Search

9-Alkylidene analogs of 19-nor-1α,25-(OH) 2 D 3 were synthesized, possessing a ‘reversed’ triene system compared to the natural hormone. The conjugated triene moiety of the novel analogs was constructed by coupling an enyne anion, representing an A-ring synthon, with a 9α-substituted Grundmann ketone derivative. Regioselective dehydration followed by semihydrogenation under Lindlar conditions, provided the desired 9-alkylated 19-norprevitamins which were thermally isomerized to the corresponding 9-methylene and 9-ethylidene analogs of 19-norcalcitriol. It was established that only the former compound had significant binding affinity to the full-length recombinant rat vitamin D receptor. The remaining in vitro studies show very low activity of both analogs. This article is part of a Special Issue entitled ‘Vitamin D Workshop’.

Primary cultures of human bone and vascular cells respond to vitamin D treatment by modulation of cell proliferation measured by DNA synthesis (DNA) and energy metabolism measured by creatine kinase specific activity (CK) via binding to vitamin D receptors (VDR) which are expressed in these cells. Vitamin D compounds also modulate the response to estradiol-17β (E₂) and the expression mRNAs of estrogen receptors (ERα and ERβ), VDR, 25-hydroxy vitamin D₃ 1-α hydroxylase (1OHase) and lipoxygenases (12LO and 15LO). We now compared our newly synthesized analog: 1α,25-dihydroxy-9-methylene-19-norvitamin D₃ JK152 (JK), on bone and vascular cells compared to other analogs. Human bone cell line SaOS₂ respond to JK by increased DNA and stimulated CK dose-dependently, similar to the less-calcemic analogs CB 1093 (CB) and EB 1089 (EB). JK also up-regulated the response to E₂ in terms of DNA and CK. JK inhibited DNA synthesis and increased CK in primary human vascular smooth muscle cells (VSMC) dose-dependently similar to EB and CB. JK up regulated the response to E₂ in terms of CK with no effect on DNA. JK similar to CB and EB stimulated mRNA expression of VDR and ERα, 12LO and 15LO, with no effect on ERβ and 1OHase mRNA expression in SaOS₂ measured by real time PCR. Similar treatments of VSMC with JK, CB and EB stimulated 12LO and 15LO, VDR and ERα mRNA expression with no effect on ERβ and 1OHase mRNA expression. The results presented here demonstrate that the new vitamin D less-calcemic analog JK is similar to other analogs in its effects on human cultured cells and therefore may be used in combined hormone replacement treatment (HRT) both in vitro and in vivo.

Convergent syntheses of three new analogues of 1α,25-dihydroxyvitamin D 3 with α-hydroxyalkyl substituents at C12 ( 4a – c ) are described. The A-ring and triene system of each analogue were assembled by a tandem Pd-catalysed intramolecular cyclization and Suzuki–Miyaura coupling process. The stereoselective introduction of substituents at C12 was achieved by Johnson–Claisen rearrangement on allylic alcohol 15 as the key step. This article is part of a Special Issue entitled ‘Vitamin D Workshop’.