derived from natural products directlyor semi-synthetically. Moreover, of the 300 pre-NDA (NewDrug Application) anticancer drug candidates, 61% areoriginated from terrestrial plants, marine, and microbialresources [1]. In other words, over the half of anticancerdrugs were produced in the natural products, especially fromthe plant kingdom. This fact suggests that natural sources arevery important research target in the market of drugdiscovery. Actually, traditional medicine, largely based onterrestrial plants, currently has a place in 85% of thetreatment regimens utilized by the inhabitants ofunderdeveloped countries, which means above 79% of theworld’s population rely on the traditional medicines to someextent [2].

There are four systematic approaches for the selection ofplants that may contain new biological agents; random,taxonomic, phytochemical and ethnomedical. The mostrational method of proceeding involves evaluation ofmaterials in a range of bioassays. Active leads are thenprioritized, and those estimated most active are subjected tobioassay-directed fractionation procedures for procurementof the active principles [3]. A broad overall scope ofbioassay capability has been retained, including a battery ofhuman tumor cell lines.

Cytotoxic activity is based on the research of anticancerdrugs. Representative activities of currently used importantanticancer drugs were mostly cytotoxicity which, simply

*Address correspondence to this author at the College of Pharmacy andResearch Institute of Pharmaceutical Sciences, Seoul National University,Seoul 151-742, Korea; Tel: +82-2-8807853; Fax: +82-2-887-8509; E-mail:[email protected]

stating, was related to reduce the cancer cells in our body.Though cytotoxicity is neither necessary nor sufficient forantitumor activity, it is consistent with antitumor activity.Interference with any mechanism required for cell survivalwill mediate a positive response. Based solely on non-specific cytotoxicity activity, a plant will generally be givena high priority. After bioactivity-guided fractionation,selected cytotoxic agent could certainly be a candidate formore advanced testing. The concept of selective cytotoxicityimplicitly suggests the presence of a cell-specific receptorthat differentiates one tumor-type from another. Such adiscovery would be of exceptional interest in terms ofdeveloping tumor-specific therapeutic strategies, and acytotoxic agent specific for one cell-type would greatly aidin identifying the appropriate subcellular target. The latestanticancer drug, taxol was also found based on its activitythrough cytotoxic activity screening system.

In this review, we will present the cytotoxic compoundsisolated from natural sources from 1996 to 2000. The aim ofthis report is to list all the structures and cytotoxicity againstcancer cell line of natural compounds isolated fromterrestrial, marine and microorganism resources. The methodof search is mainly based on MedLine, especially, Journal ofNatural Products, Phytochemistry and Planta Medica.

PLANT DERIVED CYTOTOXIC COMPOUNDS

Traditional natural products came from terristrial plantssince our ancestors used plants as a source of medicine.There are many references about medicinal plants in Westernand Eastern Society, such as the first Mesopotamia record(2600 BC), Ebers Papyrus (1500 BC), Materia Medica (1100BC), Shennong Herbal (100 BC) [4]. It means that theinformation about the clinical trials using medicinal plants isa useful approach in the selection of bioactive principles.Before the interest shifted to marine organisms, most activeprinciples such as taxol, Vinca alkaloid, podophyllotoxin,and camptothecin were isolated from plants.

486 Curr. Med. Chem. – Anti-Cancer Agents, 2002, Vol. 2, No. 4 Kim and Park

ACETOGENINS

Since 1980, reported numbers of acetogenins havereached to nearly 200 because of their strong cytotoxicity.There is a remarkable review about the classification andresources of Annonaceae acetogenin until 1996 by Zafra-Polo et al. [5]. The action mechanism of the acetogenin hasbeen known as inhibition of mitochondrial NADPH:

ubiquinone oxidoreductase [6,7]. Several annonaceousacetogenins with emphasis have been studied in more detailon the action mechanism of complex 1 of the mitochondrialrespiratory chain, as useful compounds in the biochemical,medical, pharmaceutical and agrochemical fields.

There are 40 new cytotoxic acetogenins isolatedAnnonaceae (Table 1, Table 2). The acetogenins from

Table 1. Cytotoxic Acetogenins Isolated from Plants Between 1996 to 2000

Source Compound Ref.

Annona coriacea coriaheptocin A 1 8

coriaheptocin B 2

coriadienin 3 9

A. glabra annoglaxin 4 10

27-hydroxybullatacin 5

A. muricata annomuricin E 6 11

muricapentocin 7

muricoreacin 8 12

murihexocin C 9

A. purpurea purpurediolin 10 13

purpurenin 11

purpuracenin 12 14

A. spinescens carolin A 13 15

carolin B 14

carolin C 15

A. squamosa 4-deoxyannoreticuin 16 16

cis-4-deoxyannoreticuin 17

(2,4-cis and trans)-squamoxinone 18

mosinone A 19 17

Asimina triloba asitrilobin A 20 18

asitrilobin B 21

bullatetrocin 22 19

10-hydroxyasimicin 23

10-hydroxytrilobacin 24

Goniothalamus giganteus (2,4-cis and trans)-gigantecinone 25 20

4-deoxygigantecin 26

goniotetracin 27 21

(2,4-cis and trans)-gonioneninone 28

Rollinia mucosa membranacin 29 22

desacetyluvaricin 30

rollinecin A 31 23

rollinecin B 32

Uvaria calamistrata calamistrin A 33 24

calamistrin B 34

calamistrin C 35 25

calamistrin D 36

calamistrin E 37

calamistrin F 38

calamistrin G 39

U. tonkinesis tonkinecin 40 26

Cytotoxic Anticancer Candidates from Natural Resources Curr. Med. Chem. – Anti-Cancer Agents, 2002, Vol. 2, No. 4 487

Table 2. Cytotoxicity of Acetogenins

Cell line (IC50, µg/ml)

cpd

9KB A498 A549 HT29 KB MCF-7 PACA-2 PC-3 VERO

1 0.63

2 0.18

3 2x10-6 0.15

4 1.80 1.10 0.18 4x10-4 1.60 0.87

5 3x 10-8 0.023 2x10-5 8x10-4 <10-9 <10-9

6 1.41 0.12 0.07 1.45 0.02 0.15

7 1.72 0.19 0.07 1.90 0.05 0.45

8 0.71 0.23 0.57 1.30 2.30 0.03

9 2.50 1.10 1.30 3.80 0.49 0.86

10 1.36 0.44 <10-7 0.92 1.44 0.35

11 1.25 1.29 0.32 1.67 1.98 1.07

12 <0.001 0.05 <10-3

13 10-7 0.002

14 5x10-6 0.004

15 2x10-4 0.05

16 2.23 3.87 1.69 2.23 2.88 2.66

17 1.84 1.99 1.42 1.74 1.09 2.08

18 1.48 1.89 1.44 1.71 4x10-3 2.22

19 2x10-3 0.03

cpd A2780 A298 A498 A549 HCT-8 HT29 KB MCF-7 PACA-2 PC-3

20 2.78 0.004 2.09 0.002 4x10-5 2.28

21 2.19 0.002 0.44 0.002 3x10-4 1.06

22 >1 0.35 3x10-5 0.50 >1 >1

23 >1 0.67 0.0075 0.33 >1 0.53

24 0.01 10-8 1.39 2x10-8 0.20 0.38

25 0.21 0.21 >1 >1 >1 0.001

26 0.33 0.13 0.14 1.00 0.39 0.15

27 1.50 0.39 1.50 1.70 0.03 0.21

28 2.20 1.80 2.90 3.70 0.05 1.50

29 <10-3 0.40 3.04 2.18 2.10 <10-3

30 <10-3 0.47 1.69 1.35 1.92 <10-3

31 7x10-4 10-4 1.60 1.44 3x10-5 3x10-4

32 2x10-4 4x10-4 1.44 2.72 3x10-4 4x10-4

33 1.40 0.37 2.00


(Table 2) contd….

cpd A2780 A298 A498 A549 HCT-8 HT29 KB MCF-7 PACA-2 PC-3

34 3.10 0.02 6.10

35 0.003 0.005 0.06

36 0.43 0.07 0.03

37 0.03 0.004 0.38

38 0.04 0.05

39 0.002 0.02

40 0.38

Annonaceae usually possess between two and five hydroxygroups, two of them generally flanking the tetrahydrofuranring and the others being distributed along the fatty acidchain. The unusual seven hydroxyls acetogenin,coriaheptocin A 1 and coriaheptocin B 2 were isolated fromAnnona coriacea [8]. Tropical tree A. glabra (commonname, pond-apple) used in traditional medicine as aninsecticide and a parasiticide contained annoglaxin 4 and 27-hydroxybullatacin 5, which were very toxic against severalhuman cancer cell lines, A498, A549, HT29, and MCF-7[10]. Purpurediolin 10 and purpurenin 11 were isolated fromthe seeds of A. purpurea, fruits of which are used as remedyfor fevers and colds in folk medicine. Purpurediolin 10showed strong cytotoxicity (IC50, < 10-7 µg/ml) againstHT29, selectively [13].

The new bistetrahydrofuran acetogenins, carolins A-C13-15, which were isolated from A. spinescens showed thecytotoxicity on KB and Vero cell lines [15]. Amongbullatetrocin 22, 10-hydroxyasimicin 23, and 10-hydroxy-trilobacin 24 isolated from Asimina triloba, 24 selectivelyexhibited cytotoxicity against A549 and MCF-7 [19].

Membranacin 29, desacetyluvaricin 30 [22] and twocytotoxic acetogenins, rollinecins A 31 and B 32 [23] wereisolated from the seeds and the leaves of Rollinia mucosa,respectively. Total seven of calamistrins A-G 33-39 whichwere isolated from Uvaria calamistrata, which is a climbingshrub distributed in China, exhibited strong cytotoxicityagainst human cancer cell lines, A2780, KB and HCT-8[24,25].

ALKALOIDS

Traditionally, alkaloids are well known to producebiologically active principles, and anticancer alkaloids,vinblastine 41 and vincristine 42, isolated fromCatharanthus roseus, and two other related alkaloids,vinleurosine 43 and vinrosidine 44 led to semi-syntheticcompounds being approved in Europe for the cancertreatment, viz. vinorelbine 45 and vindesine 46.

Since 1996, there have been several cytoxic alkaloidsisolated from Annonaceae, Meliaeae, Rubiaceae, andCephalotaxaceae (Table 3). The genus Cephalotaxus

(Cephalotaxaceae) has long been known to contain theantileukemic ester alkaloids, harringtonin and its congeners.Three harringtonin derivatives, 11α-hydroxyhomodeoxy-harringtonin 47, 11β-hydroxyhomodeoxyharringtonin 48 and11β-hydroxydeoxyharringtonin 49 were isolated from C.harringtonin var. drupacea and showed cytotoxicity againstP388 leukemia cells but were less cytotoxic thandeoxyharringtonin 50 (IC50, 0.0075 µg/ml) [27]. Aglafolin51 and rocaglamide 52 were isolated from the stems ofAglaia elliptifolia (Meliaceae). These compounds wereknown as 1H-2,3,3a,8b-tetrahydrocyclopenta[b]benzofuranalkaloids, and exhibited cytotoxicity against cancer cell linesas well as acted as selective and effective inhibitor of plateletaggregation induced by platelet-activation factor both invitro and in vivo [28]. Pogonopus species (Rubiaceae)contained bioactive alkaloids, 1',2',3',4'-tetrahydrotubulosine53, tubulosine 54 and psychotrine 55. Especially, tubulosine54 showed significant cytotoxicity against human cancer celllines [29].

A new oxoprotoberberine alkaloid, (-)-8-oxopolyalthiaine56 was isolated from Polyalthia longifolia (Annonaceae)along with 5-hydroxy-6-methoxyonychine 57 and 6-hydroxy-7-methoxyonychine 58, which exhibited significantcytotoxicity against human gastric and hepatoma cells [30].The six phenolic aporphine-benzylisoquinoline alkaloids, 3-hydroxy-6'-desmethyl-9-O-methylthalifaboramine 59, 3-hydroxythalifaboramine 60, 6'-desmethylthalifaboramine 61,3,5'-dihydroxythalifaboramine 62, 5'-hydroxythalifabor-amine 63 and 3-hydroxy-6'-desmethylthalifaboramine 64were isolated from the roots of Thalictrum faberi which wereused to treat stomach cancer. Similar to other thalifaberine-type aporphine-benzylisoquinonline alkaloids, all of thesealkaloids showed cytotoxicity [31].

TERPENOIDS

1. Triterpenoids (Table 4)

Several triterpene esters from the hooks of Uncariarhynchophylla (Rubiaceae) showed inhibitory activity ofphospholipase Cγ1 and cancer cell proliferation [32].Uncarinic acids A-E 65-69 showed dose-dependentinhibitory activity of cancer cell proliferation. Trevesia


1: A (erythro)2: A (threo)

9

8

7

6

5

4

3

O

OH

OH

OH

OH OH

O

OOH

O

OH

OH

OH

OH OH OH

O

O

O

OH OH

OH OH OH

O

O

O

OH OH OH

OH OH

O

O

O

OH

O O

OH

OH

O

OH

O

O

OH OHOH

OHO

O

O

O

OHOH

OH

OH

O

O

O

OH

OHOHOHOHOH

OH

A


A

16: A (trans)17: A (cis)

13: R1 = OH, R2 = H14: R1 = H, R2 = OH

19

18

15

21

20

12

11

O

OH OH

OH

O

OH

O

O

OH OH

OH

O

OH

O

O

OHOH O

OO

O

O

OH OH OHO O

O

O

OH OH OH

O

O

O

O

O O

OH OH OH

OO O

O OH OH R1

R2

O O

OH OH

O

OH

O

OH

O O

OHOH

OHOH

O

O

10

O O

OHOHOH

OHO

O


31: 14R32: 14S

22

30

24

23

29

28

27

26

25

O OO

OOHOHOH

OH

O OO

OOHOH

OH

O O

OHOH

O

O

OH

O O

O OO

OH OHOH

O O

OH OHOH

O

O

O

OH OH

OH

O

OH

O

OH

O

OH

OH

O O

O

O OO

OOH OH

O OO

OOH OH

O

O

O

OH

OH

OH

OH

OH

OH


palmate (Araliaceae), a plant native to India, has been usedin folk medicine as a general tonic. Six new oleananesaponins 70-75 from this plant exhibited strongcytotoxicities against J774, HEK-293 and WEHI-164 [33].

The barks of Physena madagascariensis (Capparaceae)are rubbed on clothing to repel terrestrial leeches effectively.Three new dinoroleanane derivatives 76-78 were isolated,and it was found that remangilone A 76 and remangilone C78 were active against human mammary epithelial cells [34].Newly isolated triterpene saponins, oleanolic acid 3-O-{O-β-D-glucopyanosyl-(1→4)-O-β-D-glucopyranosyl-(1→3)-O-α-L-rhamnopyranosyl-(1→2)-α-L-arabinopyranoside} 79 andoleanolic acid 3-O-{O-β-D-glucopyanosyl-(1→4)-O-β-D-glucopyranosyl-(1→3)-O-α-L-rhamnopyranosyl-(1→2)- O-β-D-glucopyranosyl –(1→4)}-α-L-arabinopyranoside} 80

showed cytotoxicity against HL-60 cells [35]. From the rootbarks of Hibiscus syriacus used as an antipyretic,anthelmintic, and antifungal agent, two new triterpenecaffeates were isolated. 3β,23,28-trihydroxy-12-oleanene 23-caffeate 81 and 3β,23,28-trihydroxy-12-oleanene 3β-caffeate82 showed cytotoxicity against several cancer cell lines [36].Argentinic acids A-I 83-91 were isolated from the bark ofAglaia argentea and showed moderate cytotoxic activityagainst KB cells (IC50 1-3.5 µg/ml) [37]. Holarrhena(Apocynaceae) are known to provide mainly steroidalalkaloids of the aminopregnane type. Five new steroidalalkaloids 92-96 have been obtained from H. curtisii withholacurtine 97, N-demethylholacurtine 98 and holamine 99.These compounds showed significant cytotoxic andleishmanicidal activities [38]. A new bisdesmosidicspirostanol saponin, aculeoside B 100 , has been found from

O

O

OOH OH OH

O

OH OH OH

O

O

O O

O

OH OHOH

O

O O

O

OHOH OH O

OO

OHOH OH O

O

O

OH OH OH O

O

O

OH OH OH

O

O

OOAc OHOH

33

34

40

39

38

37

36

35


Table 3-I. Cytotoxic Alkaloids Isolated from Plants Between 1996 and 2000


cpd ref

A549 BC1 Col2 HCT-8 KB LNCap Lu1 M109

47 27

48

49

51 28 <0.001 0.005 <0.001

52 0.01 0.007 0.006

53 29 3.9 2.8 2.20 6.80 3.6 4.4

54 0.1 0.05 <0.16 <0.16 <0.001 0.1

55 3.4 4.5 2.8 2.30 5.7 9.0

59 31 2.7 4.70 4.6

60 1.8 6.20 3.3

61 1.8 4.00 5.4

62 0.5 9.20 2.9

63 0.8 11.2 3.8

Table 3-II. Cytotoxic Alkaloids Isolated from Plants Between 1996 and 2000


cpd ref

M109 P388 RPMI7951 SKNSH SW620 TE-671 ZR-75-1

0.38

48 0.33

49 0.17

51 28 0.002 <0.001 <0.001

52 0.005 0.002 0.006

53 29 4.4 4.0 6.1

54 0.1 0.1 0.22

55 9.0 4.0 13.3

59 31 1.9

60 2.8

61 2.3

62 3.4

63 3.0


N

N

MeO

Me H

H

OAc

OHMeO2 C

Me

N

N

Me

OH

MeO2 C

H

N

N Me

H

MeO2 C

H

N

N

MeO

Me H

H

OAc

OH

MeO2 C

Me

OH

N

N Me

H

MeO2 C

H

N

N

MeO

Me H

H

OAc

OH

H2NOC

Me

N

N Me

H

MeO2 C

H

N

N

MeO

Me H

H

OH

OHMeO2 C

Me

OH

N

O

OH

HOMe

R1O

R2

O

O

MeO

HO

O

O

MeO

OH

O

MeO

OOH

N

O

OH

HOMe

O

R2

O

OMe

O

45

R1 = R2 = α-OH

R1 = R2 =β-OH

47

48

46

R2 =β-OH

50

N

N

MeO

OHCH

H

OAc

OH

MeO2 C

Me

N

N

Me

OH

MeO2 C

H

44

49 R1 =

H H

41 42

N

N Me

H

MeO2 C

H

N

N

MeO

Me H

H

OAc

OHMeO2 C

Me

O

43


5857

5654 55

5352

O

OMe

MeO

HOH

HOH

CO2Me

H

OMe

O

OMe

MeO

HOH

CNMe2

H

OMe

OH

N

NN

OH

MeO

MeO

H

H

H

HN

N

HN

OH

MeO

MeO

H

H

H

N

N

MeO

MeO

H

H

OH

OMe

NHO

MeO

H

O

OH

OMe

OH

NMeO

OH

O

NHO

OMeO

NMe

O

NMe

H

R

R1O

MeO

R2

MeO

MeO

MeO

OR3

H

H

51

O

59 : R=R1 =H, R2=OH, R3=Me60 : R=R3 =H, R1=Me, R2=OH61 : R=R1 =R2 =R3=H62 : R=R2 =OH, R1=Me, R3=H63 : R=OH, R1=Me, R2=R3=H64 : R=R1 =R3 =H, R2=OH


Table 4-I. Cytotoxic Triterpenes Isolated from Plants Between 1996 and 2000

Cell line (IC50, µg/ml)cpd ref

A549 HCT-15 HEK293 HL-60 HT1197 J774 MCF-7 MDA-MB-435 MDA-MB-231 WEHI164

65 32 0.7 1.4 3.5 2.0

66 1.8 1.4 2.3 2.6

67 6.5 1.9 5.8 5.9

68 2.8 2.5 4.4 0.6

69 2.4 2.8 3.2 0.6

70 33 0.17 0.18

71 0.52 1.8

72 0.2 0.1

73 0.46 1.9

74 0.15 0.11 0.24

75 0.32 0.1 0.26

76 34 3.7 2.9

78 0.9 0.7

79 35 2.6

80 2.7

Table 4-II. Cytotoxic Triterpenes Isolated from Plants Between 1996 and 2000


ACHN HCT-15 HL-60 KB MCF-7 NCI-H23 PC-3 P388 SF539 SW620 UACC62 UO-31

81 36 1.2 0.8 2.2 2.8 1.6 1.4 1.1 3.9 2.0

82 2.1 1.3 1.8 1.7 2.2 2.0 1.0 2.3 1.7

83 37 2.0

84 2.0

85 2.0

86 1.0

87 3.5

88 2.0

89 2.5

90 2.0

92 38 0.01

93 0.21

94 2.6

95 10.1 3.6

96 1.2 4.1

105 40 3.8

106 41 4.8

122 45 1.5


underground parts of Ruscus aculeatus together withaculeoside A 101 which exhibited cytotoxic activity againstHL-60 cells with an IC50 value of 0.48 µg/ml [39]. Fournovel triterpene compounds, celasdins A-C 102-104 andmaytenfolone A 105 were isolated from Celastrus hindsii.Only 105 showed cytotoxicity against hepatoma andnasopharynx carcinoma [40].

Pulsatilla chinensis is one of the most importantmedicinal plants in traditional Chinese medicine. From theroots, three lupane-type triterpenoids glycosides wereidentified. Pulsatillic acid 106 showed cytotoxic activitiesagainst P388, Lewis lung carcinoma and human large celllung carcinoma [41].

787776

R R1 R2 R3

70: Glc (1 3)-Rha (1g 2)-Ara Glc (1 3)-Rha (1 4)-Glc (1 6)-Glc Me H

71: Glc (1 3)-Rha (1g 2)-Ara Rha (1 4)-Glc (1 6)-Glc Me H

72: Qui (1 2)-Ara Rha (1 4)-Glc (1 6)-Glc Me H

73: Qui (1 2)-Ara Rha (1 4)-Glc (1 6)-Glc CH2OH H

74: Glc (1 3)-Rha (1g 2)-Ara Rha (1 4)-Glc (1 6)-Glc Me OH

75: Glc (1 3)-Rha (1g 2)-Ara Rha (1 4)-Qui (1 6)-Glc CH2OH H

(2g 1)-Glc

67: R1 = E-feruloyl68: R1 = Z-feruloyl69: R1 = p-E-coumaroyl

65: R1 = E-feruloyl66: R1 = Z-feruloyl

COOHH

HOR1

COOHH

HOR1

R3

R2

COOR1

RO

HO

O

O

OHH

HO

O

O

HH

O

OHH

HO

O

H

→→→→→→

→→→→→→

→→→→→

→→→→→→→

R R1 R2 R3

70: Glc (1→3)-Rha (1g 2)-Ara Glc (1→3)-Rha (1→4)-Glc (1→6)-Glc Me H

71: Glc (1→3)-Rha (1g 2)-Ara Rha (1→4)-Glc (1→6)-Glc Me H

72: Qui (1→2)-Ara Rha (1→4)-Glc (1→6)-Glc Me H

73: Qui (1→2)-Ara Rha (1→4)-Glc (1→6)-Glc CH2OH H

74: Glc (1→3)-Rha (1g 2)-Ara Rha (1→4)-Glc (1→6)-Glc Me OH

75: Glc (1→3)-Rha (1g 2)-Ara Rha (1→4)-Qui (1→6)-Glc CH2OH H

(2g 1)-Glc


From the bulbs of Allium jesdianum (Liliaceae), twocholestane glycoside and two spirostanol glycosides 107-110were isolated and (25R)-5α-spirostane-2α,3β-diol 3-O-{O-β-D-glucopyranosyl-(1→2)-O-[β-D-xylopyranosyl-(1→3)]-O- β - D - glucopyranosyl - (1→4) - β-D-galactopyranoside}(F-gitonin) 109 was found to exhibit cytostatic and cytotoxicactivities against several malignant tumor cells [42].

Meliaceous plants were good source of limonoids, whichshowed antifeedant, cytotoxic, antiviral activities.Chinaberry tree (Melia toosendan) has been recognized as aninsecticidal and medicinal plant in China. A number oftriterpenes and limonoids have been isolated from the fruitsof this plant that are used for the treatment of malaria andstomachache. Two new limonoids, toosendanal 111 and 12-

R2 =OH82: R1=

81: R1=OH, R2=

79: R1 = H80: R1 =β-D-glcp

H

COOH

H

HO

O

OR1

HOO

OMe

HOO

OHO

OH

HO

HOO

O

OHHO

HO

HO

R1

CH2OH

R2-H2 C

O

OH

OH

O

O

OH

OH

O

86: R1=c, R2=a87: R1=c, R2=b88: R1=b, R2=a89: R1=R2=a90:R1=R2=c

83: R1=a84: R1=b85: R1=c

O

OH

H

HH

OR1

H

MeO2 C

O

OH

H

HH

OR1

H

R2O

MeO2 C

OH

O

aOH

O

bH

O

c


92: R1 = Me, R2 = β-H93: R1 = H, R2 = β-H97: R1 = Me, R2 = α-H98: R1 = H, R2 = α-H

100

96: R=OH99: R=H9594

91

O

H

HH

O

OCOMeO

H3 C

O

H

O

O Me

Me

OH

HMe

O

H

OH

OMe

H

N

Me

H

H

R2

R1

H

O Me

Me

OH

HMe

H

HH2N

O Me

Me

HMe

H RH

H2N

O O

O

OO

O

HO

OOHO

OH

OH

OH

O

O

O

O

O

O

OHO

HOMe

O

HOOH

HO

HO

O Me

Me

OH

HMe

O

H

OH

OMe

H

N

Me

HOH

H2

101

O OO

O

HO OHO

OH

Me

OO

OH

HOO

O

O

Me

OO

OMe

OMe

O

Me

HO


112111

109: R=H110: R=OH

107: R= β-D-Glcp108: R =α-L-Rhap106

105104

103102

OO

OMe

H

OHAcO

O

O

H

HO

O

O

O

AcO

OO

HOH

H

OAc

H

OHO

HOOH

HO

O

HO

O

HO

OOHO

HOOH O

OH

OHHO

O

O

O

O

RH

HO

OH

OR

HO

O OHO

OH

OH

OHO

OH

CH2OH

O

O

O

H

O

OH

H

O O

OH

H CH2OH

OH

O

CH2OH

H

OH

O


O-methylvolkensin 112 along with three known limonoids,meliatoxin B1 113, trichilin H 114, and toosendanin 115have been identified and the last two compounds showedcytotoxicity against KB cells [43]. Among four meliacin-type limonoids isolated from Azadirachta excelsa, nimbolide116 and 28-deoxynimbolide 117 were broadly cytotoxic, buttwo new compounds, 2,3-dihydronimbolide 118 and 3-deoxymethylnimbidate 119, were not active [44]. Fromanother meliaceous plant, Melia azedarach, azadirachtinderivatives and sendanin analogues werefound. Among four new 1-tigloyl-3,20-diacetyl-11-methoxymeliacarpinin 120, 3-tigloyl-1,20-diacetyl-11-

methoxymeliacarpinin 121, 1-cinnamoyl-3-hydroxy-11-methoxymeliacarpinin 122 and 1-deoxy-3-methacrylyl-11-methoxymeliacarpinin 123, 1-cinnamoyl-3-hydroxy-11-methoxymeliacarpinin 124 showed cytotoxicity against P388[45].

2. Diterpenoids (Table 5)

The representative diterpene anticancer compounds aretaxol and its derivatives. Paclitaxel 125 is a clinicaltherapeutic agent against certain human solid tumor, such as

120: R1=OTig, R2 =R3=OCOMe121: R1=R3=OCOMe, R2=OTig122: R1=OCin, R2=R3=OH123: R1=H, R2 =OCOC(Me)=CH2, R3 =OH124: R1= OCin, R2= OCOMe, R3= OH

125

Cin

Tig

118: R1=O, R2 =O119: R1=α-OH, R2=H2

116: R1 = O117: R1 = H2

115114113

O

O

O

AcO

O

HOH

H H

HO

AcO

O

COCHMeC2H5

O

O

AcO

O

HOH

H

HO

AcO

O

COCH(Me)2

OAc

O

O

O

AcO

O

HOH

H

HO

HO

OAc

O

O

O

MeO2 C

HO

R1

O

O

R1

MeOOC

HO

R2

R2

R1CH3

O

O

O

O

Me

CO2Me

O

Me

R3

OH

OMe

Me Me

O

O

O

OH

ONH

Ph

Ph

O

OHOAcO

OHH

OAc

O

OCOPh


ovarian and breast cancers. Though paclitaxel is used widelyas a drug of choice on these cancers, there are still manypapers reporting structually related taxol-like compoundsand their mechanisms [46].

From the fresh barks and the dried barks with stems ofWikstroemia retusa, minor four daphnane-type diterpeneswere obtained along with wikstroelides H-K 126-129, inaddition to wikstroelides A-G 130-136, which showedcytotoxicity against P388 cells [47].

Cedronolactones A-D 137-140, new quassinoids, havebeen isolated from the wood of Simaba cedron(Simaroubaceae) and cedronolactone A 137 was shown toexhibit a significant in vitro cytotoxicity (IC50, 0.00074µg/ml) against P388 cells [48].

Three new ent-kauranoids, xerophilusins A-C 141-143,have been identified from the leaves of Isodon xerophilis(Labiatae), and 141 and 142 exhibited significantcytotoxicities against K562, HL-60, and MKN-28 cells [49].

Four new cytotoxic 8,9-secokauranes 144-147 and threekauren-15-one 148-150 have been identified from theliverwort Lepidolaena taylorii. The oxygenation at C-11found in three of these diterpenes has not been encounteredpreviously from the 8,9-secokauranes from higher plants.Liverworts are the structurally simplest of the terrestrialplants, but they contain a complex array of secondarymetabolites. 8,9-Secokaurane, rabdoumbrosanin 151, is themain cytotoxic compound with the less active dihydro- andepoxy- derivatives present at lower concentration [50].

3. Sesquiterpenoids (Table 6)

Sesquiterpene lactone is a large group of natural productswith many types of biological activities such as cytotoxic,antitumor, antiphlogistic, antimicrobial, and antiplasmodialactivities. The functional groups such as α,β-unsaturatedcarbonyl functions, conjugated esters, epoxides, or additionalalkylating groups may enhance the cytotoxic activity.

Compositae (Asteraceae) is a good resource to obtainsesquiterpene lactones. The eudesmanolide sesquiterpenelactones, malacitanolide 152 [51] and 4α,6α-dihydroxyeudesman-8β,12-olide 153 [52] were isolated fromCentaurea malacitana and Inula britannica, respectively.Two new germacranolides, 9α-hydroxy-1β,10α-epoxypar-thenolide 154 and parthenolid-9-one 155 have been found inAnvillea garcinii [53] and five xanthanolide derivatives 156-160 and nerolidol derivative 161 have been identified inRatibida columnifera [54]. The hypocretenolides are belongto a small group of sesquiterpene lactones with an unusualring structure. Three guaianolides of the hypocretenolide-type, 14-hydroxyhypocretenolide 162, its glycoside 163, and14- hydroxyhypocretenolide- β- D- glucoside- 4',14''-hydroxy-hypocretenoate 164 were isolated from Leontodon hispidus[55].

Some interesting trichothecenes sesquiterpenes have beenfound in Holarrhena floribunda (Apocynaceae). Amongthese similar structures, 8-dihydroxytrichothecinol A 165and trichothecinol A 166 were showed significantcytotoxicities against KB, SK-MEL 30, A549 and MCF-7cells [56].

Table 5. Cytotoxic Diterpenes Isolated from Plants Between 1996 and 2000


cpd ref

HL-60 P388

127 47 0.048

128 0.005

130 0.0025

133 0.04

134 0.0008

137 48 0.00074

142 49 0.29

144 50 0.70

145 1.20

146 0.35

147 0.17

148 0.30

149 0.22

150 0.8


From liverworts, Chiloscyphus rivularis [57] andBazzania novae-zelandiae [58], several new sesquiterpeneswere isolated such as 12-hydroxychiloscyphone 167,chiloscypha-2,7-dione 168, 12-hydroxychiloscypha-2,7-dione 169, chiloscypha-2,7,9-trione 170, rivulalactone 171from C. rivularis and naviculyl caffeate 172 and naviculol173 from B. novae-zelandiae.

FLAVONOIDS AND LIGNANS (TABLE 7)

The genus Selaginella is rich in biflavonoids and some ofthe plants of this genus are used extensively in Chinese

traditional medicine in the treatment of cancer, gastritis,hepatitis, and cardiovascular diseases. Four newrobustaflavone derivatives 174-177 were isolated from S.delicatula (Selaginellaceae) and showed mild cytotoxicitiesagainst lymphoma and leukemia cell lines [59]. Additionally,ginkgetin 178 isolated from S. moellendorffii, showedselective cytotoxicity against OVCAR-3 [60]. Three newdihydroflavonols, gericudranins A-C 179-181 were isolatedfrom the stem barks of Cudrania tricuspidata, cortex androot barks of which are used as a traditional medicine foranti-neuritis and anti-inflammation. Gericudranin A 179 andB 180 showed cytotoxicities against skin tumor and


144: R = Ac, R1 = R2 = H145: R = Ac, R1 = OH, R2 = H146: R = H, R1 = OAc, R2 = H147: R = H, R1 = OH, R2 = H

152151

143142

141140

139138137

148: R = OH149: R = OAc150: R = H

O

O

O

OH

H

O

H

OHO

OH

H

HO

O O

H

H

H

OH

H

OHO

OH

O

O O

H

OH

H

OH

H

OHO

OH

O

O

OH

H

H

OHO

H

H

OH

O

OH

O

OO

OH

OHH

AcO

O

O O

OH

OHH

OO

H

R1

OR

R2

O

HR

OH

H

OO

HOH

H

O

OO

OH

OHH

OH

O

O

O

Me

HO

H

OH

OH

OHO

O


Table 6-I. Cytotoxic Sesquiterpenes Isolated from Plants Between 1996 and 2000


cpd ref

A549 ACHN BCI BT-549 Col2 GTB HCT-116 HL-60 HOP-92 HT29 KB

152 51 0.12 0.12

153 52 3.9

154 53 3.9 4.96 4.8

155 0.3 0.34 0.45 0.63

156 54 0.3 0.8 0.3

157 0.8 0.9 0.4

158 4.2 1.4

160 1.2 0.05 0.26 0.26

162 55 0.07 0.1

164 0.05 0.07

165 56 0.11 0.1

166 0.021 0.014

167 57 2.0

Table 6-II. Cytotoxic Sesquiterpenes Isolated from Plants Between 1996 and 2000


cpd ref.

LNCap Lu1 Malme-3M MCF-7 MOLT-4 NCI-H522 OVCAR-8 P388 SKNSH SW620 U373

154 53 3.28 1.67 1.58 3.72

155 0.3 0.07 0.15 0.78 0.21

156 54 0.5 0.2

157 1.0 0.4 0.2

158 0.4 2.3

160 0.5

165 56 0.11

166 0.014

172 58 1.1

leukemic cells [61]. Two lavandulylated flavanones, (2S)-2'-methoxykurarinone 182 and (-)-kurarinone 183 were isolatedfrom the roots of Sophora flavescens (Leguminosae), whichis a well known Chinese herbal medicine used as a diureticin diarrhea, gastrointestinal hemorrhage and eczema. Theselavandulyl flavonoids exhibited significant cytotoxicitiesagainst HL-60 cells [62]. Several cytotoxic prenylated

flavanones have been identified in Monotes engleri(Diptercarpaceae). Three of them, 6-(1,1-dimethylallyl)naringenin 184, 6-(1,1-dimethylallyl)eriodictyol 185, 3'-O-methyl-6-(1,1-dimethylallyl)eriodictyol 186, showed broadcytotoxicities against human cancer cell lines [63]. Interes-ting small tree, Eysenhardita polystachya (Leguminosae)was used as an acid-base indicator in the seventeenth century


172

167166

165

164

162

173171

170168: R = H169: R = OH

163

161

155154

153

159: R1= α-OH, β-H, R2=OH160: R1= H, R2 =OMe

O

O

HOHHO

O

OH

O

O

O

OO

O

O

O

O

O

OO

OH R2

R1

O

O

O

OO OH

R1

R2

O

O

O CH2OH

OAc

OH

OH

O

OH

HOCH2

OH

O

O

O CH2O

OH

O

R

O

O

O

O

OO

OH

O

O

HO

O

OH

HOCH2

OH

OO

CH2OH

OH

O

O

O

O CH2O

O

OCOCH=CHMe

H

O

H

OH

O

OCOCH=CHMe

H

O

H OH

O O

OH

O

O

OH

HO

O

156 : R1=R2=-O-157 : R1=R2=H158 : R1=H, R2 =OH


Table 7. Cytotoxic Flavonoids and Lignans Isolated from Plants Between 1996 and 2000

Cell line (IC50, mg/ml)

cpd ref.

A431 A549 ACHN BC1 CRL1579 HL-60 HT29 KB KB16 MOLT-4F OVCAR-3 P388 U373

1.8

179 61 3.65 2.65

181 3.34

184 63 1.2 4.6 3.3

186 2.6 1.9

187 64 3.8

188 3.0

189 65 3.15 4.07 2.16

190 1.12 0.91 0.81

191 3.02 0.74 0.32

192 66 0.39 0.68 0.77 0.25

193 0.75 0.73 0.81 0.35

194 0.59 1.00 0.98 0.39

and an isoflavone has been identified as one of thefluorescent constituents. Cytotoxic isoflavans from thisplant, (3S)-7-hydroxy-2',3',4',5',8-pentamethoxyisoflavan187 and (3S)-3',7-dihydroxy-2',4',5',8-tetramethoxyisoflavan188 exhibited cytotoxicities against KB cells [64].

From the trunk barks of Hernandia nymphaeifolia , threenew lignans, (-)-6'-hydroxyyatein 189, hernone 190 and (-)-nymphone 191, were isolated [65]. Four cytotoxicneolignans were identified in Persea obovatifolia, andobovaten 192, perceal C 193 and perseal D 194 were novelcompounds. These neolignans exhibited significantcytotoxicities against several cancer cell lines (IC50, < 1µg/ml) [66].

OTHERS

There are eleven xanthone compounds 195-205 isolatedfrom Gambogo resin of Garcinia hanburyi (Guttiferae); thisresin is used as a pigment and a folk medicine [67].Naphthoquinone compounds, rhinacanthin-Q 206 andsyriacusin A 207 were isolated from Rhinacanthus nasutus[68] and Hibiscus syriacus [69], respectively. As newcytotoxic anthraquinone compounds, marcanines B-E 208-211 and a cytotoxic naphthoquinone compound, 5-hydroxy-3-amino-2-aceto-1,4-naphthoquinone 212, were isolatedfrom the barks of Goniothalamus marcanii (Annonaceae)[70]. The cytotoxic hydroquinone compounds, 2-[10Z-heptadecenyl]-1,4-hydroquinone 213 and (4R,6R)-dihydroxy-4-[10Z-heptadecenyl]-2-cyclohexenone 214 havebeen isolated from the seeds of Tapirira guianensis [71]. InMozambican traditional medicine, Salacia kraussii is usedagainst bilharziasis, dysentery, and as an antimalarial. Three

novel quinone methides, 28-nor-isoiguesterin-17-carbal-dehyde 215, 17-(methoxycarbonyl)-28-nor-isoiguesterin216, 28-hydroxyisoguesterin 217 along with knowncelastroloids, celastrol 218, pristimerin 219 and isoiguesterol220 have been found from this plant [72].

The family Araliaceae is notable as a rich source of C17polyacetylenes which are usually cytotoxic. Two newpolyacetylenes, dendroarboreols A 221 and B 222, have beenobtained from Dendropanax arboreus together with majorcytotoxic compounds, falcarinol 223, and dehydrofalcarinol224, diynene 225, falcarindiol 226, and dehydrofalcarindiol227 [73].

Leaf extracts of Garcinia parvifolia (Guttiferae) providedfour novel prenylated depsidones, garcidepsidones A-D 228-231 [74] and schweinfurthins A-C 232-234, stilbenecompounds were isolated from Macaranga schweinurthii[75].

Moreover, cytotoxic monoacylglycerides, 1,2,4-trihydroxynonadecane 235, 1,2,4-trihydroxyheptadec-16-one236, 1,2,4-trihydroxyheptadec-16-yne 237 were reportedfrom Persea americana (Lauraceae) [76]. Four heterocycliccompounds, psorothamnones A 238 and B 239, dalrubone240, emorydone 241, were isolated as cytotoxic and PKCinhibitor [77] and an unsaturated lactone, 10-epi-olguine 242from Rabdosia ternifolia showed cytotoxicity [78].

A novel cytotoxic cyclic heptapeptide, yunnanin C 243,was isolated from the roots of Stellaria yunnanensis. Thestructure of this compounds was elucidated as cyclo(-Gly-Ile-Gly-Phe-Try-Ser-Pro-), and it showed cell growthinhibitory activity against P388 cells [79].


176: R=H177: R=Me

174: R=H175: R=Me

O

O

RO

O

OMe

OH

HO

O

OH

OH

O

O

MeO

O

OMe

OH

RO

O

OH

OH

182: R1 = Me183: R1 = H

184: R =H185: R = OH186: R = OMe

181

179

178

OMeO

O

OMe

OH O

OH

HO

O

OH

O

OH

OH

OOH

OH

HO

HO

OH

O

OH

OH

OOH

HO

HO

OH

O

OH

OH

OOH

OH

HO

OH

O

OHR1O

OOMe

HO

OHO

OH O

R

OH

180

188187

O

OMe

OMe

OMe

MeO

OMe

HOO

OMe

OMe

OH

MeO

OMe

HO


194193

192191

190189

O

O

O

OMe

OMe

MeO

OH H

H

O

O

CH2OH

O

H H

OMe

OMe

MeO

MeO

MeO

O

CH2OH

O

H H

MeO

MeO

MeOO

O

O

Me

OMe

OMe

OMe

OH

OH

O

O

OMe

OH

O

O

H

O

O

OMe

H

OMe

Me

OH

OH

198

197195: R1 = Me, R2 = prenyl196: R1 = CH(OMe)2, R2 = H

OO

OOH

O

O

Me COH

OMe

OO

OOH

O

O

HO2 C Me

OMe

OOR2

OOH

O

O

R1 Me

199: R1=CO2 H, R2=Me200: R1=CHO, R2 =Me201: R1=Me, R2=CHO202: R1=Me, R2=Me203: R1=CH(OMe)2, R2=Me

OHO

OOH

O

O

R1 R2


217216

215214

213212

208: R1 =R2 =Me, R3 =R4 =H209: R1 =Me, R2 =CH2OH, R3 =R4 =H210: R1 =H, R2 =Me, R3 =OH, R4 =H211: R1 = R2 =Me, R3 =H, R4 =OH

206

204

207

205

O

HO

CH2OHO

HO

CO2Me

O

HO

CHO

O

OH

HO

OH

OH

O

N

OH

O

O H

H

Me

N

R3

O

O

O

OMe

R2

R1R4

O O

O

O

HO2 C

OH O

OH

O

O

O

O OMe

OMe

HO

CH3

OMeO

OH

OHO

OOH

O

O

Me


232

231

R2 =H

R2 =H

R2 =

230: R1=

229: R1=

228: R1=

223: R =H224: R =H, 16,17-dehydro226: R =OH227: R =OH, 16,17-dehydro

225

222221

220219218

O

OH

OH

OH

H

H

HHO

HO

O

O

OH

OH

OHO

HOH

OH

O

O

OH

OH

OHO

R1

HOR2

HO

OH

R

HO

HO

OHOH

HO

O

HO

HOH2 C H

O

HO

MeO2 C Me

O

HO

MeHOOC


234233

OH

OH

OH

HOO

OH

OH

H

H

HHO

HO

OMe

241240

239

238

237

236

235

O

O

O

O

O

MeO O

O

O

O

O

O

O

O

O

O

O

H OH

OHOH

OH

OHOH

OH

OHOH


Helianthella quinquenervis, commonly known as “littlesunflower”, is a perennial herb with large yellow floweringheads. From aerial part of this plant, one benzofuran (6-methoxy-tremetone) 244 and a new prenylacetophenone (4β-D-(glucopyranosyloxy)-3- [3-methoxy-trans-isopenten-1-yl]acetophenone 245 were isolated as cytotoxic compounds[80].

MARINE ORGANISMS

There are consecutive reviews by Faulkner since 1977[81-94]. Recent research trends on marine natural productswere directed to the metabolites from marinemicroorganisms. Sponge metabolites continue to dominate

the reports of new compounds but there is an increasinginterest in the possibility that associated microorganismsproduce some of these metabolites. Research on bioactivecompounds from marine organisms has provided the supportof marine natural products research past a quarter century.Although none of the discoveries has yet led to apharmaceutical product, there is a hope that one or more ofthese marine natural products currently under investigationwill eventually do so. Among the anticancer compoundscurrently under investigation, bryostatin1 246 serves as agood example of past and current trends in marinebiochemical research. Bryostatin 1 was isolated in very smallquantities from the bryozoan Bugula neritina in the 1970’sand its structure was determined by X-ray crystallography in1982. This compound is currently in phase II clinical trials.

247

246245

244

243

242

N

S

N N

EtPhO

Me

OMe

MeN

HN

O

O

NMe2

iPr

O

iPr

H

OMe OMe

H

O O

OO

O

OHOAc

OHO

CH

CH

HO

MeOCO

O

COH

CHCHCH

H

C

O

MeO

OOOMe

Me O

OOO

O

H

O

gluO

O OMe

O

HN

NH

O

N

H

O

N

O

H

HN

N

H

O

O O

N

O

OH

OH

H

HH

H

H

HH


Other marine natural products under investigation at presentas potential anticancer agents are dehydrodidemnin B 247,dolastatin 10 248, ecteinascidin 743 249, halichondrin B 250,isohomohalichondrin B 251, curacin A 252, discodermolide253, eleutherobin 254, and sarcodictyin A 255.

ALKALOIDS (TABLE 9)

Marine invertebrates are known as rich sources ofalkaloids with unique chemical features and pronouncedchemical activities. Manzamines are unique marine alkaloidspossessing an intricate nitrogen-containing ring system at C-1 of β-carboline ring. From Okinawan marine sponges,Amphimedon sp. [95] and a Philippine marine sponge,

Xestospongia ashmorica [96], seven manzamine congeners256-262 were isolated and tested for cytotoxicity againstL1210 cells. Also, alkylpyridine alkaloids, hachijodines A-G263-269 from marine sponges, Xestospongia andAmphimedon [97] showed cytotoxicities against P388.TheMicronesian sponge Oceanapia sp. afforded threepyridoacridone alkaloids, kuanoniamines, which showedinsecticidal activities, and especially, new N-deacylderivatives 270 appeared to be active in HeLa cells andMONO-MAC-6 cells [98]. Bromopyrrole alkaloids aretypical secondary metabolites of sponges from the familiesof Agelasidae, Axinellidae, and Hymeniacidonidae. Severalof these compounds show promising biological activities;they are, for example, cytotoxic, showing α-adrenoceptor

Table 8. Other Cytotoxic Compounds Isolated from Plants Between 1996 and 2000


cpd ref

A549 BC1 Col2 HELA HT29 KB LNCap Lu1 Malme-3M MCF-7 PC-3 P388 RPMI SK-MEL5 U251

196 67 1.6

198 3.1

201 3.1

202 0.8

204 1.6

206 68 3.6 0.6

207 69 2.4 2.3

208 70 0.35 2.1 0.18 0.7 1.4

209 1.0 0.3 1.0 0.67

210 0.04 0.4 0.08 0.08 0.28

212 2.6 2.6 3.0 3.0

213 71 1.3 0.8 0.5 0.2 0.3

214 4.3 1.8 1.5 0.3 4.4

216 72 2.3

228 74 2.4

229 2.4

230 3.2

235 76 3.0 3.0 3.2 1.2

236 3.4 2.6 4.4 0.46

237 4.8 0.062

240 77 0.2 0.02 2.0 1.0 0.4

241 3.0 4.0 1.0 3.0 3.0

242 78 1.8 2.1 1.8 1.2 4.8

243 79 2.2

244 80 1.0


248

254

253

252

251

250

249

HO

OO

O O

O O

O

OO

O

O

O

O

CH2

OH

H H

H

H

H

O

H

H

H

H

H

H H

HHH

H

H

H

O

O

HO

NHO

iBu N

O

Me

N

OMe

O

O

ON

NN

N

O CH2

O OO

O

OMe

OOEt

Me

HO

HH H

iBu

HH

O

O

OHO

HO

OAc

MeO

iPr

OO

N

N

O

OH O NH2

O

O

OH

OH

OH

OMe

Me

N

S

HO O

O

O

O O

O O

O

OO

O

O

O

O

CH2

O

OH OH

H

H

H

H

H H

H

H

H

O

H

H

H

H

H

H H

H HH

H

H

H

N

OO

O

O

OMeOH

S

HN

OH

OMe

OAc

N

H

H

OH

H

H H

255

O

HO

iPr

O

MeO

O

O

N

N


Table 9. Cytotoxic Alkaloids from Marine Organisms Between 1996 and 2000


cpd ref

A549 HeLa HT29 L1210 L5178MONO-MAC6 OVCAR-3 P388 SK-MEL5

256 95 1.8

257 3.2

258 1.6

259 1.6

260 96 1.4

261 0.5

262 0.3

263 97 2.2

264 2.2

265 2.2

266 2.2

267 2.3

268 1.0

269 1.0

270 98 1.2 2.0

275 100 1.8 5.7

blocking activity and protein kinase inhibitory properties.Debromostevensine 271 and debromohymenin 272 wereisolated from Stylissa carteri as cytotoxic compounds [99].

Other bromoalkaloids, dibromophakellstatin 273,dibromophakellin 274, and debromohymenialosine 275 havealso been found in Phakellia mauritiana [100]. The new

262261260

259258257256

N

HO

N

H

N

NH

OH

NN

H

N

HN

OH

N

H

N

N

NH

OHOH

N

N

N

N

OH

N

H ONH

N

N

N

OH

HN

ON

N

N

OH

H

N

N

N

OH

O

H O


mycalamide, mycalamides C 276 and D 277 have beenisolated from the New Zealand marine sponge, Mycale sp[101] and Stylinos sp [102]. These mycalamides are potentantiviral and antitumor compounds, which cause reversion ofras-transformed cancerous cells back to normal morphologyand block the activation of CD4+ T Lymphocytes.

TERPENOIDES

1. Triterpenoids (Table 10)

Triterpenoids are a minor group of sponge metabolites,however, one of the most interesting groups of marinenatural products is formed by polyether triterpenoid andmalabaricane / isomalabaricane triterpenoids. Thesetriterpenes derived from sponge are mostly toxic. From themarine sponge Stelletta globostellata, globostellatic acids A-D 278-281 [103] and 29-hydroxystelliferin D 282, 3-epi-29-

hydroxystelliferin E 283, and 3-epi-29-hydroxystelliferin A284 [104] were isolated. These isomalabaricanes weresignificant cytotoxic against leukemia cells. Additionally,two new cytotoxic 9,11-secosterols, 3-O-deacetylluffasterol285 and 3-O-deacetyl-22,23-dihydro-24,28-dehydroluffasterol B 286 have bee n found in a ma rines ponge , Spongia agaric ina [105].

From the soft coral, several cytotoxic sterols have beenobserved. As cholesterol derivatives, 24-methylcholesta-5,24(28)-diene-3β,15β,19-trol 287, 24-methylcholesta-5,24(28)-di e n e -3 β ,1 9- dio l- 7-o ne 28 8, 24 -me th ylc ho le s ta -5, 24 (28 )- di e n e -3 β ,1 9- dio l 28 9, 24 -me th ylc ho le s ta -5, 24 (28 )- die ne -3β,19-diol-7β-monoacetate 290, 24-methylcholesta-5,24(28)-diene-3β,7β,19-triol and 24-methylcholesta-24(28)-ene-3β,5α,6β,19-tetraol 291, have been isolated from Nephtheaerecta [106]. Sterol glycosides, riisein A 292 and riisein B293 were isolated form octocoral Carijoa riisei [107].

Table 10. Cytotoxic Triterpenes from Marine Organisms Between 1996 and 2000


cpd ref

A549 HCT-116 HT29 KB Mel-28 P388 3Y1

278 103 0.10

279 0.10

280 0.46

281 0.10

282 104 0.086 0.027

283 0.082 0.027

284 0.092 0.024

285 105 1.00 1.00 1.00 1.00

286 1.00 1.00 1.00 1.00

287 106 0.41 0.17 0.60 0.07

288 4.09 3.34 0.40

292 107 2.00

293 2.00

296 108 3.1 0.4 0.6

297 2.5 1.4 0.8

298 2.3 1.2 0.9

299 1.8 1.7 1.8 0.4

300 109 0.64 0.43 0.33 0.26

301 1.68 1.27 1.41 0.22

302 3.14 0.87 0.3 0.75

303 110 0.58 0.47 0.79 0.22

304 1.0 0.63 0.4 0.28


From the seaweeds, oxygenated fucosterols 294-299 havebeen found in Turbinaria conoides [108] and oxygenateddesmosterols 300-306 have been identified in Galaxauramarginata [109, 110]. All of the oxygenated sterols fromalga exhibited cytotoxicity against cancer cell lines.

2. Sesterterpenes (Table 11)

Scalarane sesterterpenes are characteristic secondarymetabolites of some sponges. From a sponge, Hyrtios erecta,new eight scalarane sesterterpenes 307-314 have been

274

273

272

270

269

268

267

266

265

264

263

N

N

N

N

Br Br

O

H

H2N

N

N

N

N

Br Br

O

O

H

HN

H2N

N

NN

OHH

Br

HN

H2N

N

NN

OHH

Br

N

NH

N

S

NH2

N

NMe

OH

N

NMe

OH

N

N

OH

Me

N

NOMe

H

Me

N

NOMe

HMe

N

NOMe

H

Me

N

NOMe

H

H

H

H

H

271


isolated [111,112]. Generally, they are not functionalized onA-B-ring carbons, while antitumor compounds obtainedfrom this sponge contain unique 3-oxygenated structures.The oxygen constellation on the scalarane was thought toplay a significant role for expression of the antitumoractivity. These sesterterpenes increased life span in P388lymphatic leukemia implanted mice and showed in vitrocytotoxicity against P388.

From another sponge, Spongia agaricina, newsesterterterpenes 315-316 were also isolated and showedcytotoxicities [105].

3. Diterpenes (Table 12)

From 1998 to 1999, nineteen cytotoxic excavatolides A-M 317-329 [113,114], U-Z 330-335 [115], briarane skeletonditerpenes, were reported from gorgonian Briareumexcavatum. Highly oxygenated diterpene, such as briaranesand asbestinins, have been discovered from gorgonian coralsof the genus Briareum, which showed cytotoxic, anti-inflammatory, antiviral, insecticidal, antifouling, andantibacterial activity.

283: R =OAc284: R =OH

282

281280

279278

277276275

NHHN

O

HN

N

H2N

O

O

O

N

OH

O

OH

MeO OH

OHO

O

N

O O

OMeO OH

OH

OH

OH

OH

O

CO2Na

AcO

O

OMe

OH

NaO2 CAcO

H

H

O

NaO2 CAcO

H

H

OH

OMe

O

NaO2 CHO

H

H

OH

OMe

O

H

H

O

R

H

OH

HO

H

H

H

OH

OH

H

O


Table 11. Cytotoxic Sesterterpenes Isolated from Marine Organisms Between 1996 and 2000

Cell line (µg/ml)cpd ref

A549 HT-29 Mel28 P388

307 111 0.40

308 2.10

309 0.90

310 112 0.014

311 0.25

312 0.51

315 105 1.00 1.00 1.00 1.00

316 5.00

286285

O

OH

OHO

CHO

O

H

OHO

CHO

291

287: R1 = H, R2 = OH288: R1 = O, R2 = H289: R1 = H, R2 = H290: R1 = OAc, R2 = H

295294

293: R=

292: R=

OAc

RO

OH

OH

O

OH

OH

AcO

OOH

HOOAc

O O

OOH

R2R1

OH

HO

HO

OH

OH

HO


Orange-colored gorgonian Acalycigorgia intermis(Acanthogorgiidae) from the sandy bottom offshore fromKorea afforded acalycixeniolides C-F 336-339 as thecytotoxic constituents [116].

Cembranoids and their cyclized derivatives continue tobe the most abundant metabolites of soft corals andgorgonians. Four new cembranolides, 11,12-epoxy-1(E),3(E),7(E)-cembratrien-15-ol 340, 3,4:11,12-diepoxy-15-methoxy-1(E),7(E)-cembradiene 341, 1(E),3(E),7(E),11(E)-cembratetraene-14,15-diol 342 and 3,14-epoxy-1(E),7(E),11(E)-cembratriene-4,15-diol 343 were isolatedfrom the soft corals Sinularia gibberosa and Sarcophytontrocheliophorum [117]. The genus Sinularia is reputed for itsversatile chemical constituents and their biological activity.Terpenoids, including sesquiterpenes, cembrane,norcembrane, flexibilene, cladiellane and lobane ditepenoidsand steroids compose the main secondary metabolitesisolated form this genus. The first report has been publishedon norcembrane, (1R,5S,8R,10S,11R)-11-hydroxy-1-isoprenyl-8-methyl-3,6-dioxo-5,8-epoxycyclotetradec-12-ene 10,12-carbolactone 344, lacking a methyl group at C-4.The first marine norcembrane dimmer, singardin 345 wasfound in Red Sea coral Sinularia gardineri [118]. Moreover,from the other Sinularia, three new cytotoxic cembrane

diterpenes, sinuflexolide 346, dihydrosinuflexoide 347, andsinuflexibilin 348 have been identified [119]. Terpeneperoxides are a fascinating class of compounds isolated fromboth plants and marine organisms. The marine spongeDiacarnus cf. spinopoculum has provided a series ofnorterpens, including five new compounds, nuapapuin B349, epinuapapulin B 350, muqubilin B 351, epimuqubilin B352, muquketone 353 and ent-compounds (-) muqubilin A354 and (+) epimuqubilin A 355 [120]. These compoundsshowed significant in vitro cytotoxicity but no antitumoractivity was observed in vivo.

4. Sesquiterpenes (Table 13)

Sesquiterpene quinones and hydroquinones represent agroup of still expanding C15-C6 metabolites with notablemedical applications such as antitumor, antibacterial andanti-HIV activities. Due to their potential antitumor and anti-HIV activities as well as the novelty of their structures, theexploration of natural sesquiterpene quinones has continuedto grow in the past decade. From Taiwanese marine sponge,Polyfibrospongia austalis, polyfibrospongols A 356 and B357 were isolated and exhibited significant cytotoxicityagainst human KB16, A549, and murine P388 tumor celllines [121].

301300299

298297296O

O

O

O

O2H

O

OH

O

OH

O2H

O2H

HO

O2H

HO

302 304

O

O

OHO

OH

O2H

O

OH

O2H

303


Table 12. Cytotoxic Diterpenes Isolated from Marine Organisms Between 1996 and 2000


cpd ref

A498 A549 BT-549 HL-60 HT29 IGROV1 K562 KB Mel-25 P388

317 113 2.5

319 1.9 1.9 1.9 0.3

320 1.3 4.2 1.8

321 1.2 1.6 0.8 1.6

327 114 3.0 1.3 3.3 0.9

329 0.1 2.2 1.0 0.001

335 115 2.8 1.3

336 116 1.6

338 4.7

339 0.2

340 117 1.03 0.64 0.63 0.01

341 0.36 3.26

342 0.29 1.54

343 1.7 1.81 0.23

345 118 2.5 1.0

346 119 0.68 0.39 0.46 0.16

348 0.72 0.22 1.73 0.27

349 120 0.99 0.34 0.53 0.2

350 0.7 0.58

351 1.02

353 0.76

354 0.43

Table 13. Cytotoxic Sesquiterpenes Isolated from Marine Organisms Between 1996 and 2000


cpd ref

A549 HT29 KB16 KM-12 MOLT-4 P388

356 121 0.6 1.4 0.7

357 1.0 2.0 1.0

359 122 0.1 0.1

365 123 10.0 3.5 4.9 3.0

366 2.8 2.6 3.9 2.5

367 3.8 3.3 7.2 2.9

368 3.9 6.0 4.8 1.0


318

314

323322321

320319317

316315

310: R1 = R2 =O, R3 =H311: R1 = R3 =H, R2 =OH312: R1 = H, R2 =OH, R3 =Ac313: R1 = R2 =R3 =H

309308

307306305

O

O2H

O

O

O2H

O

O

HH

H

OH

O

OH

O

HH

H

OAc

O

OH

OHO

HH

HAcOCH2

H

O

H OOR3

R2

HO

HH

H

R1

H

O

OAc

OHOOH

OAc

O

O

O

H

OCl

OAc

OH

O

O

H

OAc

HO

OAc

O

OAc

O

O

H

OH

OAc

HO

O

OAc

O

O

AcO

H

OAc

OH

HO

OO

AcO

OAc

O

O

AcO

H

OAcAcO

O

OAc

O

AcO

H

O

H

H

O

AcO

H

O

HH

H

OH

O

OH

O

O

OAc

OAc

HO

O

O

OCPr

O

AcO

AcO AcO AcO


Six new guaiane skeleton sesquiterpenes 358-363 wereisolated from the hexane extract of the Caribbean gorgoniancoral Psedopterogorgia americana collected in Puerto Rico.Although most metabolites were found to be labile anddecomposed slowly under normal conditions, americanolideD 359 showed strong cytotoxicity against the human colon(KM-12) cancer cells and methoxyamericaolide A which is aderivative of methoxyamericanolide G 363, is a strong andselective in vivo inhibitor of MOLT-4 leukemia cells [122].

Five new sesquiterpene hydrocarbons, parahigginols A-D364-367 and parahigginic acid 368 have been isolated from aTaiwanese marine sponge Parahigginsia sp. [123].

5. Monoterpenes (Table 13)

The sea hare Aplysia punctata from Sancti Petri (Spain)contains four new unusual acetates of linear polyhalogenatedmonoterpenes together with four known cyclic derivatives.

332

338337

336335

329

333: R1= Ac, R2= n-PrCO334: R1= EtCO, R2=Ac

330: R1= n-PrCO, R2 =EtCO331: R1= Ac, R2=EtCO

328326: R=COCH2CH 2CH3327: R=Ac

324: R=COCH2CH 2CH3325: R= Ac

O

OCO(CH2)2MeOAc

RO

OAc

O

O

OAc

H

O

OAcOAc

RO

OAc

O

O

OAc

H O

OAc

AcO

OH

O

O

OAc

H

O

OAcOH

HO

OH

O

O

OAc

H

O

R2O

OAc

O

O

OAc

H

OR1

OAc

O

R2O

OAc

O

OH

OAc

OR1

HO O

OAc

PrOCO

OH

O

O

OAc

HHO O

O

H

HH

OH

O

O

H

H

OH O

H

H

OH

AcO

AcO

OEtO

OH

O

O

OAc

H

OAc


(7E)-1-acetoxy-8-chloro-7-(dichloromethyl)-3-methoxyoct-7-en-4-one 369, (7Z)-1-acetoxy-8-chloro-7-(dichloromethyl)-3-methyloct-7-en-4-one 370, and (3Z,5E)-1-acetoxy-8-

bromo-4,7-dichloro-3,7-dimethylocta-3,5-diene 371 exhibi-ted significant cytotoxicity [124].

347346345

344343342

341340339

O

O

H

HH

OH

OH

O

OMe

O

O

OH

OH

OH

OH

OO

O

OO

O

H

H

OH

O

O

O

O

O

O

O

O

O

OO

OO

O

HO

OH

OH

OO

HO

OH

OH

356

353

350349348

R2 =H355:R1=

354: R1=H, R2 =

352: R=

351: R=

HO

OMe

COOMeH

CO2Me

CO2HO

O

R1R2

O

CO2Me

CO2Me

O

O

R

HO

O

O

CO2H

O

O

CO2CH3

HO

OH

OH

OHO

MeO


OTHERS

Two new cytotoxic trisoxazole macrolides,thiomycalolides A 372 and B 373 and known potent actin-depolymerizing agents mycalolides B 374 were isolated froma marine sponge of the genus Mycale sp. [125]. Four newoxazole-containing compounds, halishigamides A-D 375-378 have been isolated Halichondria sp [126]. The marinebryozoan Bugula neritina (Bugulidae) has proved to be anexciting and exceptionally useful source of new anticancerdrugs of the bryostatin class. After the isolation andstructural determination of bryostatin 1 in 1981, preclinicaldevelopment was undertaken and the first phase I humanclinical trials began in early 1991. Promising initial clinicalresults have been reported. Currently, the U.S. NationalCancer Institute has entered bryostatin 1 into phase II clinicaltrials. Now, the structural modifications of the bryostatin andisolation of new members of this important series are in theprogress. The three new bryostatins 16 379, 17 380, 18 381showed significant growth inhibitory activity against murineP388 lymphocytic leukemia [127].

Cryptophycin 46 382, 175 383, 176 384 have beenidentified as three new trace constituents of Nostoc sp.Compound 382 is an epimer of cryptophysin-3 and to date isthe only naturally occurring analogue having the Sconfiguration at C-10 (C-2 in unit B) [128].

There are three new cytotoxic cyclic peptides, jaspamidesB 385 and C 386, keenamide A 387 which were isolatedfrom marine sponge, Jaspis splendans [129] and marinemollusk Pleurobranchus forskalii [130], respectively.

Marine polyacetylenes were usually bioactive as well asunstable compounds. Their bioactive metabolites have beenassociated with H+, and K+-ATPase inhibitory, antifungal,antifouling, antimicrobacterial, HIV protease inhibitory andantitumor activity. Nine new polyacetylenes, triangulynes A-H 388-395 and triangulynic acid 396 have been isolated fromthe marine sponge Pellina triangulata through cytotoxicity-guided fractionation [131]. These compounds were testedagainst the NCI human tumor cell line panels. Repetitivetesting of 388 as representative of the series yielded meanpanel GI50, TGI, and LC50 concentrations of 0.5, 2.0 and 12µM, respectively. Three C46 397-399 and three C30 400-402polyacetylenic alcohols with cytotoxic activity against asmall panel of human solid-tumor cell lines have beenisolated from the marine sponge Petrosia sp. [132].

Malyngamides O 403 and P 404 from the sea hareStylocheilus longicauda [133], carbonimidic dichlorides,reticulidins A 405 and B 406 from the NudibranchReticulidia fungia [134], fulvinol 407, a long-chaindiacetylenic metabolite from the sponge Reniera fulva [135],stolonic acids A 408 and B 409, cyclic peroxides from anIndian Ocean Ascidian Stolonica sp. [136] have beenidentified as cytotoxic compounds from marine organisms.3-Epi-Aplykurodinone B 410, a new degraded sterol isolatedfrom Aplysia fasciate as a cytotoxic compounds was derivedfrom a parent sterol by degradative loss of ring A carbonatoms through 5,6 and 9,10 oxidative cleavages [137]. Thecytotoxicities of these compounds are listed in Table 14.

MICROORGANISMS

1. Bacteria

The myxobacteria have proved to be a rich source ofnovel natural products, and a variety of biologically activesubstances were produced by various myxobacterial species.From myxobacteria, strain JW025 of Myxobacteria fulvus(Myxococcaceae), was found to produce two closely relatedantibiotics that were active against several human tumor celllines. A new bithiazole, KR-025 411 was isolated withmyxothiazol 412 and demonstrated potent cytotoxicity [138].The actinomycins are a family of chromopeptide antitumorantibiotics isolated from various Streptomyces strains, ofwhich more than 30 native and many synthetic variants areknown. Five new piperidine alkaloids, named streptazonesA, B1, B2, C, and D, 413-417 were isolated formStreptomyces strains FORM5 and A1. Piperidine alkaloidsare typical constituents of plants but have been rarelyisolated from microbial sources until recently. Streptazone A413 exhibited significant cytotoxicity [139].

Brasilidine A 418, a new cytotoxic indole alkaloidcontaining an isonitrile group, has been isolated from theactinomycete Nocardia brasiliensis IFM 0089 [140]. Thegenus Nocardia was a rich source of 32-memberedmacrolide possessing immunosuppressive and antifungalactivity.

2. Cyanobacteria

Terrestrial and marine cyanobacteria are producers ofnumerous bioactive compounds such as the cryptophycins

Table 14. Cytotoxic Monoterpenes Isolated from Marine Organisms Between 1996 and 2000


cpd ref

A549 HT-29 MEL-28 P388

369 124 1.5 2.5 1.5 2.5

370 1.5 2.5 1.5 2.5

371 1.5 2.5 1.5 2.5


370369

368367366365

364362361

360

363

359358357

OMe

COOH

ClCl

O

O

O

Cl

ClCl

O

O

O

Cl

OH

CHO

OH

OAc

OH

OAc

OH

CHO

OH

OH

O

CH3

O

CH3

H

Me

HO

CH3

O

CH3

H

Me

OMe

O

CH3

O

CH3

H

Me

OH

O

CH3CH3

H

Me

O

CH3

O

CH3

H

Me

H

O

CH3

O

CH3

H3 COMe

HO

OMe

COOMeCH2OHH

372: R= O373: R=

371

O

O

Cl

S

NHH2N

O

NH

CO2H

O

CO2H

N

O

O

O

H

Me OMeOMe

O

OH

OMe

NO

NO

O

NOAc R

O

OMe

OMe

H

Cl

Br


377

376

375

374

N

O

O

O

H

Me OAc OMeOMe

O

OH

OMe

NO

NO

O

N

O

OMe

OMe

O

HOCN

O

Me OMe O OMe O

O

O

OH

NH2

NO

NO

OMe

N

HOCN

O

Me OMe O OMe O

O

O

OH

HN

NO

OMe

N

O

O

HOCN

O

Me OMe O OMe O

O

O

OH

CONH2

NO

OMe

N

MeO2 C

378

HOCN

O

Me OMe O OMe O

O

O

OH

NO

CO2NH2

OMe

NCO2Me


387386385

383

382

381

380379

S

N

NH

N

O

NH

N

NO

O

O

O

O

H

H

O

O

O

HN

N

OH

O

N

O

N

BrHHO

O

O

O

O

HN

N

OH

O

N

O

N

BrH

OO HN

O

OO NH

Cl

OMe

O

Cl

OO HN

O

OO N

Cl

OMe

O

O

O

O

OH

H

O

O

O

MeOOCOCMe3

H

H

HOH

HHO

H

H

H

H

HOH

O

MeO

O

O

O

OH

H

O

O

O

MeOOCOCMe3

H

H

HOH

HHO

H

H

H

H

H

MeO

O

O

O

O

OH

H

O

O

O

MeOOCOCMe3

H

OOMe

H

HOH

HHO

H

H

H

H

H

H H

H

384

OO HN

O

OO NH

H

Cl

OH

O

O


402

401

400: m+n=12

399

398

397

396

395

392: m = 4, n = 7, R =OH393: m = 6, n = 7, R =OH394: m = 6, n = 7, R =H

388: m =5, n =8389: m =6, n =8390: m =6, n =6391: m =12, n =10

OH

OH

OH

OH

HO H

(CH2)m(CH2)n

HO H

H OH

HO H

(CH2)7

(CH2)14

HO H

HO H

(CH2)10

(CH2)14

HO H

HO H

(CH2)14

HOOC

OH

HO

(CH2)9

OH

(CH2)9

OH

OH

HO

(CH2)m

R (CH2)n

OH

(CH2)nHO

(CH2)m

OH


and curacins. Lyngbyabellin A 419, a significantly cytotoxiccompound with unusual structural features, was isolatedfrom a Guamanian strain of the marine cyanobacteriumLyngbya majuscula. This novel peptide is structurally relatedto dolabellin 420 in that both depsipeptides bear adichlorinated β-hydroxy acid and two funtionalized thiazolecarboxylic acid units [141]. Also a Papua New Guineacollection of the marine cyanobacterium L. majusculayielded two new and toxic natural products, hermitamides A421 and B 422 [142].

3. Fungi

From the sclerotia of Aspergillus arenarius(Trochocomaceae), which were produced by solid substratefermentation on corn kernels, arenarins A-C 423-425 wereisolated [143]. Arenarin A 423 and B 424 showedcytotoxicity against human tumor cells in the NCI’s 60-cellline panels, displaying average GI50 values of 4.8 and 3.8µg/ml, respectively.

411: R = CO2CH3412: R = CO2NH2

410

409

408

407

406

405

404

403

N

OMe O

Me

Cl

OMe

OMeO

N

O

Me

Cl

O

OMe

O

HO

HCl

NCCl2

HO

HCl

NCCl2

OHH

(CH2)3 (CH2)8 (CH2)8 (CH2)3

HHO

HO

O(CH2)7

O OO

HH

H

H

HO

O(CH2)7

O OO

HH

H

H

O

O

O

R

OMeH

N

S N

S

OMe

OMe

416413 415414

NH

H

Me

O

NH

O

Me

H

NH

O

Me

H

NH

O

OH

Me

418417

N N H

H

CH3

Me

NH

MeO

C

Me


PROMISING NATURAL PRODUCT AND ITSDERIVATIVES

The cytotoxic natural compounds are still being isolatedfrom natural resources to contribute to the cancer treatment.During last 5 years, hundreds of compounds were reportedbut only a few compounds were promising candidates orregarded as lead compounds in clinical study. Flavopiridol426, a synthetic flavone closely related to rohitukine 427which is originally isolated from the stem barks of the nativeIndian plant, Dysoxylum binectariferum has attracted muchinterest recently, not only because of its novel cellular targetsas potent cyclin-dependent kinase inhibitor, but also becauseit inhibits the growth of noncycling tumor cell in vivo, andcauses apoptosis in a variety of human cancer cells and celllines in vitro and in vivo [144-146].

As yet, no compound isolated from a marine source hasadvanced to commercial use as a chemotherapeutic agent,though several are in various phase of clinical developmentsas potential anticancer agents. One of these is bryostatin 1that exerts a wide range of biological effects, thought tooccur through modulation of protein kinase C, and hasshown some promising activity against melanoma and non-Hodgkin’s lymphoma in phase I/II studies.

Ecteinascidine-743 249, tetrahydroisoquinoline alkaloidisolated from Ecteinasidia turbinate has shown cytotoxicityagainst a variety of solid tumor cell lines, includingmelanoma, non-small cell lung tumor, ovarian, and coloncell lines at nanomolar concentrations. The results obtainedso far in phase I clinical trials are quite encouraging andmechanism study through protein-DNA binding is now inprocess [147].

424: R = H425: R = Me

427426

423

422

421

420419

O

N

OH

OH O

Me

MeHOO

N

OH

OH O

Cl

Me

HO

HO

MeO

O

CH2OHO

O OR

O OH

OHO

HO

MeO

N

OOMe

H

N

H

N

OOMe

H

O

HO

OH

S

N

O OO

O

NS

ClCl

MeO

N

O

HN

O

S

N

O OO

O

NS

OH

ClCl

H

H


Antimitotic agents that interact with microtubulecomponents are of interest for their potential activity in thetreatment of human neoplastic diseases. Sarcodictyins andeleutherobin, which are coral-derived natural products,showed effect on the assembly of purified tubulin with andwithout microtubule-associated proteins and binding at thepolymer taxoid site [148]. Like taxol, these antimitoticagents are under intense investigation as anticancer drugcandidates.

DISCUSSION

In this review, we reported more than four hundredcytotoxic compounds isolated from natural sources since1996 based on their IC50 value less than ≤ 4 µg/ml (Table 2-16) and the cell lines used for evaluation of cytotoxicity(Table 17). The strongest cytotoxic groups were acetogenins,diterpenes, marine triterpenes, and macrolide compounds.This report shows that recent research trend on cytotoxiccompounds is moving from earth to marine. During past 25

Table 15. Cytotoxic Compounds Isolated from Marine Organisms Between 1996 and 2000


A549 HT29 KB L1210 LOX Mel-28 NSCLC-N6 OVCAR-3 P388

372 125 0.018

373 0.018

375 126 0.01 0.004

376 4.4

377 5.2

378 1.8 1.1

385 129 3.3

386 1.1

387 130 2.5 5.0 2.5

397 132 1.1

398 1.6

399 1.7

400 1.3

402 1.4

403 133 2.0 2.0 2.0

405 134 0.41 0.59

406 0.42 0.11

407 135 1.0 1.0 1.0 1.0

408 136 0.05 0.1

409 0.05 0.1

410 137 2.5 2.5 2.5 2.5

Table 16. Cytotoxic Compounds Isolated from Microorganisms Between 1996 and 2000


A549 CHO HCT-15 HEPG2 HM02 KB L1210 MCF-7 P388 SK-OV3 SL-Mel2 XF-498

411 138 0.00002 0.00006 0.00004 0.0085 0.03

413 139 0.018 0.089 2.7

418 140 3.26 0.75 0.25 0.44

419 141 0.03


years, techniques for isolation and identification from marineorganism are improving to overcome low yield from thesources. The novel structure and skeleton were expected tocome from marine products.

Nowadays, natural product itself seems to be moreimportant because it can be used as the lead compounds fornew drugs. In other words, natural products suggested basicstructures of bioactivity and pharmacokinetic properties butmore practical approach is the optimization of lead structure.Instead of using classical medicinal chemistry techniques,rapid combination/parallel synthesis methods would beapplied. Additionally, improvement of delivery systems intocancer cells should be another pivotal point for the new drug

development. As can be seen from recent FDA approveddrugs, old compounds with new delivery system became thenew developed drugs.

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Table 17. Cell lines and Descriptions

Cell line Description Cell line Description

3Y1 rat embyonic fibroblast Malme-3M human melanoma

9KB human nasopharingeal carcinoma MCF-7 human breast carcinoma

A2780 human epithelial tumor cell MDA-MB-231 human breast carcinoma

A298 human kidney carcinoma MDA-MB-435 human breast carcinoma

A-498 human kidney carcinoma MEL-28 human melanoma

A-549 human lung carcinoma MOLT-4 human acute lymphoblast leukemia

ACHN human renal cancer MOLT-4F human leukemia

BC1 human breast carcinoma NCI-H23 human lung carcinoma

BT-549 breast carcinoma cell line NCI-H522 human non-small cell lung cancer

Col2 human colon cancer OVCAR-3 human ovarian cancer

CRL-59 human skin carcinoma OVCAR-8 human ovarian cancer

DLD1 human colon cancer P388 murine leukemia

GTB human lymphoma PACA-2 human pancreatic carcinoma

HCT-15 human colon cancer PC-3 human prostate adenocarcinoma

HCT-8 human ileocecal carcinoma RPMI-7951 human melanoma

HEK-293 human epithelial kidney carcinoma SF539 human central nervous system cancer

HELA human epithelial cervix adenocarcinoma SK-MEL5 human melanoma

HOP92 human non-small cell lung cancer SKNSH human neuroblastoma cancer

HT-1197 human bladder cancer SW620 human ovarian cancer

HT-29 human colon adenocarcinoma TE-671 human medullablastoma

J774 murine monocyte macrophage cell line U251 human brain carcinoma

KB16 human mouth epithelial carcinoma U373 human glioblastoma

L1210 murine leukemia UACC62 human melanoma

L5178 mouse lymphoma UO-31 human renal cancer

LNCaP hormone-dependent human prostate cancer Vero monkey epitheloid renal cell

Lu1 human lung carcinoma WEHI-164 murine fibtosarcoma cell line

M109 mouse lung cancer ZR-75-1 hormone-dependent human breast cancer


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