Short communication Novel approach to bis(indolyl)methanes: De novo synthesis of 1-hydroxyiminomethyl derivatives with anti-cancer properties Carla Grosso a, b , Ana Lúcia Cardoso a , Am  erico Lemos b, * , Jo ~ ao Varela c , Maria Jo ~ ao Rodrigues c , Luísa Cust  odio c , Luísa Barreira c , Teresa M.V.D. Pinho e Melo a, * a Department of Chemistry, University of Coimbra, 3004-535 Coimbra, Portugal b CIQA, FCT, University of Algarve, Campus de Gambelas, 8005-139 Faro, Portugal c CCMAReCentre of Marine Sciences, Faculty of Sciences and Technology, University of Algarve, Ed. 7, Campus of Gambelas, Faro 8005-139, Portugal article info Article history: Received 13 June 2014 Received in revised form 22 January 2015 Accepted 24 January 2015 Available online 26 January 2015 Keywords: Bis(indolyl)methanes Nitrosoalkenes Indoles Anti-cancer activity Leukaemia Lymphoma abstract A versatile and broad range approach to previously unknown bis(indolyl)methane oximes based on two consecutive hetero DielseAlder cycloaddition reactions of electrophilic conjugated nitrosoalkenes with indoles is disclosed. The cytotoxic properties and selectivity of some adducts against several human cancer cell lines pointing to a promising role in the development of anti-tumoural drugs, in particular for leukaemia and lymphoma. © 2015 Elsevier Masson SAS. All rights reserved. 1. Introduction Bis(indolyl)methanes (BIMs) isolated from marine or terrestrial matrices exhibit a wide range of biological activities including anticancer activity against various types of tumour cells [1] (Scheme 1). Naturally occurring BIMs such as vibrindole (1) are useful in the treatment of fibromyalgia, chronic fatigue, and irri- table bowel syndrome [2e4]. Furthermore, various studies point out that 3,3 0 -diindolylmethane (DIM) (2) possesses protective cancer activity, especially against mammary and prostate tumour cells [5]. Additionally, DIM inhibits mammary tumour growth in rodents [6] and also exhibits potent antiproliferative and anti- androgenic properties in androgen-dependent human prostate cancer cells [7,8]. Synthetic bis(indolyl)methanes have been used not only in biological applications but also as dyes and colorimetric sensors [1,9e26]. Consequently, a great deal of interest and effort has been put into the development of efficient synthetic protocols for the preparation of these molecules. The vast majority of synthetic routes involve the reaction of indole with various carbonyl com- pounds or their synthetic equivalents in the presence of acid, base or metal catalyst (Scheme 2) [27e44]. Although several elegant, efficient and environment friendly methods producing good yields and selectivity have been reported, in most of the above reactions the resulting BIMs generally lacked functionalities, especially at the methylene bridge, which could allow an easy manipulation or conversion into more elaborate compounds, eventually of greater interest and value. Conjugated nitrosoalkenes, unsubstituted or bearing C- or P- bonded functional groups at the 4-position, have been at the basis of the preparation of an impressive plethora of new heterocyclic systems, used either as electron-deficient heterodienes in cyclo- addition or as Michael-type acceptors in conjugate 1,4-addition reactions [45e50]. Although in a much smaller extent, nitrosoalkenes bearing a good leaving group at the 4-position have also been explored. The presence of such as functionality provided an extra feature and was of added value in the subsequent manipulation of adducts and cycloadducts so formed [51e54]. Indeed, we recently described a novel route to 5-substituted dipyrromethanes by bis-hetero- * Corresponding authors. E-mail addresses: alemos@ualg.pt (A. Lemos), tmelo@ci.uc.pt (T.M.V.D. Pinho e Melo). Contents lists available at ScienceDirect European Journal of Medicinal Chemistry journal homepage: http://www.elsevier.com/locate/ejmech http://dx.doi.org/10.1016/j.ejmech.2015.01.050 0223-5234/© 2015 Elsevier Masson SAS. All rights reserved. European Journal of Medicinal Chemistry 93 (2015) 9e15