Synthesis of phosphinic acid analogues of anti-tumour agents

Abstract

Synthetic ether analogues (prototypes: miltefosine, perifosine and cdelfosine) of natural phospholipids are a family of anti-cancer drugs with a wide range of pharmacological behaviour. There is a growing interest in anti-cancer ether phospholipids owing to their seleC;!1vity against tumours which has resulted in a much lower toxicity, as compared with other classical anti-cancer chemotherapeutic agents. However, due to the presence of the phosphate diester, these compounds can be quickly biodegraded by enzymes of phospholipid metabolism. Consequently, the aims of this research project were to synthesise isosteric analogues of miltefosine, perifosine and edelfosine by replacing the two phosphorus-oxygen bonds with phosphorus-carbon bonds. Several methodologies for the preparation of phosphorus-carbon bonds were investigated and phosphinic acid analogues of miltefosine, perifosine and edelfosine were efficiently synthesised in good overall yields. The first phosphorus-carbon bond of miltefosine and edelfosine analogues was prepared by a radical hydrophosphorylation addition reaction, and the second by conversion to the P(III) silyloxy intermediate, followed by Michael-type addition to acrylonitrile and acidic hydrolysis of the silyl groups. Miltefosine analogue was synthesised in a total of six steps from hexadecene, in 69% overall yield, and edelfosine analogue was synthesised in a total of ten steps from hexadecanol, in 8.5% overall yield. Perifosine analogue was successfully synthesised by a double radical hydrophosphorylatipn process, in a total of six steps, in 50% overall yield from hexadecene.EThOS - Electronic Theses Online ServiceGBUnited Kingdo