Structure-activity relationships of 3-deoxy androgens as aromatase inhibitors. synthesis and biochemical studies of 4-substituted 4-ene and 5-ene steroids

Article abstract of DOI:10.1016/S0039-128X(03)00085-0

As part of our investigation into the structure-activity relationship of a novel class of aromatase inhibitors, two series of 3-deoxy androgens, androst-5-en-17-ones with a non-polar alkoxy (5 and 6), alkyl (20-22), or phenylalkyl (23 and 24) group at C-4β and 4-acyloxyandrost-4-en-17-ones (29-32, and 34) were synthesized and evaluated. The 4β-alkyl and 4β-phenylalkyl compounds were obtained through reaction of 4α,5α-epoxy steroid (8) with RMgBr (R: alkyl and phenylalkyl) followed by dehydration of the 4β-substituted 5α-hydroxy products (15-19) with SOCl₂ as key reactions. Acylation of 4α,5α-diol (25) with (RCO)₂O in pyridine and subsequent dehydration with SOCl₂ gave the 4-acyloxy steroids. All of the steroids studied, except for 4-acetoxy-19-ol (34) that was a non-competitive inhibitor of human placental aromatase, blocked aromatase activity in a competitive manner. 4-Benzoyloxy- and 4-acetoxy steroids (31) and (32) were the most powerful inhibitors of aromatase (K_i=70 and 60nM, respectively). Elongation of an acetoxy group in a series of 4-acyloxy steroids or a methyl group in a series of 4β-alkyl steroids decreased affinity for aromatase principally in relation to carbon number of the acyl or alkyl function. The present findings are potentially useful for understanding the spatial and electronic nature of the binding site of aromatase as well as for developing effective aromatase inhibitors.