pdf - Molecules 2009, 14, 894-903;...

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Molecules 2009 , 14, 894-903; doi:10.3390/molecules14020894 molecules ISSN 1420-3049 www.mdpi.com/journal/molecules Article Synthesis of 1 α ,25-Dihydroxyvitamin D Analogues Featuring a S 2 -symmetric CD-ring Core Garrett Minne 1 , Lieve Verlinden 2 , Annemieke Verstuyf 2 and Pierre J. De Clercq 1, * 1 Department of Organic Chemistry, Ghent University, Krijgslaan 281, B-9000 Gent, Belgium 2 Laboratory of Experimental Medicine and Endocrinology, Catholic University of Leuven, Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium * Author to whom correspondence should be addressed; E-mail: Pierre.DeClercq@UGent.be. Received: 29 January 2009; in revised form: 17 February 2009 / Accepted: 23 February 2009 / Published: 24 February 2009 Abstract: Three analogues of 1 α ,25-dihydroxyvitamin D 3 (calcitriol), featuring a trans- fused decalin C,D-core with local S 2 -symmetry, and possessing identical side-chain and seco-B,A-ring structures, have been synthesized starting from readily available (4a R ,8a S )- octahydronaphthalene-1,5-dione ( 7 ). The very short sequences involve the simultaneous introduction of the side-chain and seco-B,A-ring fragments via Suzuki and Sonogashira coupling reactions. The analogues are devoid of relevant biological activity. Keywords: Suzuki coupling; Sonogashira reaction; Calcitriol analogues. Introduction Since the discovery that the biological action of vitamin D 3 originates from the dihydroxylated metabolite 1 α ,25-dihydroxyvitamin D 3 ( 1 , calcitriol) and that, next to its classical role in the regulation of calcium homeostasis, these actions also involve immunomodulation, cell differentiation and antiproliferation, there has been an intense search for structural analogues of calcitriol that might show a separation in calcemic and antiproliferative-prodifferentiating activities (Scheme 1) [1]. In this context various successful structural modifications have been introduced in each one of the three parts that one may distinguish in its structure: the rigid central C,D-ring system and the flexible parts of the molecule, comprising the side chain and the seco-B,A-ring [2]. OPEN ACCESS
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Molecules 2009 , 14 895 At the molecular level calcitriol generates biological responses via signal transduction pathways in which interaction with the nuclear receptor (n-VDR) leads to gene transcription regulation (genomic pathway) and in which interaction with a putative membrane receptor (m-VDR) leads to rapid actions such as transcaltachia (non-genomic pathway) [3]. A turning point in the rational development of analogues has been the disclosure of the detailed structure of the ligand binding domain of the n-VDR, obtained via X-ray diffraction analysis of the complex between calcitriol and a truncated mutant of the n-VDR [4]. Interestingly, this study revealed that the position of the ligand within the binding site was opposite to the location that was previously suggested on the basis of extensive molecular modeling studies [5]. This could indicate that the two polar parts of the molecule are interchangeable so that each bonding type could be associated with a different biological action. In this context we became
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pdf - Molecules 2009, 14, 894-903;...

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