Design, synthesis, and preliminary biological evaluation of analogs of 1alpha,25-dihydroxyvitamin D3: Modifications to the A-ring and C,D-ring side chain

We report here the first example of a successful high pressure 4+2-cycloaddition between commercial 3-carbomethoxy-2-pyrone and a new geminally difluorinated vinyl ether dienophile; chromatographically pure racemic cycloadduct 15 was isolated in 73% yield, formed regiospecifically and stereospecifically with the desired 1,3-trans dioxygenation pattern necessary for ultimate transformation into the first reported 2,2-disubstituted calcitriol analogs 23a and 23b.; Novel side-chain diene sulfones 42a and 42b were designed to incorporate some of the most favorable structural features of the Leo Pharmaceutical Company's drug candidate seocalcitol (EB1089, 35) and of our non-calcemic side-chain tert-butyl sulfone analogs reported recently. Novel synthetic features include: (1) regioselective Swern oxidation of a primary silyl ether in a primary-secondary bis-silyl ether and (2) Horner-Wadsworth-Emmons aldehyde addition by a 1-phosphonyl-3-sulfonyl stabilized allylic carbanion, regiospecifically adjacent to the phosphorus, to form E,E-diene sulfone 40. Sulfone diene analogue 42a with natural 1α,3β-diol functionality, but not its diastereomer 42b with unnatural A-ring stereochemistry, is antiproliferative in vitro toward murine keratinocytes and toward MCF-7 human breast cancer cells. When combined with the currently used anticancer drug adriamycin (ADR), 42a caused a noteworthy 3-fold enhancement of ADR antiproliferative potency in MCF-7 cells and desirably is non-calcemic in vivo at a daily dose (7 d) of 10 μg/kg of rat body weight.; New C,D ring side-chain-modified sulfones 52a–59a, with natural 1α,3β-hydroxyl groups but lacking the 25-hydroxyl group characteristic of the natural hormone 1α,25-dihydroxyvitamin D ₃ (calcitriol, 1α,25-D₃, 7), have been prepared and characterized. Novel synthetic features include smooth reductive etherification or Williamson ether synthesis without interference by a neighboring alkyl or aryl sulfonyl or sulfide group. Several of these novel sulfones 52a–59a are powerfully antiproliferative and transcriptionally active in vitro but desirably noncalcemic in vivo . Although sulfone 52a, designed to resemble Leo Pharmaceutical Co.'s KH-1060, is recognized by catabolic enzymes, the selective biological profile of 52a is likely not due to its metabolites.