Acenaphtho[1,2-b]pyrrole derivatives as new family of intercalators: various DNA binding geometry and interesting antitumor capacity.
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 IC(50) 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 IC(50) 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.
Zhang
Zhichao
Z
State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian 116012, China.
Yang
Yuanyuan
Y
Zhang
Danni
D
Wang
Yuanyuan
Y
Qian
Xuhong
X
Liu
Fengyu
F
D000073:Acenaphthenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001665:Binding Sites; D045744:Cell Line, Tumor; D002942:Circular Dichroism; D004247:DNA / Q000737:chemistry / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor; D006367:HeLa Cells; D006801:Humans; D066298:In Vitro Techniques; D007364:Intercalating Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D009690:Nucleic Acid Conformation / Q000187:drug effects; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D012680:Sensitivity and Specificity; D013329:Structure-Activity Relationship; D013696:Temperature
D000073:Acenaphthenes; D000970:Antineoplastic Agents; D007364:Intercalating Agents; D011758:Pyrroles; D004247:DNA