A Series of Alpha-amino Acid Ester Prodrugs of Camptothecin: in Vitro Hydrolysis and A549 Human Lung Carcinoma Cell Cytotoxicity

Overview

Journal J Med Chem

Publisher American Chemical Society

Specialty Chemistry

Date 2010 Jan 13

PMID 20063889

Citations 17

Authors

Manjeet Deshmukh

Piyun Chao

Hilliard L Kutscher

Dayuan Gao

Patrick J Sinko

Affiliations

Soon will be listed here.

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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