CONJUGATES OF NITROIMIDAZOLES AND THEIR USE AS CHEMOTHERAPEUTIC AGENTS

摘要

Novel compounds which are derivatives of tetra-O-methyl nordihydroguaiaretic acid (NDGA), as well as pharmaceutically acceptable salts, solvates, and stereoisomers thereof are provided. These NDGA derivatives have a nitroimidazole moiety and these derivatives show preferential toxicity to hypoxic cells as hypoxic cytotoxins. Their cytotoxicity toward hypoxic cells is a result of abstraction of hydrogen from target molecules by free radicals formed in the reduction of the nitro group. This makes the disclosed compounds an effective anti cancer drug because hypoxic cells are generally considered to be more resistant to anti cancer drugs than normal cells. Pharmaceutical compositions comprising such compounds, as well as methods of use, and treatment for cancers, including hepatocellular carcinoma, breast cancer and prostate cancer, are also provided.

主权项

1. A compound of Formula I: wherein X1 and X2 cannot be the same and are selected from the group consisting of H, OMe, and a nitroimidazole moiety of Formula Ia: with the proviso that one of X1 and X2 must be the nitroimidazole moiety of Formula Ia; wherein R1 and R2 are the same or different, and are each selected from the group consisting of H and electron withdrawing groups; and wherein Y is a linking group consisting of a water soluble polymer having n subunits, and wherein the polymer is selected from the group consisting of polyethylene glycol, polyvinyl alcohol, polycaprolactone, polypropylene glycol, polyethyloxazoline, and poly-L-lactic acid and related polymers and isomers thereof.