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.