&organic & h4edicinalChemistry Letters.Vo1.3. No.9, pp. 1799-1804. 1993 Printed in GreatBritain 0960-894X,93 $6.00 + .OO Pcrgam PressLtd Effect of C20 Stereochemistry on the Conformational Profile of the Side Chains of Vitamin D Analogs.1 M. Mark Midland’, Joaquin Plumet and William H. Ckamura Department of Chemistry, University of California Riverside, California 92521 (Received 3 1 January 1993) Abstract: The occupancy volumes have been explored usin s molecular mechanics based conformational analysis for the side chain of vitamin D analogs KH 1060, its C 0 epimer, 1a,25_dihydroxyvitamin D3 and its C20 epimer. Dot maps reflect the sites most accessible by the hydroxyl group. The stereochemistry at C20 causes the hydroxyl group to preferentially populate different (but not exclusively different) regions of space. Side chain analogs of ia,25-dihydroxyvitamin Dg [la,25-(OH)2-Ds] have recently been shown to exhibit a bewildering array of biological activities of potential interest in biomedical applications. Of considerable interest is an analog developed by Leo Pharmaceutical Products in Denmark, KH 1060 (l), which exhibits extraordinarily potent effects in inhibiting T-cell activation in vitro, several orders of magnitude more active than cyclosporin A.23 Because of the potent immunosuppressive effects of KH 1060 in vitro, this side chain analog is of considerable interest for the prevention of graft reject and treatment of autoimmune disorders. From a structural and drug development standpoint, KH 1060 is especially remarkable when compared to 1a,25-(OH)2-D3 because it possesses the unnatural configuration at C20 (in addition to the formal insertion of an oxygen atom between C20 and C22 as well as two extra methyl groups at C25 and C26 of the side chain). Because several structural changes are involved in relating the side chain of KH 1060 to that of la,25- (OH)2-Ds (4), this finding would not have been so remarkable were it not for the additional finding that a family of analogs possessing the unnatural C20 stereochemistry exhibit high potency in the above assay as Well as in other biological activities characteristic of la,25-(OH)s-Ds. Most notably, 20-epi-la,25(OH)2-Ds (Leo MC-1288, 3) has been shown using human histiocytic lymphoma cell line U 937 to be several OrderS Of magnitude more effective than la,25(OH)2-D3 in inhibition of cellular proliferation and induction of Cdl differentiation, characteristics which may be of great value in the design of a cancer chemopreventive agent. Thus, there is some justification in the claim that no future vitamin D analog study would be complete without an evaluation of both C20 epimeric series, both natural and unnaturaL4 1799