Synthesis, hydrolytic DNA-cleaving activities and cytotoxicities of EDTA analogue-tethered pyrrole-polyamide dimer-based Ce(IV) complexes

Two EDTA analogue-tethered C2-symmetrical dimeric monopyrrole-polyamide 5 and dipyrrole-polyamide 6, and their corresponding Ce(IV) complexes Ce-5 and Ce-6 were synthesized and fully characterized. Agarose gel electrophoresis studies on pBR322 DNA cleavage indicate that complexes Ce-5 and Ce-6 exhib...

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Published in:European journal of medicinal chemistry 2014-11, Vol.87, p.168-174
Main Authors: Yang, Jian-Wei, Lin, Yan-Ling, Dong, Cheng, Zhou, Chun-Qiong, Chen, Jin-Xiang, Wang, Bo, Zhou, Zhong-Zhen, Sun, Bin, Chen, Wen-Hua
Format: Article
Language:English
Subjects:
Antineoplastic Agents - chemical synthesis
Antineoplastic Agents - pharmacology
Ce(IV) complex
Cell Proliferation - drug effects
Cerium - chemistry
Coordination Complexes - chemistry
Cytotoxicity
DNA Cleavage - drug effects
DNA, Superhelical - chemistry
Drug Design
Drug Screening Assays, Antitumor
Edetic Acid - chemistry
EDTA analogue
Flow Cytometry
Humans
Hydrolytic DNA cleavage
Molecular Structure
Neoplasms - drug therapy
Neoplasms - pathology
Nylons - chemistry
Organometallic Compounds - chemical synthesis
Organometallic Compounds - pharmacology
Pyrrole-polyamide dimer
Pyrroles - chemistry
Structure-Activity Relationship
Tumor Cells, Cultured
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Summary:Two EDTA analogue-tethered C2-symmetrical dimeric monopyrrole-polyamide 5 and dipyrrole-polyamide 6, and their corresponding Ce(IV) complexes Ce-5 and Ce-6 were synthesized and fully characterized. Agarose gel electrophoresis studies on pBR322 DNA cleavage indicate that complexes Ce-5 and Ce-6 exhibited potent DNA-cleaving activities under physiological conditions. The maximal first-order rate constants (kmax's) were (0.42 ± 0.02) h−1 for Ce-5 and (0.52 ± 0.02) h−1 for Ce-6, respectively, suggesting that both complexes catalyzed the cleavage of supercoiled DNA by up to approximately 108-fold. Complex Ce-6 exhibited ca 10-fold higher overall catalytic activity (kmax/KM) than Ce-5, which may be ascribed to its higher DNA-binding affinity. Inhibition experiments and a model study convincingly suggest that both complexes Ce-5 and Ce-6 functioned as hydrolytic DNA-cleavers. In addition, both complexes were found to display moderate inhibitory activity toward A549 and HepG-2 cells. Two EDTA analogue-tethered C2-symmetrical dimeric monopyrrole-polyamide 5 and dipyrrole-polyamide 6 were synthesized and their Ce(IV) complexes were found to exhibit potent hydrolytic DNA-cleaving activities. [Display omitted] •Two EDTA analogue-tethered C2-symmetrical pyrrole-polyamide dimers were synthesized.•Their Ce(IV) complexes were synthesized and fully characterized.•Both complexes showed potent DNA-cleaving activities, via a hydrolytic mechanism.•The activities of the Ce(IV) complexes correlated with their binding affinities.•Both Ce(IV) complexes had moderate inhibitory activity towards HepG-2 and A-549 cells.
ISSN:0223-5234
1768-3254
DOI:10.1016/j.ejmech.2014.09.057