Diastereoselective synthesis, binding affinity for vitamin D receptor, and chiral stationary phase chromatography of hydroxy analogs of 1,25-dihydroxycholecalciferol and 25-hydroxycholecalciferol.
A series of analogs of 1,25-dihydroxycholecalciferol and 25-hydroxycholecalciferol were obtained with an additional hydroxyl in the aliphatic side chain at carbon atom C-24. These analogs were synthesized by direct and diastereo-selective alpha-hydroxylation of enolates derived from respective vitamin D esters using Davies chiral oxaziridines. The use of (+)-(2R,8aS)-(8, 8-dichlorocamphoryl)sulfonyl oxaziridine resulted in (R) stereochemistry of the new asymmetric center for both series of analogs. Similarly, (-)-(2S,8aR) oxaziridine gave (S) analogs. The diastereomeric purity of hydroxy analogs was determined by high-performance liquid chromatography on a chiral stationary phase. High diastereopurity of hydroxylation of vitamin D esters was obtained without the use of any chiral auxiliary. The binding affinity of (24R)-1,24,25-trihydroxycholecalciferol for the calf thymus intracellular vitamin D receptor was one order of magnitude higher than that of the respective (24S)-diastereomer.
Odrzywolska
M
M
Pharmaceutical Research Institute, Warszawa, Poland.
Chodyński
M
M
Zorgdrager
J
J
Van De Velde
J P
JP
Kutner
A
A
D000818:Animals; D002112:Calcifediol / Q000138:chemical synthesis* / Q000302:isolation & purification / Q000378:metabolism; D002117:Calcitriol / Q000138:chemical synthesis* / Q000302:isolation & purification / Q000378:metabolism; D002417:Cattle; D002851:Chromatography, High Pressure Liquid / Q000379:methods*; D009682:Magnetic Resonance Spectroscopy; D011485:Protein Binding; D018167:Receptors, Calcitriol / Q000378:metabolism*; D013237:Stereoisomerism
D018167:Receptors, Calcitriol; D002117:Calcitriol; D002112:Calcifediol