Phenolic Compounds in Food and Their Effects on Health II

Chapter 29

Plant Phenolic Compounds as Cytotoxic Antitumor Agents Downloaded by UNIV OF CALIFORNIA SAN FRANCISCO on December 12, 2014 | http://pubs.acs.org Publication Date: October 1, 1992 | doi: 10.1021/bk-1992-0507.ch029

Kuo-Hsiung Lee Natural Products Laboratory, Division of Medical Chemistry and Natural Products, School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599

The cytotoxic antitumor plant phenolics and their analogs are reviewed with emphasis on those discovered from the author's laboratory. The active compounds include, in addition to those which are in clinical use or trials as anticancer drugs, alkaloids, anthraquinones, coumarins, flavonoids, lignans, macrolides, naphtho-quinones, and polyphenols. The compounds are discussed briefly with respect to their in vitro cytotoxicity and in vivo antitumor activity as well as their structure-activity relationships and mechanism of action, when sufficient data are available. Plant-derived natural products and their synthetic analogs have been a promising source of novel anticancer drugs. The clinical utility of the vinca alkaloids, vinblastine and vincristine, and their analog vindesine, as well as the podophyllotoxin-derived lignan glycosides, etoposide and teniposide, testify to the validity of this thesis (1-5). The progress in the discovery and development of plant antitumor agents and analogs during the past two decades has been reviewed (6-16). Numerous plant phenolics have been isolated as the cytotoxic antitumor principles involved in this study. Plant Phenolics and Analogs in Clinical Use or Trials A s Anticancer Drugs Currently, there are at least six plant phenolics and their analogs in clinical use or trials as anti-cancer drugs. These include the above-mentioned etoposide (1) and teniposide (2), 10-hydroxycamptothecin (3), lycobetaine (4), gossypol (5), and 9-hydroxy-N-2methylellipticinum acetate (6). Etoposide (1) and teniposide (2) are semi-synthetic analogs of podophyllotoxin, a cytotoxic lignan isolated from Podophyllum peltatum and related species. Compounds 1 and 2 are effective anticancer drugs used clinically for the treatment of small cell lung cancer, testicular cancer, lymphoma, and leukemia (17,18). There exists ample evidence suggesting that these drugs block the catalytic activity of D N A

0097-6156/92/0507-0367$06.00/0 © 1992 American Chemical Society

In Phenolic Compounds in Food and Their Effects on Health II; Huang, M., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1992.

Downloaded by UNIV OF CALIFORNIA SAN FRANCISCO on December 12, 2014 | http://pubs.acs.org Publication Date: October 1, 1992 | doi: 10.1021/bk-1992-0507.ch029

368

PHENOLIC COMPOUNDS IN FOOD AND THEIR EFFECTS ON HEALTH II

topoisomerase Π by stabilizing an enzyme-DNA complex in which the D N A is cleaved and covalendy linked to the enzyme (19-21). The cytotoxicity of 1 and 2 might also be associated with the phenoxy free radical and its resulting ortho-quinonc species formed by biological oxidation of the drugs (22,23). The phenoxy free radical and orthoquinone derivatives of 1 were believed to be produced by metabolic activation of 1, which could bind to critically important cellular macromolecules as alkylating species causing dysfunction and, subsequently, cell death (24,25). Recent studies involving the replacement of the 4P-sugar moiety with 4p-aryl-arnino groups in the author's laboratory has yielded several compounds (7-12) which were 5- to 10-fold more potent than 1 as inhibitors of D N A topoisomerase II in vitro. A l l of these compounds (7-12) could generate the same amount or more protein-linked D N A breaks in cells than 1 at 1-20 μΜ. In addition, these new compounds were cytotoxic not only to K B cells but also to their 1-resistant and vincristine-resistant variants which showed decreased cellular uptake of 1 and a decrease in D N A topoisomerase Π content or over expression of MDR1 phenotype (26-28). 10-Hydroxycamptothecin (3) was isolated from Camptotheca acuminata a tree common to Southern China. C. acuminata also yielded camptothecin (13), which was first isolated, tested, and found to be extremely toxic in the United States (29). 10Hydroxycamptothecin was found to be more potent and less toxic than 13, and has been in clinical use in China in patients with head and neck malignancies and primary liver carcinoma. It is also useful for the treatment of gastric cancer and leukemia (30). It inhibits strongly the S phase of tumor cells, D N A synthesis, and in particular D N A polymerase (31). Recently, 3 and 13 were both found to be the potent inhibitors of D N A topoisomerase I (32,33). Three analogs and derivatives of 3 and 13, including hycamp-tamine ( 14) (34), 9-aminocamptothecin ( 15) (35), and CPT-11(16) (36), are currently in clinical trials as anticancer drugs for colon and other cancers in Europe, U.S.A., and Japan, respectively (37). Lycobetaine (4) is a derivative of lycorine, an alkaloid common to many Lycoris and Narcissus species, such as Lycoris radiata and Narcissus pseudonarcissus (38). Compound 4 is used in patients having ovarian carcinoma and gastric cancer in China (30,39). Gossypol (5), isolated from Gossypium herbaceum, is a well-known male contraceptive developed in China (40). It is also* used as an anticancer drug for the treatment of stomach, esophageal, liver, mammary, and bladder cancers in China (39). 9-Hydroxy-N-2-methylellipticinum acetate (6) is an analog of ellipticine and 9-methoxyellipticine, which are alkaloids isolated from Ochrosia elliptica or O. acuminata (9,41). Compound 6 is a D N A topoisomerase Π inhibitor and active against thyroid and renal cancers. Several of its analogs are in European clinical trials as anticancer drugs (4,37). Plant Phenolics As Cytotoxic A n t i t u m o r Agents Discovered in Author's Laboratory

the

Studies on plant cytotoxic antitumor agents including phenolic compounds are proceeding in many laboratories (6-16). However, to limit the scope of the present discussion, this review will only deal with the work carried out in the author's laboratory. In our program, bioassay-directed fractionation and isolation studies are employed. This includes mainly an in vitro K B (cell culture) and an in vivo P-388 murine lymphocytic leukemia screening system as routine procedure for detecting cytotoxic antileukemic substances according to a protocol of the U.S. National Cancer



29. LEE

Plant Phenolic Compounds as Cytotoxic Antitumor Agents 369

OCH,

H,CO

H

1 1, Etoposide : R = H C

CN

8,NH

j^O—

3

HoJ^i— Ο H

//

9, NH

W-NO,

OH j 10, N H

2, Teniposide : R =//

\\

ο HO

11, OH

7, NH

NH

2

2

'/ W o '

12, N H

R

^ COOCH2CH3

H

j

· HC1

R

N

3

3, 10-Hydroxycamptothecin : R = OH, R = R3 = Η x

2

13, Camptothecin : R = R = R = Η x

2

3

14, Hycamptamine : R = OH, R = C H N ( C H ) , R = Η x

2

2

3

2

3

15, 9-Aminocamptothecin : R = OH, R = N H , R = Η x

2

16, CPT-11 : R = O C O - N ^ ) — * x

2

H

C

3

1

,

R

2

=

Η

' *

3 =

C H

2


C H

3

370



Institute (NCI) (42). In keeping up with the new screening strategy developed by the NCI (43-46), we have recently also included several disease-oriented human tumor cell lines, such as A-549 (lung carcinoma), HCT-8 (colon carcinoma), and MCF-7 (breast adenocarcinoma), into our routine screening program in order to discover new compounds with potential specificity against slowly growing solid tumors. On the basis of this approach, many new cytotoxic antitumor phenolics have been isolated and characterized, and are briefly discussed below. Alkaloids. 1. (+)-Thalifarazine (17) was isolated from Thalictrum sessile (Ranunculaceae). It showed cytotoxicity with E D * (KB) = 1.50, (HCT) = 4.30, (A5 0

549) = 6.53, (P-388) = 3.75, and (L-1210) = 5.69 μg/ml for the first time (47). 2. Three canthin-6-one alkaloids, including ll-hydroxycanthin-6-one [18, E D (KB) = 1.0 μg/ml], 11-hydroxy-l-methoxycanthin-6-one [19, E D (KB) = 2.0 μg/ml], and 1-hydroxy-ll-methoxycanthin-6-one [20, E D Q (KB) = 2.0 μg/ml] were first isolated as cytotoxic phenolic alkaloids from the stem of Brucea antidysenterica (Simaroubaceae) (48). A structure-activity relationships study of 1820 and their related derivatives indicated that hydroxylation or methoxylation of canthin-6-one alkaloids at C - l 1 or C-10 are essential for the cytotoxicity in the K B cells (49). 3. (-)-Norannuradhapurine · HBr [21, E D (HCT-8) = 3.32 μg/ml] isolated 5 0

5 0

5

5 0

from Fissistigma oldhamii (Annonaceae) and (-)-armepavine N-oxide [22, ED50 (KB) = 4.00 μg/ml] were found to show significant cytotoxicity (50). Anthraquinones. 1. Five cytotoxic antileukemic phenolic anthraquinones were isolated from Morinda parvifolia (Rubiaceae). These include the new morindaparvin-B [23, ED50 (KB) = 4.0 μg/ml], and the known alizarin-1-methyl ether [24, T / C (P388) = 136% (10 mg/kg)], lucidin-ω-methyl ether [25, E D (KB) = 0.62 μg/ml], digiferruginol [26, E D (P-388) = 5.9 μg/ml, (KB) = 0.09 μg/ml], and l-hydroxy-6 or 7-hydroxymethylanthraquinone [2 7, E D (KB) = 2.6 μg/ml, T/C (P-388) = 150% (10 mg/kg)]. Compounds 24-27 were isolated for the first time to demonstrate significant cytotoxic antileukemic activity (51,52). Compounds 15 and 18 were also synthesized by this laboratory (53). 5 0

5 0

5 0

Coumarins. 1. The Euphorbia splendens (Euphorbiaceae) afforded a weak cytotoxic coumarin, 3,3',4-tri-O-methylellagic acid [28, ED59 (KB) = 7.7 μg/ml ]. However, its demethylated polyphenols ellagic acid [2 9, ED59 (KB) = 4.6 μg/ml] was reported to be able to inactivate carcinogen benzo[a] pyrene-7,8-diol-9,10-epoxide (Lee, Κ. H.; Hayashi, N . ; Nozaki, H.; Okano, M . unpublished data.) (54). *ED o* The drug concentration in μg/ml which inhibits the growth by 50% as compared with controls. K B (human epidermoid carcinoma of the nasopharynx) response of < 4 μg/ml is considered as indicative of cytotoxicity (42). T/C: The ratio of mean survival rate of treated animals to the mean survival rate of control animals. According to NCI protocols, T/C > 125% is required for significant activity in the P-388 lymphocytic leukemia screen (42). 5

f



29. LEE

Plant Phenolic Compounds as Cytotoxic Antitumor Agents

4, Lycobetaine

OH

CHO O H

H C 3

CHO

CH

3

5, Gossypol


371


372


18, ll-Hydroxycanthin-6-one : R = H , R = O H x

2

19, 11-Hydroxy-l-methoxycanthin-6-one

: Ri = O C H , R = O H

20, 1- Hydroxy-ll-methoxycanthin-6-one

: R = OH, R = O C H

21, (-)-Norannuradhapurine · HBr

3

x

2

2

3

22, (-)-Armepavine N-oxide Ο

Ri

II

ι

Ο

R4

23, Morindaparvin-B : R = O H , R = C H O H , R = R = H , R = O H x

2

2

3

5

4

24, Alizarin-l-methyl ether : R = O C H , R = OH, R = R = R = Η x

3

2

3

4

5

25, Lucidin-û)-methyl ether : R = OH, R = C H O C H , R = O H , x

2

2

3

3

R4 = R5 = H

26, Digiferruginol : R = OH, R = R = R = H , R = C H O H x

2

3

4

5

2

27, l-Hydroxy-6 or 7-hydroxymethylanthraquinone : Rj = O H , R — R — R — H , R^ — C H O H 2

3

4

2


29. LEE


373

2. The chloroform extract of Brucea javanica (Simaroubaceae) furnished a phenolic coumarino-lignan cleomiscosin-A (30), which showed potent cytotoxicity [ E D (P-388) = 0.4 μg/ml] (55). 3. The known phenolic dicoumaryl ether, daphnoretin (31), was isolated from the whole plant of Wikstroemia indica (Thymelaeaceae). Compound 31 showed significant inhibitory activity in vivo against the Ehrlich ascites carcinoma growth in mice (97% inhibition at 3 mg/kg) but did not demonstrate significant activity against P388 lymphocytic leukemia growth (56). Compound 3 1 inhibits D N A and protein syntheses of Ehrlich ascites tumor cells (57,55).


5 0

F l a v o n o i d s . 1. The aforementioned W. indica also yielded two antileukemic flavonoids, tricin [32, T/C (P-388) = 133 (6 mg/kg) and 174% (12.5 mg/kg)] and kaempferol-3-0-p-glucopyranoside [33, T/C (P-388) = 130% (12.5 mg/kg)]. The good antileukemic activity demonstrated by 32 is noteworthy, as the cytotoxic flavonoids seldom show significant in vivo antileukemic (P-388) activity. It is also interesting to note that both 3 2 and 3 3 possess the same 7,5,4'-trihydroxylated pattern (56). 2. Hinokiflavone [3 4, ED50 (KB) = 2.0 μg/ml] was isolated as the cytotoxic principle from the drupes of Rhus succedanea (Anacardiaceae). A comparison of the cytotoxicity of 34 and other related biflavonoids indicates that an ether linkage between two units of apigenin as seen in 34 is structurally required for significant cytotoxicity (59). L i g n a n s . 1. The antitumor lignan isolated from W. indica mentioned above was identified as (+)-nortrachelogenin (i.e. wikstromol) (35) Compound 35 revealed activities of T/C = 122, 130, and 130% at doses of 4, 8, and 16 mg/kg, respectively, when tested against in vivo P-388 lymphocytic leukemia in B D F j mice (56). The reported data for 35 in the same in vivo screen were T/C = 130, 141, 137, 146, and 154% at doses of 1, 2,4, 10, and 16 mg/kg in C D F j mice (60). 2. A bioassay-directed fractionation of an antileukemic (P-388) extract of Justicia pro-cumbens (Acanthaceae) has led to the isolation of diphyllin (36), whose potent cytotoxicity [ED50 (KB) < 1.0 μg/ml] was shown for the first time. A comparison of the cytotoxicity of 36 and its related compounds indicated that the γlactone ring carbonyl α to C-3 instead of C-2 is required for the potent cytotoxicity (61) . 3. The known phenolic lignan, a-peltatin [37, ED50 (KB) = 0.09 μg/ml], was isolated as a potent cytotoxic principle from Podophyllum peltatum (Berberidaceae) (62) . M a c r o l i d e s . Lasiodiplodin (38), a resorcylate macrolide, was first isolated as a potent antileukemic [T/C (P-388) > 140% (0.2 mg/kg)] agent from the stem, root, and latex of the aforementioned E. splendens (63). Compound 3 8 was previously reported as a fungal metabolite of Lasiodiplodia theobromae (64). Naphthoquinones. The binaphthoquinone isodiospyrin [39; ED50 (HCT-8) = 4.9 μg/ml, (P-388) = 0.59 μg/ml], isolated from Diospyros morrisiana (Ebenaceae), was shown for the first time to be cytotoxic in the HCT-8 and P-388 screens (65). P o l y p h e n o l s . Acrovestone (40) was isolated from the stem and root bark of Acronychia pedunculata (Rutaceae). It demonstrated potent cytotoxicity for the first


374



Ο

OCH

3

31

30, Cleomiscosin-A

OCH

> Daphnoretin

3

Ο-β-D-Glucose OH

Ο

33, Kaempferol-3-0- β-D-glucopyranoside



29. LEE


OH

Ο 34, Hinokiflavone

OH 35, (+)-Nortrachelogenin (Wikstromol)

37, a-Peltatin

36, Diphyllin

38, Lasiodiplodin


375


376


OH

Ο

39, Isodiospyrin

H C 3

CH

3

H C 3

CH

3

40, Acrovestone


29. LEE


time against K B ( E D

5 0

= 0.5 μg/ml), A-549 ( E D

3.28 μg/ml), and L-1210 ( E D

5 0

5 0

= 0.98 μg/ml), P-388 ( E D

377

5 0

=

= 2.95 μg/ml) tumor cells (66).


Conclusions As discussed above, plant phenolics play an important role in providing new leads as cytotoxic anti-tumor agents. Some of these new leads and their analogs have already been developed for clinical use as anticancer drugs. Those cytotoxic antitumor agents discovered in the author's laboratory will undoubtedly serve continuously as templates for further synthetic modifications which may lead to more potent and less toxic clinically useful compounds. In addition, these new phenolic natural products and/or their analogs can also be used as tools for studying the biochemical mechanisms involved in the growth and control of tumors. Acknowledgements. I would like to thank my collaborators who contributed in many ways to the completion of much of this research work. These collaborators are cited in the accompanying references. This investigation was supported by a grant from the National Cancer Institute (CA-17625). Literature Cited 1. Neuss, N.; Gorman, M . ; Johnson, I. S. Methods in Cancer Res.; Academic Press: New York, NY, 1967; 633-702, and literature cited therein. 2. Lomax, N . R.; Narayanan, V. L . Chemical Structures of Interest to the Division of Cancer Treatment; NCI: 1988; Vol. 6. 3. Barnett, C . J.; Cullinan, G . J.; Gerzon, K . ; Hoying, R. C.; Jones, W. E . ; Newlon, W. M . ; Poore, G . Α.; Robinson, R. L . ; Sweeney, M . J.; Todd, G . C. J. Med. Chem. 1978, 21, 88-96, and literature cited therein. 4. Cragg, G . ; Suffness, M . Pharmac. Ther. 1988, 37, 425-461, and literature cited therein. 5. Etoposide (VP-16) - Current Status and New Developments; Issell, B . F.; Muggia, F. M . ; Carter, S. K., Eds.; Academic Press: Orlando, F L , 1984; 1355, and literature cited therein. 6. Suffness, M . ; Douros, J. In Methods in Cancer Research; DeVita, V. T., Jr.; Busch, H . , Eds.; New York, NY, 1979; Vol. 16, 73-126. 7. Douros, J.; Suffness, M . J. Nat. Prod. 1982, 45, 1-14. 8. Driscoll, J. S. Cancer Treat. Rep. 1984, 68, 63-76. 9. Anticancer Agents Based on Natural Product Models; Cassady, J. M . ; Douros, J. D., Eds.; Academic Press: New York, NY, 1980. 10. Cassady, J. M . ; Chang, C . J.; McLaughlin, J. L. In Natural Products as Medicinal Agents; Beal, J. L.; Reinhard, E . , Eds.; Hippokrates, Verlag, Stuttgart: 1981; 93-124, and literature cited therein. 11. Aszalos, A . Antitumor Compounds of Natural Origin; C R C Press: Boca Raton, F L , 1981. 12. Lee, Κ. H . In Adv. in Chinese Med. Materials Res.; Chang, H . M . , Ed.; World Sci. Publ. Co.: Singapore, 1985; 353-367. 13. Pettit, G . R.; Cragg, G . M . ; Herald, C . L. Biosynthetic Products for Cancer Chemotherapy; Elsevier: New York, NY, 1985; and four earlier volumes under the same title. 14. Lien, E . J.; L i , W. Y. Anticancer Chinese Drugs; Oriental Healing Arts Institute: Los Angeles, C A , 1985. 15. Lee, Κ. H . Oriental Healing Arts Internat. Bull. 1986, 11, 53-72. 16. Lee, K. H.; Yamagishi, T. Abs. Chinese Med. 1987,.1, 606-625. 17. Jardine, I. In Anticancer Agents Based on Natural Product Models; Cassady, J.;


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18. 19.


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29. LEE Plant Phenolic Compounds as Cytotoxic Antitumor Agents

44.


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Phenolic Compounds in Food and Their Effects on Health II

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