This invention consists of novel non-natural Cephalotaxus ester compounds which are cytotoxic against both hematological and solid tumors, and the method of synthesis of these compounds.
A versatile and streamlined synthetic approach was devised to allow for the chemical synthesis of virtually any naturally occurring Cephalotaxus ester, as well as the synthesis of certain novel non-natural Cephalotaxus esters.
This method presents new avenues for molecular design of these alkaloids to offset multi-drug resistance. Further, the non-natural Cephalotaxus esters that have been synthesized using this approach can be used as new lines of chemotherapeutic defense against leukemia and solid tumors.
These non-natural compounds were assayed by cytotoxicity screening against an array of human hematopoietic and solid tumor cell lines including multi-drug resistant cell lines. It was found that the novel compounds have potent anti-tumor activity.
Cephalotaxus esters are present in the crude alkaloid extract of the plant, Cephalotaxus harringtonia, commonly known as the Japanese plum-yew, which is a small evergreen shrub native to Eastern Asia.
Several Cephalotaxus esters demonstrate acute toxicity toward various murine leukemia, murine lymphoma, and human epidermoid carcinoma cells. Homoharringtonine (HHT), a Cephalotaxus ester, has advanced through clinical studies and is now used for the treatment of chronic myeloid leukemia. Difficulties relating to production, hematologic toxicity, and susceptibility to multidrug resistance (MDR) have, however, hindered its clinical development.
This invention solves problems relating to production, toxicity, and multi-drug resistance of natural Cephalotaxus esters.
In vitro testing
David Gin, PhD
- U.S. patent application pending
- National stage applications in Europe, Hong Kong
- PCT application published: WO2009/148654