Search

Both 25R- and 25S-25-adamantyl-23-yne-26,27-dinor-1α,25-dihydroxyvitamin D3 (4a and 4b) were stereoselectively synthesized by a Pd(0)-catalyzed ring closure and Suzuki–Miyaura coupling between enol-triflate 7 and alkenyl-boronic ester 8. The 25S isomer (4b) showed high vitamin D receptor (VDR) affinity (50% of that of the natural hormone 1α,25-dihydroxyvitamin D3, 1) and transactivation potency (kidney HEK293, 90%). In endogenous gene expression, it showed high cell-type selectivity for kidney cells (HEK293, CYP24A1 160% of 1), bone cells (MG63, osteocalcin 64%), and monocytes (U937, CAMP 96%) over intestine (SW480, CYP24A1 8%) and skin (HaCaT, CYP24A1 7%) cells. The X-ray crystal structural analysis of 4b in complex with rat VDR-ligand binding domain (LBD) showed the highest Cα positional shift from the 1/VDR-LBD complex at helix 11. Helix 11 of the 4b and 1 VDR-LBD complexes also showed significant differences in surface properties. These results suggest that 4b should be examined further as another can...

A convergent synthesis of side-chain locked vitamin D analogs 3 and 4, which bind strongly in silico to the vitamin D receptor (VDR), is described. The synthetic approach features an SN2'- syn displacement of carbamates by cuprates to set the challenging quaternary stereogenic center at C17 and a Pd-catalyzed construction of the triene system in the presence of a diyne moiety.

Continuing the structure-activity relationship studies in the vitamin D area, we designed and synthesized novel C-9 substituted calcitriol analogues, possessing different nonpolar groups at this position. 9α-Methyl-1α,25-(OH)2D3, both epimers of 9-methylene-10,19-dihydro-1α,25-(OH)2D3 as well as the parent vitamin with the "reversed" triene system, 9-methylene-19-nor-1α,25-(OH)2D3, were obtained from the previtamin D precursors, constructed by either Suzuki-Miyaura, Sonogashira, or Stille couplings of the corresponding A- and C,D-ring fragments. An alternative synthetic path, leading to the latter vitamin and its homologue with 9-ethylidene group, involved formation of dienynes as precursors of the respective 19-norprevitamin D compounds. 9β-Methyl-19-nor-1α,25-(OH)2D3 was prepared by homogeneous hydrogenation with Wilkinson catalyst, and this analogue was found to be the most active in vitro. Moreover, 9α-methyl-1α,25-(OH)2D3 and 9-methylene-19-nor-1α,25-(OH)2D3 showed some in vitro activity, however, the in vivo assays indicated only weak calcemic potency of these compounds in the intestinal calcium transport.

Structure-guided optimization was used to design new analogues of 1α,25-dihydroxyvitamin D3 bearing the main side chain at C12 and a shorter second hydroxylated chain at C17. The new compounds 5a–c were efficiently synthesized from ketone 9 (which is readily accessible from the Inhoffen–Lythgoe diol) with overall yields of 15%, 6%, and 3% for 5a, 5b, and 5c, respectively. The triene system was introduced by the Pd-catalyzed tandem cyclization–Suzuki coupling method. The new analogues were assayed against human colon and breast cancer cell lines and in mice. All new vitamin D3 analogues bound less strongly to the VDR than 1α,25-dihydroxyvitamin D3 but had similar antiproliferative, pro-differentiating, and transcriptional activity as the native hormone. In vivo, the three analogues had markedly low calcemic effects. © 2012 American Chemical Society., We thank the Spanish Ministry of Education and Innovation (SAF2007-67205 and SAF2010-15291 to A. Mouriño, SAF2010-18302 to A. Muñoz, and SAF2009-07631 to RPF) for financial support.

The vitamin D nuclear receptor is a ligand-dependent transcription factor that controls multiple biological responses such as cell proliferation, immune responses, and bone mineralization. Numerous 1 alpha,25(OH)(2)D(3) analogues, which exhibit low calcemic side effects and/or antitumoral properties, have been synthesized. We recently showed that the synthetic analogue (20S,23S)-epoxymethano-1 alpha,25-dihydroxyvitamin D(3) (2a) acts as a 1 alpha,25(OH)(2)D(3) superagonist and exhibits both antiproliferative and prodifferentiating properties in vitro. Using this information and on the basis of the crystal structures of human VDR ligand binding domain (hVDR LBD) bound to 1 alpha,25(OH)(2)D(3), 2 alpha-methyl-1 alpha,25(OH)(2)D(3), or 2a, we designed a novel analogue, 2 alpha-methyl-(20S,23S)-epoxymethano-1 alpha,25-dihydroxyvitamin D(3) (4a), in order to increase its transactivation potency. Here, we solved the crystal structures of the hVDR LBD in complex with the 4a (C23S) and its epimer 4b (C23R) and determined their correlation with specific biological outcomes.

Novel analogues of the hormone 1alpha,25-(OH)(2)-D(3) with side chains attached to C-18 were synthesized by a versatile route in which key steps were the remote radical-induced functionalization of the 18-methyl by the C-8beta-hydroxyl group and the introduction of the side chains by Wittig reactions on a C-18-aldehyde. The triene system of the novel analogues was constructed by the convergent Lythgoe-Hoffmann la Roche approach, which involves reaction of a phosphine oxide (the ring A fragment) with a ketone (the upper fragment).

The design and synthesis of vitamin D(3) dimers 2 and 3 and 1 alpha, 25-dihydroxyvitamin D(3) (calcitriol) dimers 4 and 5 are described. The dimers were designed with a view to doubly binding the vitamin D receptor (VDR) and inducing the receptor homodimerization. In the dimers the units are linked through the C-11 position in ring C by an alkyl side chain of six or 10 carbon atoms, far from the hydroxy groups responsible for the VDR binding. The linker is formed by olefin metathesis of an olefinic side chain at the C-11 position introduced by stereoselective cuprate addition. The synthesis, which is both short and convergent, uses the Wittig-Horner approach to construct the vitamin D triene system and allows the preparation of dimers with a linker of modulated length with the purpose of optimizing the vitamin D(3)-VDR interaction.

The synthesis of four new analogues of calcitriol (1α,25-(OH)2-D3)possessing aromatic and conjugated double bond units at the side chain are described. The triene system is introduced using the Lythgoe−Hoffmann La Roche convergent Wittig−Horner approach. The key steps in the preparation of the requisite upper fragments are the introduction of the side chain with the E-conjugated aromatic system and its photochemical conversion to the Z counterpart.

Two synthetic routes to the nonnatural hormone 1α,25-dihydroxyergocalciferol [2b, 1α,25-(OH)2-D2] and analogs modified at C-24 have been developed both starting from aldehyde 7b. Key steps in route A (eight steps, ≈38% overall yield from 7b) are (1) stereoselective addition of (E)-vinyllithium reagent 8c to aldehyde 7b; and (2) SN2‘ anti-displacement of the allylic phosphate of 5e by organocuprates derived from Grignard reagents and CuCN in the presence of LiCl. Key steps in route B (eight steps from 7b, 48% overall yield) are (1) Wittig−Horner type coupling between ketone 22, which bears an allylic phosphate group on the side chain, and the ylide derived from the Lythgoe−Roche phosphine oxide to form the vitamin D triene unit; and (2) efficient SN2‘ anti-displacement of the phosphate group of 23 by the organocuprate derived from MeMgCl, CuCN, and LiCl, without affecting the labile vitamin D triene system, to give, after deprotection, 1α,25-(OH)2-D2. Route B is particularly attractive as an approach to di...

3-Hydroxy-4-pyridones, which are easily prepared from commercially available 3-hydroxy-4-pyrones, can be readily transformed into 4-methoxy-3-oxidopyridinium ylides by treatment with methyl trifluoromethanesulfonate and subsequent deprotonation with a non-nucleophilic base. These ylides are capable of undergoing cycloaddition to several electron-deficient alkenes, thus allowing the synthesis of highly functionalized azabicyclo[3.2.1]octane moieties. The rich substitution patterns of these frameworks might allow their divergent conversion to a variety of natural and non-natural tropane alkaloids.

A versatile method for the rapid construction of fragments related to the upper part of vitamin D3 from the Lythgoe-Inhoffen diol is described. The key feature of the strategy is a new zinc-copperinduced conjugate addition of iodo triflate 10a to electron-deficient olefins under sonochemical aqueous conditions. These fragments are rapidly and efficiently transformed via the dienyne convergent approach to several derivatives of the hormone 1α,25-(OH)2-D3 modified at C-25. © 1993, American Chemical Society. All rights reserved.

The Lewis-acid-mediated nucleophilic substitution of dioxanone and acetal templates for the construction of 25-hydroxylated side chains of vitamin D 2 metabolites and analogs has been studied. As an application a highly stereoselective synthesis of 1α,25-dihydroxyvitamin D 2 by the dienyne route is described

Total synthesis of A-ring fragments of 10(S),19-dihydrovitamins D and 10(R),19-dihydro-(5E)-epivitamins D from (+)-(S)-carvone and (-)-(R)-carvone is described. These fragments were used for convergent synthesis of dihydrotachysterol 2 (DHT 2 ), 25-hydroxydihydrotachysterol 2 , 10(R),19-dihydro-(5E)-3-epivitamin D 2 , and 25-hydoxy-10(R),19-dihydro-(5E)-3-epivitamin D 2

Temporary connection of alkenes to 3-alkoxy-4-pyrones via sulfur or silicon tethers allows their thermal [5 + 2] cycloaddition and ensures complete regio- and stereochemical control. © 1993, American Chemical Society. All rights reserved.

A general method for the synthesis of the principal vitamin D3 metabolites whether unlabeled or with radiolabeled side chains is described. The synthesis of the key de-A,B-(ethylenedioxy)cholestanone derivative 7d is based on the coupling between the iodide 4c and 3-(trimethylsilyl)-3-buten-2-one (5b) via cuprate chemistry. The synthesis of 25-ketovitamin D3 (a suitable intermediate compound for radiolabeling) was achieved by coupling between 7d and the n-butyllithium-induced carbanion of the phosphine oxide 8c using Lythgoe’s strategy and deprotection. As an example of the utility of this route, 25-hydroxyvitamin D3 was synthesized. © 1986, American Chemical Society. All rights reserved.

On introduit le centre chiral en C 24 par deplacement stereo- et regiospecifique d'un carbamate allylique par un cuprate