steroids 71 ( 2 0 0 6 ) 809–816 available at www.sciencedirect.com journal homepage: www.elsevier.com/locate/steroids Stereoselective synthesis of some 17-dihydrooxazinyl steroids, as novel presumed inhibitors of 17-hydroxylase-C 17,20 -lyase J´ anos W ¨ olfling a,* , ´ Eva Andrea Oravecz a ,D´ ora Ondr´ e a , Erzs´ ebet Merny ´ ak a , Gyula Schneider a , Istv ´ an T ´ oth b , Mih ´ aly Sz´ ecsi b ,J´ anos Julesz b a Department of Organic Chemistry, University of Szeged, D´ om t´ er 8, H-6720 Szeged, Hungary b Endocrine Unit and Research Laboratory, University of Szeged, Kor´ anyi Fasor 8, H-6720 Szeged, Hungary article info Article history: Received 7 February 2006 Received in revised form 3 May 2006 Accepted 17 May 2006 Published on line 30 June 2006 Keywords: Heterocyclic steroids Schmidt reaction C 17,20 -lyase activity abstract 17-Dihydrooxazinyl steroids 5a–l and 6a–l were synthetized. The acid-catalyzed reactions of 21-azidomethyl-20-hydroxy- and 21-hydroxymethyl-20-azidosteroids with substituted aromatic aldehydes led to the formation of androst-5-en-3-ols substituted in position 17 with dihydrooxazine residues. The inhibitory effects of these compounds on rat testicular C 17,20 -lyase were investigated with an in vitro radioincubation technique. © 2006 Elsevier Inc. All rights reserved. 1. Introduction 17-Hydroxylase-C 17,20 -lyase (P450 17 ) is a key regulator enzyme of the androgen biosynthetic pathway that catalyzes both the 17-hydroxylation and the cleavage of the C 17 –C 20 side-chain of 21-carbon steroids in both the testes and the adrenals. Inhibition of this enzyme can block androgen syn- thesis in an early step, and may thereby be useful in the treat- ment of prostatic carcinoma, which is androgen-dependent in the majority of cases [1]. The syntheses of abiraterone [17- (3-pyridyl)androsta-5,16-dien-3-ol] and its 4-en-3-one analog were reported recently; these display high inhibitory activi- ties against P450 17 . It has been suggested that such activity is related to the presence of the heterocyclic moiety in ring D, with the nitrogen lone pair coordinating to the heme iron atom at the active site of the enzyme [2]. Considerable effort has therefore been made during the past decade to synthetize ∗ Corresponding author. E-mail address: wolfling@chem.u-szeged.hu (J. W ¨ olfling). novel inhibitors of P450 17 . A broad class of steroid derivatives substituted with a heterocycle at C-17 exhibit good inhibition of this enzyme [3]. We recently set out to synthetize a novel series of steroidal oxazolines and tetrahydrooxazin-2-ones, in which there is a heterocycle containing two heteroatoms at position 17 of androst-5-en-3-ol [4,5]. We report here on the synthesis and P450 17 -inhibitory activity of a variety of steroidal compounds with the common structural feature of a C-17-dihydrooxazine in the steroid skeleton. 2. Experimental 2.1. General Melting points (m.p.) were determined on a Kofler block and are uncorrected. Specific rotations were measured in CHCl 3 0039-128X/$ – see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.steroids.2006.05.011