MOLECULAR-CONFORMATION OF ESTRAMUSTINE AND 2 ANALOGS

The crystal and molecular structures of estramustine and two of its an alogues have been determined by X-ray crystallographic techniques (a t otal of three different compounds). The compounds studied are estramus tine 3,17-beta-diol-3-N,N-bis(2'-chloroethyl)carbamate] and its monohy drate, estromustine stratriene-3-yl-N,N-bis(2'-chloroethyl)carbamate], and rosten-3-beta-yl-N,N-bis(2'-chloroethyl)carbamate. Three views of estramustine were obtained from the study of its two crystal forms. T he main structural features found are as follows: (a) the geometries o f the steroid moieties are closely similar to those of the parent ster oids, (b) the bonds around the nitrogen atom of the nitrogen mustard g rouping lie approximately in a plane in each structure, (c) the plane through the carbon atoms of the steroid A-ring lies approximately perp endicular to the plane through the carbamate atoms in each structure, (d) the carbonyl C-O of the carbamate points to the alpha side of the steroid moiety in each structure, and (e) one chlorine atom of the nit rogen mustard grouping makes a close contact [3.13 angstrom], in each structure, to the nitrogen atom. Hydrogen bonding to the carbamate app ears to occur from the alpha side of the steroid; there is no hydrogen bonding to the nitrogen atom of the carbamate group. These structural data provide some steric explanations for the resistance of the carba mate to enzymatic hydrolysis. The long in vivo half-life of the intact estramustine molecule is a result of this stability. This is responsi ble for the absence of alkylating ability and the propensity of the dr ug to bind microtubule-associated proteins and express an antimitotic mechanism of action.