Synthesis of 6- or 4-functionalized indoles via a reductive cyclization approach and evaluation as aromatase inhibitors Marie-Pierre Lézé a , Anja Palusczak b , Rolf W. Hartmann b , Marc Le Borgne a, * a Université de Nantes, Nantes Atlantique Universités, Département de Pharmacochimie, IICiMed UPRES EA 1155, UFR de Sciences Pharmaceutiques, 1 rue Gaston Veil, Nantes, F-44035 Cedex 1, France b Fachrichtung 8.5 Pharmaceutische und Medizinische Chemie, Universität des Saarlandes, PO Box 151150, D-66041 Saarbrücken, Germany article info Article history: Received 1 May 2008 Revised 27 June 2008 Accepted 28 June 2008 Available online 3 July 2008 Keywords: Breast cancer Aromatase inhibitors Indole Azoles Benzonitrile derivatives Reductive cyclization abstract Two new series of benzonitrile derivatives on position 6 or 4 of indole ring were successfully synthesized via a Leimgruber–Batcho reaction. All the compounds were evaluated in vitro on the inhibition of aroma- tase (CYP19) and 17a-hydroxylase-C17,20-lyase (CYP17). The racemate, 4-[(1H-imidazol-1-yl)(1H-indol- 4-yl)methyl]benzonitrile 9, showed high level of inhibitory activity towards CYP19 (IC 50 = 11.5 nM). Ó 2008 Elsevier Ltd. All rights reserved. About two-thirds of breast cancers are dependent on estrogens for growth, so endocrine therapies are widely used for the treat- ment of hormone-dependent breast cancer (HDBC). 1 Amongst endocrine therapies available today, we find (i) selective estrogen receptor modulators (SERMs), (ii) estrogen deprivation therapy using LHRH agonists and aromatase inhibitors, and (iii) estrogen receptor downregulators and complete antagonists. 2 Recent stud- ies 3–5 have shown that aromatase inhibitors (AIs) are superior to SERMs, such as tamoxifen in terms of survival and side effects. So, the reduction or blockade of estradiol (E2) biosynthesis be- comes an important strategy of treatment. The efficacy of AIs can be explained by the fact that they block both genomic and non genomic activities of the estrogen receptor. 2 Then aromatase (CYP19) is a prime target and many researchers intensively worked to find selective AIs. 6 Two non steroidal AIs, letrozole and anastroz- ole, are daily used in postmenopausal women with HDBC (Fig. 1). In previous works, 7,8 we presented diverse synthetic routes to 5 or 7-aroylindoles. In series 5, racemic compound 1 and chloro derivative 2 exerted aromatase inhibitory activity at nanomolar level. In this letter, we describe a synthetic route to access to 6- and 4- aroylindoles, key intermediates in the synthesis of 4-[(azol-1- yl)(indol-6 or 4-yl)methyl)]-benzonitriles. All target compounds were evaluated in vitro for inhibitory activity against CYP19 and CYP17 enzymes. As outlined in Scheme 1, the key intermediate 7 was prepared in three steps. First, an acylation of bromobenzene followed by a Leimgruber–Batcho reaction involving (i) the formation of enamine 6 and (ii) the catalytic reduction of the nitro group followed by spontaneous cyclization to provide the 6-aroylindole 7. For the Friedel-Crafts acylation, the bromobenzene 3 was trea- ted with the 4-methyl-3-nitrobenzoyl chloride 4 in the presence of aluminium chloride at 80–85 °C to afford the benzophenone derivative 5 in 66% yield. 9,10 The condensation of 5 with N,N- 0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2008.06.094 * Corresponding author. Tel.: +33 2 40 41 11 14; fax: +33 2 40 41 28 76. E-mail address: marc.le-borgne@univ-nantes.fr (M. Le Borgne). NC CN N N N N NH 2 O O CN NC N N N N N N H Cl N N N H NC CN N N 2 Letrozole Aminoglutethimide Anastrozole 1 .HCl Fadrozole Figure 1. Non steroidal aromatase inhibitors (NSAIs). Bioorganic & Medicinal Chemistry Letters 18 (2008) 4713–4715 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl