Diastereoselective synthesis, binding affinity for vitamin D receptor, and chiral stationary phase chromatography of hydroxy analogs of 1,25‐dihydroxycholecalciferol and 25‐hydroxycholecalciferol

Abstract

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 diastereoselective ␣-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. 10,11 is thought to be a common metabolite of both 1,25-dihydroxycholecalciferol (vitamin D hormone 1,2 ) and its synthetic precursor, (24R)-1,24-dihydroxycholecalciferol. 12,13,14 The biological significance of this metabolite, discovered long ago, is still not fully recognized. This might be partly due to the very limited access to this most highly hydroxylated metabolite of vitamin D 3 . It was therefore desirable to develop a direct and regioselective hydroxylation of vitamin D side chain with a readily available oxidant. A method was needed to provide both diastereomers separately for structure analysis, determination of diastereomeric purity, and evaluation of biological enantioselectivity. There was also a need for a practical synthesis of (24R)-1,24,25-trihydroxycholecalciferol in quantity, for a detailed biological examination. An efficient synthesis of (24R)-24,25-dihydroxycholecalciferol 11 was also of our interest. As a part of our work on side chain modified analogs, 15,16,17,18,19,20 we previously described a convergent synthesis 21 of vitamin D compounds with ter-

Vitamin D Analogs in Cutaneous Malignancies

“…2). The vitamin D 3 most highly hydroxylate metabolite [(1S,24R)-1,24,25-trihydroxycholecalciferol, 1,24R,25-(OH) 3 D 3 ] and its C-24 diastereomer [1,24S,25-(OH) 3 D 3 ] were obtained by direct diastereoselective α-hydroxylation of enolate derived from vitamin D ester using Davies chiral oxaziridines [72]. The metabolic precursor of this metabolite, (1S,24R)-1,24-dihydroxyvitamin D 3 [1,24R-(OH) 2 D 3 ] and its C-24 diastereomer [1,24S-(OH) 2 D 3 ] were obtained by convergent synthesis from vitamin D C-22 synthon and a side-chain fragment with the respective chirality at C-24 [73].…”

<b>Specific interactions between vitamin D receptor and ligand depending on its chirality: </b><i><b>ab initio</b></i><b> fragment molecular orbital calculations</b>

“…In contrast, synthesized compounds can have different chirality, and their biochemical and pharmaceutical properties depend on their chirality. For example, the binding affinity between vitamin D receptor (VDR) and its ligand was found to depend significantly on the chirality of the ligand [1].…”

Biological Activity In Vitro of Side-Chain Modified Analogues of Calcitriol

“…The mechanism of the observed synergistic effect remains still unclear, especially in the context of the data providing evidence that human HL-60 promyelocytic leukaemia cells pretreated in vitro with calcitriol or its analogues appeared to be resistant to apoptosis induced by some cytostatics [15,16,Siwinska et al,unpublished data*]. chiral oxaziridines [5,19]. The metabolic precursor of this metabolite, (1S, 24R)-1,24-dihydroxyvitamin D 3 (PRI-2191), and its C-24 diastereomer (PRI-2192) were obtained by convergent synthesis from the vitamin D C-22 synthon and from a side-chain fragment with the respective chirality at C-24 [20].…”