Abstract
Continuing our structure-activity studies on the vitamin D analogs with the altered intercyclic seco-B-ring fragment, we designed compounds possessing dienyne system conjugated with the benzene D ring. Analysis of the literature data and the docking experiments seemed to indicate that the target compounds could mimic the ligands with a good affinity to the vitamin D receptor (VDR). Multi-step synthesis of the C/D-ring building block of the tetralone structure was achieved and its enol triflate was coupled with the known A-ring fragments, possessing conjugated enyne moiety, using Sonogashira protocol. The structures of the final products were confirmed by NMR, UV and mass spectroscopy. Their binding affinities for the full-length human VDR were determined and it was established that compound substituted at C-2 with exomethylene group showed significant binding to the receptor. This analog was also able to induce monocytic differentiation of HL-60 cells.
Highlights
Calcitriol (1; 1α,25-dihydroxyvitamin D3; 1α,25-(OH)2D3; Figure 1) is the most active metabolite of the vitamin D3 [1], representing its hormonal form [2]
Two compounds, characterized by a presence of dienyne moiety conjugated with the aromatic D ring, were successfully synthesized using convergent strategy
Compound with a 2-exomethylene substituent exhibited moderate affinity to the vitamin D receptor (VDR) predicted by molecular docking experiments
Summary
Calcitriol (1; 1α,25-dihydroxyvitamin D3; 1α,25-(OH)2D3; Figure 1) is the most active metabolite of the vitamin D3 [1], representing its hormonal form [2]. Numerous studies demonstrated that this active form of vitamin D3 is responsible for calcium and phosphorus homeostasis, and, plays an important role in cell proliferation and differentiation as well as apoptosis and immunomodulation [3,4,5]. DDoocckkiinngg SSttuuddiieess TThhee ddoocckkiinngg ssiimmuullaattiioonnss ooff tthhee ssyynntthheessiizzeedd ccoommppoouunnddss 55 aanndd 66 ttoo tthhee lliiggaanndd bbiinnddiinngg ddoommaaiinn ((LLBBDD))ooffthteheVDVRDRwewreerpeerpfoerrmfoermd uedsinugsiMngoleMgoroleVgirrotuValirDtuoaclkeDro(rcekleeras(ere4l.e0a, sCeL4C.0b,ioC,LQCiabgieon,, QAiaargheuns,, DAeanrhmuasr,kD).eTnhmeaLrkB)D. TThhee ddoocckkiinngg ssttuuddiieesssshhoowwtthhaatt bbootthh ccoommppoouunnddss aanndd 66 aanncchhoorr tthhee rreecceeppttoorr ssiimmiillaarrllyy ttoo ccaallcciittrriiooll ((FFiigguurree22aa,,bb)). BBiioollooggiiccaall EEvvaalluuaattiioonn:: BBiinnddiinngg ttoo tthhee VViittaammiinn DD RReecceeppttoorr TThhee aafffifinniittiieess ooff tthhee ssyynntthheessiizzeedd ccoommppoouunnddss 55 aanndd 66 ttoo VVDDRR wweerree aasssseesssseedd bbyy aa flfluuoorreesscceennccee ppoollaarriizzaattiioonn ((FFPP))--bbaasseedd ccoommppeettiittiioonn aassssaayy. TThhee VVDDRR aaffffiinniittiieess ooff ccoommppoouunnddss wweerree cchheecckkeedd uussiinngg aa wwiiddee rraannggee ooff ccoonncceennttrraattiioonnss aanndd ccoommppaarreedd ttoo tthhaatt ooff ccaallcciittrriiooll. CCoommppoouunndd 55,, uunnssuubbssttiittuutteedd aatt CC--22,, wwaass pprraaccttiiccaallllyy ddeevvooiidd ooff bbiinnddiinngg aaffffiinniittyy ttoo tthhee VVDDRR,, wwhheerreeaass iittss aannaalloogg 66 wwiitthh tthhee 22--eexxoommeetthhyylleenneeggrroouuppwwaassttwweennttyyttiimmeesslleessssppootteenntttthhaannccaallcciittrriiooll.
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