Conformational analysis of podophyllotoxin and its congeners. Structure-activity relationship in microtubule assembly

Curtis F. Brewer, John D. Loike, Susan Band Horwitz, Himan Sternlicht, Walter J. Gensler

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126 Citations (Scopus)

Abstract

Conformational analysis of podophyllotoxin and 11 congeners was carried out using 360-MHz 1H NMR techniques in order to determine the effects of substituent modifications in the C and D rings of these compounds on their conformational properties. The results are used to explore structure-activity relationships for this series of congeners related to their ability to inhibit microtubule assembly. The derivatives studied include the antitumor compound VP-16-213 (4′-demethylepipodophyllotoxin ethylidene-β-D-glucoside); the cyclic ether, cyclic sulfide, and cyclic sulfone derivatives of podophyllotoxin and deoxypodophyllotoxin; epipodophyllotoxin; and picropodophyllotoxin. From an analysis of the Overhauser enhancement effects and the J couplings, the conformations of these derivatives were found to be identical, with the exception of picropodophyllotoxin. The relationship between the antimitotic activity of these compounds and the substituent modifications in their structures suggests that the C and D rings of the derivatives are involved in their interactions with tubulin. Specifically, their activities were shown to be sensitive to the configuration, size, and/or hydrophilic character of substituents at the 4 position in the C ring and to the steric features of substituents at the 12 position in the D ring. In the case of picropodophyllotoxin, we suggest that its reduced antimitotic activity may be due to two conformational forms of the drug: a minority conformation which is active and a majority conformation which is inactive.

Original languageEnglish (US)
Pages (from-to)215-221
Number of pages7
JournalJournal of Medicinal Chemistry
Volume22
Issue number3
StatePublished - 1979

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Podophyllotoxin
Structure-Activity Relationship
Microtubules
Antimitotic Agents
Derivatives
Conformations
Cyclic Ethers
Sulfones
Glucosides
Sulfides
Etoposide
Tubulin
Nuclear magnetic resonance
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Organic Chemistry

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Conformational analysis of podophyllotoxin and its congeners. Structure-activity relationship in microtubule assembly. / Brewer, Curtis F.; Loike, John D.; Band Horwitz, Susan; Sternlicht, Himan; Gensler, Walter J.

In: Journal of Medicinal Chemistry, Vol. 22, No. 3, 1979, p. 215-221.

Research output: Contribution to journalArticle

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