Structural optimization of icaritin for advanced cancer: novel carbamates via oral administration

Abstract

Advanced cancer is a leading cause of disability and mortality globally, with an ever-increasing incidence. In China, icaritin (ICT), a naturally occurring compound with established efficacy and safety, is widely administered orally for treating advanced cancer. However, due to significant phase II metabolism with a positional preference on 3-OH, its usage in clinical settings is restricted. To minimize the phase II metabolism, we synthesized N-monomethyl carbamate and N-monoethyl carbamate (3N-Me and 3N-Et) that were modified on the 3-OH group of ICT. Just as we expected, 3N-Me and 3N-Et remained stable during the absorption process, and they were metabolized in plasma to the ICT. The rate of phase II metabolism of carbamate in vitro was significantly lower compared to ICT. Additionally, the different forms of the carbamate resulted in similar or stronger cytotoxicity than ICT. Furthermore, the pharmacokinetics of 3N-Me and 3N-Et were studied after oral administration. Compared to ICT, the oral administration of 3N-Me led to a significantly enhanced bioavailability of ICT and 3N-Me in rats. It was found that 3N-Me was more effective in exerting its anticancer pharmacological activity and was equally safe as the form of ICT alone. Additionally, our results indicated that ICT and 3N-Me both have beneficial effects on immunotoxicity and spleen functions altered by cancer. This suggests the potential for further development of 3N-Me medicine in the anticancer field for oral administration.