Chemoenzymatic synthesis and biological evaluation of C-3 carbamate analogues of 1α,25-dihydroxyvitamin D 3

Abstract

The synthesis of new analogues of 1α,25-dihydroxyvitamin D 3 containing a carbamate function at the A-ring fragment has been described using the cross-coupling approach. The carbamate group was selectively introduced at the C-3 position by regioselective enzymatic alkoxycarbonylation of A-ring enyne 3 and subsequent treatment with ammonia, amines, amino alcohols, and amino acids. Biological studies to evaluate the potency of all five of these carbamate analogues were performed and demonstrated very low binding affinity for the vitamin D receptor compared with 1α,25-dihydroxyvitamin D 3. Moreover, all the carbamate analogues were less active than 1α,25-dihydroxyvitamin D 3 in inhibiting cell proliferation or stimulating cell differentiation. Of all the five analogues, the 3- O-carbamoyl-1α,25-(OH) 2-D 3 analogue 10a was the most potent one in vitro. However, all investigated carbamate analogues demonstrated lower calcemic effects in vivo than the parent compound.