Macrocyclic hexaoxazoles: Influence of aminoalkyl substituents on RNA and DNA G-quadruplex stabilization and cytotoxicity

A series of 24-membered macrocyclic hexaoxazoles containing one or two aminoalkyl substituents was synthesized and evaluated for cytotoxicity and for their ability to selectively stabilize G-quadruplex DNA and RNA. The most cytotoxic analog 4a, with IC50 values of 25 and 130 nM using KB3-1 and RPMI 8402 cells, is efficacious in vivo in athymic nude mice with a human tumor xenograft from the breast cancer cell line MDA-MB-435.

Several monoaminoalkyl derivatives with R′′ being isopropyl and various bis-aminoalkyl substituted hexaoxazoles derivatives were evaluated for cytotoxicity and stabilization of G-quadruplex RNA and DNA. One of the more cytotoxic analogs (where n = 1, R′′ is isopropyl and both R and R′ are methyl substituents) inhibits human tumor growth in the athymic nude mouse xenograft model.Figure optionsDownload as PowerPoint slide