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

Masao Nagaoka, Yoko Watari, Hiromi Yajima, Kaoru Tsukioka, Yasuyo Muroi, Keiko Yamada and Mitsuteru Numazawa,

Tohoku Pharmaceutical University, 4-1 Komatsushima-4-chome, Aobaku, Sendai 981-8558, Japan

Received 20 March 2003; revised 13 May 2003; accepted 16 May 2003. ; Available online 19 July 2003.

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-4 and 4-acyloxyandrost-4-en-17-ones (29–32, and 34) were synthesized and evaluated. The 4-alkyl and 4-phenylalkyl compounds were obtained through reaction of 4,5-epoxy steroid (8) with RMgBr (R: alkyl and phenylalkyl) followed by dehydration of the 4-substituted 5-hydroxy products (15-19) with SOCl2 as key reactions. Acylation of 4,5-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 (Ki=70 and 60 nM, respectively). Elongation of an acetoxy group in a series of 4-acyloxy steroids or a methyl group in a series of 4-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.

Author Keywords: Aromatase; Inhibitor; 4-Alkyl steroid; 4-Acyloxy steroid; 3-Deoxy androgen; Human placental microsomes

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