AI Article Synopsis
- A-ring modifications in 1α,25-dihydroxyvitamin D enhance its binding to the vitamin D receptor (VDR) and increase its stability in cells by resisting metabolism, leading to longer-lasting effects.
- Various modified A-ring precursors synthesized from d-glucose showed specific biological activities with minimal calcemic side effects, including MART-10's potent antitumor effects in cancer models and AH-1's superior bone-forming properties in osteoporosis models compared to natural vitamin D.
- Ongoing research includes developing a library of fluorinated vitamin D analogs with potential anti-inflammatory effects and therapeutic applications for conditions like psoriasis, alongside the creation of the VDR-silent analog KK-052, which selectively inhibits SREBP/SC
Article Abstract
2α-Functionalization of 1α,25-dihydroxyvitamin D (active vitamin D) A-ring enhances binding affinity for the vitamin D receptor (VDR) and prolongs the half-life in target cells due to gaining resistance to CYP24A1-dependant metabolism. The wide variety of modified A-ring precursor enynes for Trost coupling with CD-ring bromoolefin were synthesized from d-glucose. The A-ring modification provided potent, selective biological activities without calcemic side-effects in vivo; for example, 2α-(3-hydroxypropyl)-19-nor-1α,25-dihydroxyvitamin D (MART-10) exhibits potent antitumor activity (0.3µg/kg/d, twice/week for 3 weeks) in nude mice inoculated with BxpC-3 cancer cells, 2α-[2-(tetrazol-2-yl)ethyl]-1α,25-dihydroxyvitamin D (AH-1) shows better bone-forming effects (0.02µg/kg/d, 5d/week for 4 weeks) in ovariectomized (OVX) rats as an osteoporosis model than natural active vitamin D, and NS-74c exhibits potent VDR-antagonistic activity (IC 7.4pM) in HL-60 culture cells. The A-ring modification was also applicable to the synthesis of stable 14-epi-19-nortachysterols, and their novel VDR binding mode was confirmed by X-ray co-crystallographic analysis. 25-Hydroxyvitamin D has two independent target molecules: VDR and a sterol regulatory element-binding protein (SREBP)/SREBP cleavage-activating protein (SCAP) complex, and 25-hydroxyvitamin D shows SREBP/SCAP inhibitory activity. The VDR-silent vitamin D analog KK-052 with selective SREBP/SCAP inhibitory activity in vivo was developed. A chemical library of side-chain fluorinated vitamin D analogs is currently under construction, and some analogs have shown potent anti-inflammatory activity and therapeutic effects on psoriasis model mice.
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| http://dx.doi.org/10.1248/cpb.c24-00598 | DOI Listing |
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