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Indexed by:期刊论文

Date of Publication:2006-10-15

Journal:BIOORGANIC & MEDICINAL CHEMISTRY

Included Journals:SCIE、PubMed

Volume:14

Issue:20

Page Number:6962-6970

ISSN No.:0968-0896

Key Words:antitumor agents; DNA; intercalation; geometry

Abstract:A series of acenaphtho[1,2-b]pyrrole derivatives were synthesized and their intercalation geometries with DNA and antitumor activities were investigated in detail. From combination of SYBR Green-DNA melt curve, fluorescence titration, absorption titration, and circular dichroism (CD) studies, it was identified that to different extent, all the compounds behaved as DNA intercalators and transformed B form DNA to A-like conformation. The different intercalation modes for the compounds were revealed. The compounds containing a methylpiperazine substitution (series I) intercalated in a fashion that the long axis of the molecule paralleled to the base-pair long axis, while the alkylamine-substituted compounds (series II and III) located vertically to the long axis of DNA base pairs. Consequently, the DNA binding affinity of these compounds was obtained with the order of II > III > I, which attributed to the role of the substitution in binding geometry. Further, cell-based studies showed all the compounds exhibited outstanding antitumor activities against two human tumor cell lines with IC50 ranging from 10(-7) to 10(-6) M. Interestingly, compound (1)a (a compound in series I), whose binding affinity was one of the lowest but altered DNA conformation most significantly, showed much lower IC50 value than other compounds. Moreover, it could induce tumor cells apoptosis, while the compounds (2)a and (3)a (in series II and III, respectively) could only necrotize tumor cells. Their different mechanism of killing tumor cells might lie in their different DNA binding geometry. It could be concluded that the geometry of intercalator-DNA complex contributed much more to the antitumor property than binding affinity. (c) 2006 Elsevier Ltd. All rights reserved.