Novel Oligopyrrole Carboxamide based Nickel(II) and Palladium(II) Salens, Their Targeting of Human G-Quadruplex DNA, and Selective Cancer Cell Toxicity.
DNA targeting by various metal complexes is a key strategy toward the restriction of cancer cell proliferation. Toward this end, we designed and synthesized novel salen-based Ni(II) and Pd(II) metal complexes with positively charged flanking side chains comprising N-methylpyrrole carboxamides of varying lengths. The compounds showed high specificity toward G-quadruplex DNA over duplex DNA. Sufficient inhibition of the telomerase activity was observed, which was ascertained by the prominent restriction of cancer cell proliferation in the long-term cell viability and telomerase inhibition assays. The compounds exhibited selective cancer cell death following an apoptotic pathway. Analysis of the binding mode showed partial stacking of the salen moiety over the G-tetrads and association of the pendant oligopyrrole carboxamide units with the grooves. The conjugation of the tetrad-binding metal salen core with groove-oriented flexible oligopyrrole moieties resulted in the high selectivity and stabilization of the human G-quadruplex DNA structures.
Department of Organic Chemistry, Indian Institute of Science, Bangalore, 560 012, India.
Asfa
A
Ali
Department of Organic Chemistry, Indian Institute of Science, Bangalore, 560 012, India.
Mohini
M
Kamra
Department of Organic Chemistry, Indian Institute of Science, Bangalore, 560 012, India.
Soma
S
Roy
Department of Biochemistry, Indian Institute of Science, Bangalore, 560 012, India.
K
K
Muniyappa
Department of Organic Chemistry, Indian Institute of Science, Bangalore, 560 012, India. sb@orgchem.iisc.ernet.in.|Director's Research Unit, Indian Association for the Cultivation of Science, Kolkata, 700 032, India. sb@orgchem.iisc.ernet.in.
Santanu
S
Bhattacharya
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004273:DNA, Neoplasm / Q000187:drug effects* / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D005029:Ethylenediamines / Q000737:chemistry / Q000494:pharmacology; D054856:G-Quadruplexes / Q000187:drug effects*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D009532:Nickel / Q000494:pharmacology; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010165:Palladium / Q000737:chemistry / Q000494:pharmacology; D011758:Pyrroles / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D019098:Telomerase / Q000037:antagonists & inhibitors / Q000378:metabolism
D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D004791:Enzyme Inhibitors; D005029:Ethylenediamines; D009942:Organometallic Compounds; D011758:Pyrroles; D010165:Palladium; D009532:Nickel; C011452:disalicylaldehyde ethylenediamine; D019098:Telomerase
G-quadruplexes; N ligands; nickel; palladium; salen ligands