Design and synthesis of axial chiral anthracenes: In search of novel anti-tumor chemotherapeutics.

摘要

A series of anthracene isoxazole amides was rationally designed and synthesized as potential cancer chemotherapeutic agents. The in vitro and in vivo biological data obtained from this series established a structure to activity relationship that was used in the design of the next generation of antitumor compounds. Based on molecular modeling, fluorescence binding studies, and 2D NMR data our anthracene isoxazole system was determined to be a poor B-DNA intercalator. Further fluorescence microarray work established a distinct interaction between our lead compound 3-(9-anthracynyl)-N-[[2-[[2-[3-(N, N-dimethylamino)propyl]carbonyl]1-methyl-1H-pyrrol-4-yl] carbonyl]1-methyl-1 H-pyrrol-4-yl]-5-methyl-4-isoxazole carboxamide and a G-quadruplex forming oligonucleotide. These results aided in the development of an unsymmetrical anthracene system based upon the previous tumor cell growth-inhibiting compounds.; Chiral C5 isoxazole alcohol analogues were also synthesized to aid in establishing a metabolism profile for the anthracene-isoxazole system. Additionally, the chiral alcohol may have a dual function offering another potential hydrogen bonding site for stabilization of c-MYC G-quadruplex structures.