Structure-activity Relationships of VP-16 Analogues

Overview

Journal Cancer Chemother Pharmacol

Specialty Oncology

Date 1994 Jan 1

PMID 8070024

Citations 4

Authors

B H Long

A M CASAZZA

Affiliations

Soon will be listed here.

Abstract

A total of 27 selected analogues of VP-16 and VM-26 were compared with VP-16 and VM-26 for their relative abilities to stabilize the enzyme-substrate intermediate normally formed between eukaryote topoisomerase II and DNA. This activity was compared with cytotoxicity results obtained using the human colon HCT116 cell line and antitumor results obtained after intraperitoneal injection of mice with murine leukemia P388. The most potent analogues were those containing OH groups (demethyl) in either the 3' and 4' or the 3', 4', and 5' positions, the latter being twice as potent as VP-16. VM-26 was only 40% more potent than VP-16 in this assay. It was generally found that the 4'-esters had little activity in vitro, yet were cytotoxic and had antitumor activities. All other analogues with little in vitro activity were not very cytotoxic and had little if any antitumor activity. A very good correlation exists between stabilization of topoisomerase II-DNA intermediates, cytotoxicity, and antitumor activity.

Citing Articles

Dirigent Proteins Guide Asymmetric Heterocoupling for the Synthesis of Complex Natural Product Analogues.

Kim S, Sattely E J Am Chem Soc. 2021; 143(13):5011-5021.

PMID: 33780244 PMC: 8450019. DOI: 10.1021/jacs.0c13164.

Interactions between the etoposide derivative F14512 and human type II topoisomerases: implications for the C4 spermine moiety in promoting enzyme-mediated DNA cleavage.

Gentry A, Pitts S, Jablonsky M, Bailly C, Graves D, Osheroff N Biochemistry. 2011; 50(15):3240-9.

PMID: 21413765 PMC: 3086367. DOI: 10.1021/bi200094z.

Substituents on etoposide that interact with human topoisomerase IIalpha in the binary enzyme-drug complex: contributions to etoposide binding and activity.

Bender R, Jablonksy M, Shadid M, Romaine I, Dunlap N, Anklin C Biochemistry. 2008; 47(15):4501-9.

PMID: 18355043 PMC: 2737519. DOI: 10.1021/bi702019z.

Topoisomerase II - drug interaction domains: identification of substituents on etoposide that interact with the enzyme.

Wilstermann A, Bender R, Godfrey M, Choi S, Anklin C, Berkowitz D Biochemistry. 2007; 46(28):8217-25.

PMID: 17580961 PMC: 2888091. DOI: 10.1021/bi700272u.

References

WILLSON J, Bittner G, Oberley T, Meisner L, Weese J . Cell culture of human colon adenomas and carcinomas. Cancer Res. 1987; 47(10):2704-13. View

Osheroff N, Zechiedrich E, Gale K . Catalytic function of DNA topoisomerase II. Bioessays. 1991; 13(6):269-73. DOI: 10.1002/bies.950130603. View

DArpa P, Liu L . Topoisomerase-targeting antitumor drugs. Biochim Biophys Acta. 1989; 989(2):163-77. DOI: 10.1016/0304-419x(89)90041-3. View

Liu L, Davis J, Calendar R . Novel topologically knotted DNA from bacteriophage P4 capsids: studies with DNA topoisomerases. Nucleic Acids Res. 1981; 9(16):3979-89. PMC: 327409. DOI: 10.1093/nar/9.16.3979. View

Glisson B, Ross W . DNA topoisomerase II: a primer on the enzyme and its unique role as a multidrug target in cancer chemotherapy. Pharmacol Ther. 1987; 32(2):89-106. DOI: 10.1016/0163-7258(87)90054-4. View

Loike J, Horwitz S . Effect of VP-16-213 on the intracellular degradation of DNA in HeLa cells. Biochemistry. 1976; 15(25):5443-8. DOI: 10.1021/bi00670a004. View

Gale K, Osheroff N . Intrinsic intermolecular DNA ligation activity of eukaryotic topoisomerase II. Potential roles in recombination. J Biol Chem. 1992; 267(17):12090-7. View

Ross W, Rowe T, Glisson B, Yalowich J, Liu L . Role of topoisomerase II in mediating epipodophyllotoxin-induced DNA cleavage. Cancer Res. 1984; 44(12 Pt 1):5857-60. View

Rose W, Basler G . An in vivo human tumor xenograft model of etoposide resistance. In Vivo. 1989; 3(4):249-53. View

10.

STAHELIN H, von Wartburg A . From podophyllotoxin glucoside to etoposide. Prog Drug Res. 1989; 33:169-266. DOI: 10.1007/978-3-0348-9146-2_8. View

11.

Wang J, MARTIN K, Calendar R . On the sequence similarity of the cohesive ends of coliphage P4, P2, and 186 deoxyribonucleic acid. Biochemistry. 1973; 12(11):2119-23. DOI: 10.1021/bi00735a016. View

12.

STAHELIN H . 4'-Demethyl-epipodophyllotoxin thenylidene glucoside (VM 26), a podophyllum compound with a new mechanism of action. Eur J Cancer (1965). 1970; 6(4):303-11. DOI: 10.1016/0014-2964(70)90095-2. View

13.

Potter M, BRIGGS G . Inhibition of growth of amethopterinsensitive and amethopterin-resistant pairs of lymphocytic neoplasms by dietary folic-acid deficiency in mice. J Natl Cancer Inst. 1962; 28:341-51. View

14.

Ohnuma T, Obata R, Nishiyama Y, Yamasaki T, Kamei H, Naito T . Preparation and antitumor activity of 2''-O-, 3''-O- and 2'',3''-di-O-substituted derivatives of etoposide. Chem Pharm Bull (Tokyo). 1992; 40(7):1783-8. DOI: 10.1248/cpb.40.1783. View

15.

STAHELIN H . Activity of a new glycosidic lignan derivative (VP 16-213) related to podophyllotoxin in experimental tumors. Eur J Cancer (1965). 1973; 9(3):215-21. DOI: 10.1016/s0014-2964(73)80021-0. View

16.

Long B, Wang L, Lorico A, Wang R, Brattain M, CASAZZA A . Mechanisms of resistance to etoposide and teniposide in acquired resistant human colon and lung carcinoma cell lines. Cancer Res. 1991; 51(19):5275-83. View

17.

Hofmann G, Mirabelli C, Drake F . Quantitative adaptation of the bacteriophage P4 DNA unknotting assay for use in the biochemical and pharmacological characterization of topoisomerase II. Anticancer Drug Des. 1990; 5(3):273-82. View

18.

Chen G, Yang L, Rowe T, Halligan B, Tewey K, Liu L . Nonintercalative antitumor drugs interfere with the breakage-reunion reaction of mammalian DNA topoisomerase II. J Biol Chem. 1984; 259(21):13560-6. View

19.

Ross W, Glaubiger D, Kohn K . Qualitative and quantitative aspects of intercalator-induced DNA strand breaks. Biochim Biophys Acta. 1979; 562(1):41-50. DOI: 10.1016/0005-2787(79)90124-2. View

20.

Rose W, Basler G, Trail P, Saulnier M, Crosswell A, CASAZZA A . Preclinical antitumor activity of a soluble etoposide analog, BMY-40481-30. Invest New Drugs. 1990; 8 Suppl 1:S25-32. DOI: 10.1007/BF00171981. View