Anticancer and antimicrobial metallopharmaceutical agents based on palladium, gold, and silver N-heterocyclic carbene complexes.
Complete synthetic, structural, and biomedical studies of two Pd complexes as well as Au and Ag complexes of 1-benzyl-3-tert-butylimidazol-2-ylidene are reported. Specifically, trans-[1-benzyl-3-tert-butylimidazol-2-ylidene]Pd(pyridine)Cl2 (1a) was synthesized from the reaction of 1-benzyl-3-tert-butylimidazolium chloride (1) with PdCl2 in the presence of K2CO3 as a base. The other palladium complex, [1-benzyl-3-tert-butylimidazol-2-ylidene]2PdCl2 (1b), and a gold complex, [1-benzyl-3-tert-butylimidazol-2-ylidene]AuCl (1c), were synthesized by following a transmetallation route from the silver complex, [1-benzyl-3-tert-butylimidazol-2-ylidene]AgCl (1d), by treatment with (COD)PdCl2 and (SMe2)AuCl, respectively. The silver complex 1d in turn was synthesized by the reaction of 1 with Ag2O. The molecular structures of 1a-d have been determined by X-ray diffraction studies. Biomedical studies revealed that, while the palladium complexes 1a and 1b displayed potent anticancer activity, the gold (1c) and silver (1d) complexes exhibited significant antimicrobial properties. Specifically, 1b showed strong antiproliferative activity against three types of human tumor cells, namely, cervical cancer (HeLa), breast cancer (MCF-7), and colon adenocarcinoma (HCT 116), in culture. The antiproliferative activity of 1b was found to be considerably stronger than that of cisplatin. The 1b complex inhibited tumor cell proliferation by arresting the cell cycle progression at the G2 phase, preventing the mitotic entry of the cell. We present evidence suggesting that the treated cells underwent programmed cell death through a p53-dependent pathway. Though both the gold (1c) and silver (1d) complexes showed antimicrobial activity toward Bacillus subtilis, 1c was found to be ca. 2 times more potent than 1d.
Ray
Sriparna
S
Department of Chemistry, Indian Institute of Technology Bombay, Powai, Mumbai 400 076, India.
Mohan
Renu
R
Singh
Jay K
JK
Samantaray
Manoja K
MK
Shaikh
Mobin M
MM
Panda
Dulal
D
Ghosh
Prasenjit
P
D000890:Anti-Infective Agents / Q000737:chemistry* / Q000633:toxicity; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000633:toxicity; D001412:Bacillus subtilis / Q000166:cytology / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D006046:Gold / Q000737:chemistry*; D006571:Heterocyclic Compounds / Q000737:chemistry* / Q000633:toxicity; D006801:Humans; D006838:Hydrocarbons / Q000737:chemistry; D008697:Methane / Q000031:analogs & derivatives* / Q000737:chemistry; D050296:Microbial Viability / Q000187:drug effects; D015394:Molecular Structure; D012834:Silver / Q000737:chemistry*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D000890:Anti-Infective Agents; D000970:Antineoplastic Agents; D006571:Heterocyclic Compounds; D006838:Hydrocarbons; D016159:Tumor Suppressor Protein p53; C030011:carbene; D012834:Silver; D006046:Gold; D008697:Methane; D002945:Cisplatin