Synthesis of acylhydrazido-substituted cephems. Design of cephalosporin-vinca alkaloid prodrugs: substrates for an antibody targeted enzyme

Cephalosporin 20 substituted at the C-3' position with the potent oncolytic agent desacetylvinblastine hydrazide (3) was synthesized as a potential prodrug for the treatment of solid tumors. The design of this novel prodrug was based on the knowledge that hydrolysis of a cephalosporin's be...

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Bibliographic Details
Published in:Journal of organic chemistry 1992-04, Vol.57 (8), p.2334-2340
Main Authors: Jungheim, Louis N, Shepherd, Timothy A, Meyer, Damon L
Format: Article
Language:English
Subjects:
Chemistry
Chemistry, Organic
Exact sciences and technology
Heterocyclic compounds
Heterocyclic compounds with n hetero atom and also o and/or s, se, te hetero atoms
Organic chemistry
Physical Sciences
Preparations and properties
Science & Technology
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Summary:Cephalosporin 20 substituted at the C-3' position with the potent oncolytic agent desacetylvinblastine hydrazide (3) was synthesized as a potential prodrug for the treatment of solid tumors. The design of this novel prodrug was based on the knowledge that hydrolysis of a cephalosporin's beta-lactam bond can result in the expulsion of the C-3' substituent. Proper selection of the linkage used to join the cephem to the vinca, e.g., 8 vs 20, provided a releasable form of the drug as well as a chemically stable prodrug. We envisioned the conversion of prodrug to free vinca to be mediated by an immunoconjugate, consisting of a beta-lactamase enzyme covalently attached to a monoclonal antibody, which has been prelocalized at the tumor. Treatment of candidate prodrugs with the P99 beta-lactamase enzyme isolated from Enterobacter cloacae 265A efficiently catalyzed their conversion to the free drug form. A study of model compounds 11 and 18 indicated that cephem 1-beta-sulfoxide 18 was a better substrate for the enzyme than its sulfide counterpart 11. This finding prompted the synthesis of cephem sulfoxide 20 which was efficiently accomplished via condensation of desacetylvinblastine hydrazide with the cephalothin derived cephem 3'-p-nitrophenyl carbonate 15.
ISSN:0022-3263
1520-6904
DOI:10.1021/jo00034a027