Antitumor AHMA linked to DNA minor groove binding agents: Synthesis and biological evaluation

Kamesh Rastogi, Jang Yang Chang, Wen Yu Pan, Ching Huang Chen, Ting Chao Chou, Li Tzong Chen, Tsann Long Su

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40 Citations (Scopus)


DNA minor groove binder hybrid molecules, netropsin derivatives such as N-[2-(dimethylamino)-ethyl]-1-methyl-4-aminopyrrolo-2-carboxamide (MePy) or its derivatives containing two units of N-methylpyrrolecarboxamide (diMePy) and bisbenzimidazole (Ho33258), were linked to the NH2 function of AHMA or to the CH2OH group of AHMA-ethylcarbamate to form AHMA-N-netropsins (13-16) and AHMA-ethylcarbamate-O-netropsins (19-22), and AHMA-bisbenzimidazole (AHMA-Ho33258, 25), respectively. These conjugates' in vitro antitumor activity, inhibition of a variety of human tumor cell growth, revealed that AHMA-ethylcarbamate-O-netropsin derivatives were more cytotoxic than AHMA-N-netropsin compounds. In the same studies, all compounds bearing MePy were more potent than those compounds linked with diMePy. Moreover, AHMA-netropsin derivatives bearing a succinyl chain as the linking spacer were more potent than those compounds having a glutaryl bridge. Among these hybrid molecules, AHMA-ethylcarbamate-O-succinyl-MePy (19) was 2- to 6-fold more cytotoxic than the parent compound AHMA (5) in various cell lines, whereas compound 25 had very poor solubility and was inactive. Studies on the inhibitory effect against topoisomerase II (Topo II) and DNA interaction of these conjugates showed no correlation between the potency of DNA binding and inhibitory activity against Topo II.

Original languageEnglish
Pages (from-to)4485-4493
Number of pages9
JournalJournal of Medicinal Chemistry
Issue number20
Publication statusPublished - Sept 2002
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery


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