Discovery and Investigation of Anticancer Ruthenium–Arene Schiff-Base Complexes via Water-Promoted Combinatorial Three-Component Assembly

The
structural diversity of metal scaffolds makes them a viable
alternative to traditional organic scaffolds for drug design. Combinatorial
chemistry and multicomponent reactions, coupled with high-throughput
screening, are useful techniques in drug discovery, but they are rarely
used in metal-based drug design. We report the optimization and validation
of a new combinatorial, metal-based, three-component assembly reaction
for the synthesis of a library of 442 Ru–arene Schiff-base
(RAS) complexes. These RAS complexes were synthesized in a one-pot,
on-a-plate format using commercially available starting materials
under aqueous conditions. The library was screened for their anticancer
activity, and several cytotoxic lead compounds were identified. In
particular, [(η6-1,3,5-triisopropylbenzene)­RuCl­(4-methoxy-N-(2-quinolinylmethylene)­aniline)]Cl (4) displayed
low micromolar IC50 values in ovarian cancers (A2780, A2780cisR),
breast cancer (MCF7), and colorectal cancer (HCT116, SW480). The absence
of p53 activation or changes in IC50 value between p53+/+ and p53–/– cells suggests that 4 and possibly the other lead compounds may act independently
of the p53 tumor suppressor gene frequently mutated in cancer.