Efficient Asymmetric Synthesis of an A-Ring Synthon for Pd-Catalyzed Preparation of 1α-Hydroxyvitamin D Metabolites and Analogs

An efficient Lewis acid-assisted asymmetric carbonyl-ene reaction to set the 1α-hydroxyl functionality of enol-triflate, precursor of the A-ring of the hormone calcitriol and its 1α-hydroxyderivatives, is described. The secondary parallel hypercalcemic effects associated with the treatment of several hyperproliferative diseases with the natural hormone 1α,25-dihydroxyvitamin D3 (calcitriol) and/or known active vitamin D metabolites and analogs, demand the development of efficient and rapid methods for the preparation of vitamin D receptor (VDR) ligands as new selective and non-calcemic agonists. Here we describe an efficient and adaptable multigram-scale synthetic sequence to access an A-ring synthon as useful precursor of the vitamin D triene system of 1α-hydroxylated vitamin D derivatives via Pd-catalyzed carbocyclization/Suzuki–Miyaura cross-coupling reactions in a protic medium. The key step is an asymmetric Lewis acid-promoted carbonyl-ene reaction to a chiral glyosylate ester to establish the 1α-hydroxyl group of 1α,25-dihydroxyvitamin D3 and its derivativesThis research was funded by ENDOTHERM GmbH, Xunta de Galicia (GRC/ED431B/20) and the University of Santiago de Compostela (Spain)S

Studies on the Synthesis of Vitamin D Analogs with Aromatic D-Ring

Herein, we describe our studies on the synthesis of 1α,25-dihydroxyvitamin D3 analogs possessing a benzene ring replacing the natural 5-membered D-ring by the Wittig-Horner and dienyne approaches. A key feature is the synthesis of a Cr(CO)3-complexed previtamin D derivative that enables the construction of vitamin D analogs with aromatic D-ring through a thermal [1,7]-H sigmatropic shift. This study establishes the basis for the design of new vitamin D analogs containing aromatic D-ring, complexed or uncomplexed to Cr(CO)3 type moieties for specific molecular recognition and drug research and developmentWe thank Xunta de Galicia (project GPC2014/001) and for financial support. Silvina Eduardo thanks the Spanish MEC for a fellowship. Rita Sigüeiro thanks Xunta de Galicia for a post-doctoral fellowship (Axudas posdoutorais, plan I2C, mod B)S

Design, synthesis, evaluation and structure of Allenic 1α,25-Dihydroxyvitamin D3 analogs with locked mobility at C-17

Vitamin D receptor ligands have potential for the treatment of hyperproliferative diseases and disorders related to the immune system. However, hypercalcemic effects limit their therapeutical uses and call for the development of tissue-selective new analogs. We have designed and synthesized the first examples of 1α,25-dihydroxyvitamin D3 analogs bearing an allenic unit attached to the D ring to restrict the side-chain conformational mobility. The triene system was constructed by a Pd0-mediated cyclization/Suzuki-Miyaura cross-coupling process in the presence of an allenic side chain. The allenic moiety was built through an orthoester-Claisen rearrangement of a propargylic alcohol. The biological activity and structure of (22S)-1α,25-dihydroxy-17,20-dien-24-homo-21-nor-vitamin D3 bound to binding domain of the vitamin D receptor, provide information concerning side-chain conformational requirements for biological activityWe thank FCT of Portugal (project PTDC/BIA-MIB/29059/2017), UIDB/50006/2020 to LAQV-REQUIMTE Research Unit, the European Union (European Regional Development Fund-ERDF), and Xunta de Galicia, Spain (GRC/ED431B/2018/13), for financial support. We also thank the Ligue contre le cancer, Agence Nationale de la Recherche ANR-13-BSV8-0024-01, and institucional funds from Instruct-ERIC for support and use of resources of the French Infrastructure for Integrated Structural Biology (ANR-10-LABX-0030-INRT and ANR-10-IDEX-0002-02). ERB and JL thank FCT (SFRH/BSAB/150309/2019) and (PTDC/BIA-MIB/29059, 2017-REQUIMTE2019-86) for postdoctoral fellowships, respectivelyS

Carborane-based design of a potent vitamin D receptor agonist

The vitamin D nuclear receptor (VDR) is a potential target for cancer therapy. It is expressed in many tumors and its ligand shows anticancer actions. To combine these properties with the application of boron neutron capture therapy (BNCT), we design and synthesize a potent VDR agonist based on the skeleton of the hormone 1 a,25-dihydroxyvitamin D3(1,25D) and an o -carborane (dicarba-o-closo-1,2-dodecaborane) at the end of its side chain. The present ligand is the first secosteroidal analog with the carborane unit that efficiently binds to VDR and functions as an agonist with 1,25D-like potency in transcriptional assay on vitamin D target genes. Moreover it exhibits similar antiproliferative and pro-differentiating activities but is significantly less hypercalcemic than 1,25D. The crystal structure of its complex with VDR ligand binding domain reveals its binding mechanism involving boron-mediated dihydrogen bonds that mimic vitamin D hydroxyl interactions. In addition to the therapeutic interest, this study establishes the basis for the design of new unconventional vitamin D analogs containing carborane moieties for specific molecular recognition, and drug research and developmentWe thank the Spanish Ministry of Economy and Innovation (MEI, SAF2010-15291 and SAF2012-38240), Xunta de Galicia (project GPC2014/001), Agence Nationale de la Recherche (ANR- 13-BSV8-0024-01), French Infrastructure for Integrated Structural Biology (FRISBI) (ANR-10-INSB-05-01), and INSTRUCT as part of the European Strategy Forum on Research Infrastructures (ESFRI), for nancial support and CESGA for computing time. R. O. thanks the Spanish MEI for an FPI fellowship (BES-2011-0419192). S. S. thanks the Asociaci´on Espanola Contra el Cáncer for a fellowship (AIOA1101SEOA). R. S. thanks the Xunta de Galicia for a postdoctoral fellowship (POS-A/2012/112)S