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Chemistry of Heterocyclic Compounds

, Volume 45, Issue 2, pp 228–244 | Cite as

Synthesis and cytotoxic activity of derivatives of the tert-butyl ester of 7Z-acetylmethylene-3-methyl-3-cephem-4-carboxylic acid

  • I. Potorocina
  • M. Vorona
  • G. VeinbergEmail author
  • I. Shestakova
  • I. Kanepe
  • M. Petrova
  • E. Liepinsh
  • E. Lukevics
Article

The condensation of the acetylmethylene group in the tert-butyl esters of 7Z-acetylmethylene-3-methyl-3-cephem-4-carboxylic acid and 7Z-acetylmethylene-3-methyl-1,1-dioxo-3-cephem-4-carboxylic acid and in 7Z-acetylmethylene-3-methylene-1,1-dioxo-3-cephem with arylmethoxyamines and O-alkylation of the tert-butyl ester of 7Z-(2-hydroxyimino)propylidene-3-methyl-1,1-dioxo-3-cephem-4-carboxylic acid using substituted benzyl bromides as well as pyridylmethyl chlorides gave arylmethoxyimino and pyridylmethoxyimino derivatives of these compounds in the syn and anti isomeric forms. The Vilsmaier reagent was used to introduce the N,N-dimethylaminomethylene group at C-2 of the cephem system in the tert-butyl esters of 7Z-[2-(arylmethoxyimino)propylidene]-3-methyl-1,1-dioxo-3-cephem-4-carboxylic acid. Subsequent transformation of the N,N-dimethylaminomethylene cephems using hydroxylamine led to 3Z-[2-(anti-arylmethoxyimino)propylidene]-tert-butoxycarbonylmethyl-4-(5-methyl-4-isoxazolylsulfonyl)- azetidin-2-ones. Condensation of the acetyl group in the tert-butyl ester of 7Z-acetylmethylene- 3-methyl-1,1-dioxo-3-cephem-4-carboxylic acid with 4-bromophenylhydrazine gave a cephem with a 2-(4-bromophenylhydrazono)propylidene group at C-7. Acylation of the tert-butyl ester of 7Z-(2-hydroxyimino)propylidene-3-methyl-1,1-dioxo-3-cephem-4-carboxylic acid by 2-bromobenzoyl chloride gave a cephem with a 2-(2-bromo-benzoyloxyimino)propylidene group at C-7. Biological screening of these products towards to malignant and normal cells in vitro showed that their antitumor activity and cytotoxic selectivity towards to malignant and normal cells depend on the structure and configuration of the arylmethoxyimino and pyridylmethoxyimino groups in the 7-alkylidene substituent as well as on the presence or absence of N,N-dimethylaminomethylene and carboxyl groups, respectively, at C-2 and C-4 of the cephem system.

Keywords

3Z-[2-(arylmethoxyimino)propylidene]-1-tert-butoxycarbonylmethyl-4-(5-methyl-4-isoxazolyl- sulfonyl)azetidin-2-ones tert-butyl ester of 7Z-[2-(arylmethoxyimino)propylidene]-3-methyl-3-cephem- 4-carboxylic acid tert-butyl ester of 7Z-[2-(2-bromobenzoyloxyimino)propylidene]-3-methyl-1,1-dioxo- 3-cephem-4-carboxylic acid tert-butyl ester of 7Z-[2-(4-bromophenylhydrazono)propylidene]-3-methyl-1,1-dioxo-3-cephem-4-carboxylic acid tert-butyl ester of 7Z-[2-(hydroxyimino)propylidene]-3-methyl-1,1-dioxo-3-cephem-4-carboxylic acid tert-butyl esters of 7Z-[2-(arylmethoxyimino)-propylidene]-2-(dimethylaminomethylene)-3-methyl-1,1-dioxo-3-cephem-4-carboxylic acid tert-butyl esters of 7Z-(arylmethoxyimino)propylidene]-3-methyl-1,1-dioxo-3-cephem-4-carboxylic acid tert-butyl esters of 3-methyl-1,1-dioxo-7Z-[2-(pyridylmethoxyimino)propylidene]-3-cephem-4-carboxylic acid 

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Copyright information

© Springer Science+Business Media, Inc. 2009

Authors and Affiliations

  • I. Potorocina
    • 1
  • M. Vorona
    • 1
  • G. Veinberg
    • 1
    Email author
  • I. Shestakova
    • 1
  • I. Kanepe
    • 1
  • M. Petrova
    • 1
  • E. Liepinsh
    • 1
  • E. Lukevics
    • 1
  1. 1.Latvian Institute of Organic SynthesisRigaLatvia

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