Solution conformational analysis, crystal structure determination, and anticancer activity of ring-constrained 1,3,2-dioxa- and oxazaphosphorinane cyclophosphamide analogues

Abstract

Conformational analysis of 2-[bis-(2-chloroethyl)amino]-2-trans-tetramethylene-1,3,2-dioxa- and oxazaphosphorinanes 5–8, cyclophosphamide-type anticancer drugs, show that diastereometric six-membered ring 1,3,2-dioxaphosphor- inanes can adopt either a chair conformation with bis-(2-chloroethyl)amino mustard group equatorial ( 5) or twist-boat conformation with the bis-(2-chloroethyl)amino group pseudoequatorial ( 6). An X-ray crystal structure and NMR solution conformational analysis of the diastereomeric oxazaphosphorinanes 7 and 8 show that 7 adopts a chair conformation with equatorial bis-(2-chloroethyl)amino group, and 8 exists as mixture of chair-twist boat conformations with ca. 50% twist boat population. The diastereomeric pairs 5 6 and 7 8 show similar, moderate activity against lymphocytic leukemia P388 cells in mice. This is explained in terms of a flexible chair-twist boat interconversion.