Document Detail

A series of alpha-amino acid ester prodrugs of camptothecin: in vitro hydrolysis and A549 human lung carcinoma cell cytotoxicity.
MedLine Citation:
PMID:  20063889     Owner:  NLM     Status:  MEDLINE    
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.
Manjeet Deshmukh; Piyun Chao; Hilliard L Kutscher; Dayuan Gao; Patrick J Sinko
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.    
Journal Detail:
Title:  Journal of medicinal chemistry     Volume:  53     ISSN:  1520-4804     ISO Abbreviation:  J. Med. Chem.     Publication Date:  2010 Feb 
Date Detail:
Created Date:  2010-02-04     Completed Date:  2010-03-12     Revised Date:  2014-05-23    
Medline Journal Info:
Nlm Unique ID:  9716531     Medline TA:  J Med Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1038-47     Citation Subset:  IM    
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MeSH Terms
Alanine / chemistry
Aminobutyrates / chemistry
Antineoplastic Agents, Phytogenic / chemical synthesis,  chemistry,  pharmacology*
Camptothecin / chemical synthesis,  chemistry,  pharmacology*
Cell Proliferation / drug effects*
Cell Survival
Esters / chemistry*
Glycine / chemistry
Lung Neoplasms / drug therapy*
Prodrugs / chemical synthesis,  chemistry,  pharmacology*
Tumor Cells, Cultured
Valine / analogs & derivatives,  chemistry
Grant Support
Reg. No./Substance:
0/Aminobutyrates; 0/Antineoplastic Agents, Phytogenic; 0/Esters; 0/Prodrugs; A70UKS48FE/norvaline; HG18B9YRS7/Valine; OF5P57N2ZX/Alanine; TE7660XO1C/Glycine; XT3Z54Z28A/Camptothecin

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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