Calcitriol analogs 3 and 4, prepared by convergent coupling of 1-hydroxymethyl A-ring phosphine oxide (+)-5 and structurally modified C,D-ring ketones (-)-6, are shown to be hybrid analogs with blended and potent, but variable, biological activities.
We recently proposed and evaluated a new concept for design of physiologically active analogs of hormonally potent let,25-dihydroxyvitamin D3 (calcitriol, 1). 1 Combining a calcemia-inactivating structural change in the A-ring (i.e. a 1-CH2OH substituent) 2 with a differentiation-activating structural change in the C,D-ring side-chain (i.e. KH-1060 side-chain) 3 produced hybrid analog (+)-2b with blended and powerful biological activities.l Now we report the results of further biological testing of this hybrid analog (+)-2b and also synthesis and initial biological testing of hybrid analogs 3 and 4 that incorporate the same 1-CH2OH structural modification but that feature different potentiating C,D-ring side-chain structural modifications. These side-chain modifications were chosen as key structural features characteristic of the most potent vitamin D3 analogs (i.e., MC-1357 and GS-1500) described recently by the Leo Pharmaceutical Company. 4,5 Convergent syntheses of hybrid analogs 3 and 4 from previously prepared A-ring allylic phosphine oxide (+)-52 and enantiomerically pure C,D-ring ketones (-)-66 are shown in eq. 1.7,8
Homer-Wadsworth-Emmons coupling and silyl ether deprotection as in eq. 1 produced, in each case, two diastereomeric products that were separated easily by preparative HPLC. Characterization of each diastereomer was achieved tentatively as in previous casesl, 2 using especially 400 MHz 1H NMR spectroscopy. For each pair of analogs 3 and 4, the let-diastereomer showed the C-18 methyl group at 0.02-0.03 ppm lower field than the l~l-diastereomer. A similar trend in chemical shift was observed also for the C-19 methylene group; coupling constants also allowed distinction between the let-and the l[3-diastereomers (see Table I).