Multiple drug resistant (MDR) carcinomas represent an urgent and growing problem in the field of human health. Because these cancer phenotypes respond poorly to treatment with known chemotherapeutic agents, there exists a need for novel cytotoxic reagents to combat them. The marine alkaloid N-methylwelwitindolinone C isothiocyanate is well poised to address this situation. Not only has this natural product displayed potent cytotoxic activity against MDR breast cancer cells (MCF-7, IC50=130 nM), but it has also been shown to reverse the drug resistant capacity of these cell lines, making them up to one-hundred fold more susceptible to conventional cancer drugs such as taxol. Because its isolation from natural sources is a painstaking process that affords little material, the total synthesis of N-methylwelwitindolinone C isothiocyanate is poised as an effective technique to access additional quantities of this potent bioactive compound. The research proposed herein describes a novel, concise approach toward the preparation of N- methylwelwitindolinone C isothiocyanate. The project will involve the development of an enantioselective oxidative dearomatization reaction for the coupling of aryl halides with ortho-carboxy phenols. This new method will provide access to enantioenriched cyclohexadienone products bearing all-carbon 1-quaternary stereocenters. By applying this technique to the synthesis of the N-methylwelwitindolinone C isothiocyanate it will be possible to rapidly construct the complex tetracyclic carbon scaffold of the natural product, which will in turn allow expedient preparation of this marine alkaloid.
The research proposed herein describes the preparation of the bioactive, multi-drug resistant, cancer fighting natural product known as N-methylwelwitindolinone C isothiocyanate. The project involves the development of a novel reaction for the efficient construction of complicated organic molecules, a technique that will be applied to the rapid completion of the aforementioned natural product. Because N- methylwelwitindolinone C isothiocyanate has displayed potent efficacy against resilient cancer lines, but is only naturally available in sparingly small amounts, these efforts will aid in the evolution of novel chemotherapeutic agents by affording expedient access to this scarce compound for testing and study.
|Kong, Ke; Enquist Jr, John A; McCallum, Monica E et al. (2013) An enantioselective total synthesis and stereochemical revision of (+)-citrinadin B. J Am Chem Soc 135:10890-3|