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A series of alpha-amino acid ester prodrugs of camptothecin: in vitro hydrolysis and A549 human lung carcinoma cell cytotoxicity.

Authors
  • Deshmukh, Manjeet1
  • Chao, Piyun
  • Kutscher, Hilliard L
  • Gao, Dayuan
  • Sinko, Patrick J
  • 1 Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854, USA. , (Jersey)
Type
Published Article
Journal
Journal of Medicinal Chemistry
Publisher
American Chemical Society
Publication Date
Feb 11, 2010
Volume
53
Issue
3
Pages
1038–1047
Identifiers
DOI: 10.1021/jm901029n
PMID: 20063889
Source
Medline
License
Unknown

Abstract

The objective of the present study was to identify a camptothecin (CPT) prodrug with optimal release and cytotoxicity properties for immobilization on a passively targeted microparticle delivery system. A series of alpha-amino acid ester prodrugs of CPT were synthesized, characterized, and evaluated. Four CPT prodrugs were synthesized with increasing aliphatic chain length (glycine (Gly) (2a), alanine (Ala) (2b), aminobutyric acid (Abu) (2c), and norvaline (Nva) (2d)). Prodrug reconversion was studied at pH 6.6, 7.0, and 7.4 corresponding to tumor, lung, and extracellular/physiological pH, respectively. Cytotoxicity was evaluated in A549 human lung carcinoma cells using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The hydrolytic reconversion rate to parent CPT increased with decreasing side chain length as well as increasing pH. The Hill slope of 2d was significantly less than CPT and the other prodrugs tested, indicating a higher cell death rate at lower concentrations. These results suggest that 2d is the best candidate for a passively targeted sustained release lung delivery system.

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