Synthesis and Biological Study of a New Series of 4‘-Demethylepipodophyllotoxin Derivatives

Abstract

Etoposide (VP-16) is a potent human DNA topoisomerase II poison, derived from 4'-demethylepipodophyllotoxin, widely used in cancer chemotherapy. Continuous efforts have driven to synthesize new related compounds, presenting decreased toxic side effects, metabolic inactivation, drug resistance, and increased water solubility. Identified structure-activity relationships have pointed out the importance of the 4beta-substitution and of the configuration of the D ring. Here we report the synthesis of two novel series of derivatives of 4'-demethylepipodophyllotoxin. The first bears a carbamate chain in the 4 position (13a-f), whereas, in the second series, in addition to this chain, the lactone ring has been modified by shifting the carbonyl from position 13 to position 11 (27a-f). Moreover, an analogue of TOP-53 having this lactone modification has also been prepared (32). From this study, structure-activity relationships were established. Compounds 13a and 27a displayed potent cytotoxic activity against the L1210 cell line (10 to 20-fold higher than VP-16) and proved to be strong topoisomerase II poisons more potent than VP-16. From preliminary in vivo investigation of both compounds against P388 leukemia and orthotopically grafted human A549 lung carcinoma, it appeared that 13a and 27a constitute promising leads for a new class of antitumor agents.

A Review on Hemisynthesis, Biosynthesis, Biological Activities, Mode of Action, and Structure-Activity Relationship of Podophyllotoxins: 2003- 2007

“…Compound 147, bearing a 2-[2-(N,Ndimethylamino)ethyl]aminoethyl side chain, was weakly cytotoxic (IC 50 = 27.9 μM) and had no effect on topo II. Thus, the 4-carbamate substituents seemed essential for the activity in this retrolactone series [57].…”

Synthesis of New Conjugates of Modified Podophyllotoxin and Stavudine

“…-The synthetic route to the target compounds involved the intermediate 6,7-de-O-methylene-6,7-di-O-methyl-4-epipodophyllotoxin 1 ) (4) which was prepared from 1 [13], and 3 ( Fig. 1) which was synthesized by treatment of 2 with 4-nitrophenyl chloroformate (¼ 4-nitrophenyl carbonochloridate) [14] according to a previously published method [12]. Compound 4 was condensed with the appropriate (benzyloxy)carbonyl(Cbz)-protected amino acids 5a -5f in the presence of N,Ndicyclohexylcarbodiimide (DCC) and N,N-dimethylpyridin-4-amine (DMAP) to provide 6a -6f in high yield [15].…”

Podophyllotoxin derivatives: a patent review (2012 – 2014)

“…However, the mode of action of these compounds is distinct from that of PPT. These are reported to inhibit DNA-topoisomerase II, causing cell cycle arrest in the late S-G2 phase leading to cell death [8]. It is noteworthy that almost all the compounds developed based on the PPT scaffold are reported to exert cytotoxic activity either by inhibiting tubulin polymerization or topoisomerases.…”