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Synthesis of Lipophilic Benz[cd]indole Antifolates and Their Antitumor Activity In Vitro  

Baek Du-Jong (Department of Chemistry, College of Natural Sciences, Sangmyung University)
Publication Information
YAKHAK HOEJI / v.49, no.1, 2005 , pp. 60-67 More about this Journal
Abstract
Nonclassical aminobenz[cd]indole antifolates 4, 5 and 6, in which the glutamic acid moiety of the classical antifolates is substituted by 2-phenylglycinamide or 3-aminobenzamide, were synthesized and their in vitro antitumor activity was evaluated. The purpose of this substitution is that the lipophilicity is enhanced due to the aromatic ring of the target compounds for the passive transport through lipid membrane of cells while the hydrogen bonding of the amide is retained in the active site of the enzyme, thymidylate synthase, where the glutamate is originally present. The target compounds were highly cytotoxic against tumor cell lines of murine and human origin with micromolar to nanomolar $IC_{50}$ values. Most effective was compound 4 ($N^6-methyl-N^6$-[4-[(${\alpha}$(S)-aminocarbonylbenzyl) aminocarbonyl]benzyl]-2,6-diaminobenz[cd]indole)with $IC_{50}$ of 2 nM against SW480, human colon adenocarcinoma cell line, which is 650-fold more potent than the reference compound 3.
Keywords
benz[cd]indole; nonclassical antifolates; in vitro antitumor activity;
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Times Cited By KSCI : 1  (Citation Analysis)
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