Available free online at www.medjchem.com Mediterranean Journal of Chemistry 2016, 5(2), 423-433 *Corresponding author : Generosa Gómez, Yagamare Fall Received Mars 21 st , 2016 Email adress : ggomez@uvigo.es, yagamare@uvigo.es Accepted April 4 th , 2016 DOI : http://dx.doi.org/10.13171/mjc52/016041430/Gomez/fall Published April 6 th , 2016 Click chemistry approach to a series of calcitriol analogues with heterocyclic side chains Zoila Gándara 1 , Pedro-Lois Suárez 1 , Alioune Fall 2 , Massène Sène 2 , Ousmane Diouf 2 , Mohamed Gaye 2 , Generosa Gómez 1, * and Yagamare Fall 1, * 1 Departamento de Química Orgánica, Facultad de Química and Instituto de Investigación Biomedica (IBI), University of Vigo, Campus Lagoas de Marcosende, 36310 Vigo, Spain 2 Laboratoire de Chimie de Coordination Organique (LCCO), Département de Chimie, Faculté des Sciences et Techniques: Université Cheikh Anta Diop de Dakar, Sénégal Abstract: We report a straightforward synthesis of a series of novel calcitriol analogues from vitamin D 2 with some modification of the procedures described by Calverley and Choudhry. This approach allows the large scale synthesis of a late-stage intermediate common to all the analogues of the series.This intermediate was successfully employed to synthesize a huge number of calcitriol analogues using a “click” chemistry approach. Keywords: Calcitriol; Vitamin D 2 ; triazole; azaanalogue; “Click” chemistry. Introduction 1,25-Dihydroxyvitamin D 3 (1, calcitriol) (Fig.1), the hormonally active metabolite of vitamin D 3 (2), acts as a regulator in calcium and phosphate homeostasis 1 . Next to these classical activities, calcitriol has been shown to inhibit cellular proliferation and to induce cellular differentiation 2 . However the therapeutic utility of 1 is hampered by the effective doses leading to calcemic side effects and this has stimulated the search for analogues having a relatively weak systemic effect on calcium metabolism while maintainig potent regulatory effects on cell differentiation and proliferation. As part of our ongoing program on the synthesis of vitamin D analogues modified at the side chain, 3 we envisaged the synthesis of various calcitriol analogues having heteroatoms on their side chain. The rational that could explain this choice was: we have already synthesized Aza-vitamin D analogues 3r and the biological activity of some of these derivatives was later studied showing that they had less calcemic effect than calcitriol. The strategy we used so far involved construction of the triene unit on the CD fragment following the introduction of the side chain. This strategy is inconvenient if a lengthy series of analogues with modified side chains are to be prepared for systematic biological evaluation. Figure 1. Structures of 1,25-Dihydroxyvitamin D 3 (1) and vitamin D 3 (2). Results and Discussion We examined the possibility of preparing a series of analogues modified at the side chain from a common intermediate, in which the labile triene system was already present. The use of this strategy involved the concept of the triene system protection to allow chemical modification of the vitamin D side chain. This concept received relatively little attention. 4 Among these approaches, the one using the preparation and subsequent thermolysis of the sulfur dioxide adducts of vitamin D 2 4b,c seemed to us more appropriate for a large scale synthesis of a late- stage intermediate such as 10 (Scheme 1).