Part I. Noncalcemic, antiproliferative, transcriptionally active hybrid analogs of the hormone 1alpha,25-dihydroxyvitamin D(3): Design, synthesis, and preliminary biological evaluation. Part II. New synthetic methodology: n + 3 ring expansion casca

Part I. We have designed and synthesized a series of novel 1α, 25-(OH)₂D₃ (calcitriol) analogs. Our goal is to make analogs that possess the high antiproliferative activity of calcitriol, but at the same time have low or no calcemic effect which is often encountered in vitamin D therapy. Therefore, we synthesized QW1624F2-2, which has a combination of unnatural (1-hydroxymethyl) A-ring and 24-fluorination. The unnatural A-ring can diminish the calcemic effect, and the 24-fluorination can block the metabolic oxygenation at this position and enhance the analog's half-life in vivo. Initial biological testing shows QW1624F2-2 meets all the requirement and stands out as a very good drug candidate.; We also designed and synthesized a series of sulfone containing calcitriol analogs. Several of these analogs (QW-1624F2-25SO2-1 and QW-1623E-diene-24F-25SO2-1) also show very high antiproliferative activities and are non-calcemic. We have established for the first time that the side chain sulfone group may be binding to the nVDR (nuclear Vitamin D Receptor) as a hydrogen-bond acceptor, in contrast to the hydrogen-bond donor function of the 25-OH group of calcitriol.; Part II. The methodology to synthesize small/medium sized ring lactones by using atom economical one-pot sequential reactions has been developed. The reaction involves an enolate attacking an epoxide. The ring opening of epoxide is facilitated by a Lewis acid BF₃·Et ₂O). The formed lactol is then oxidized by Pb(OAc)₄ to give the corresponding unsaturated lactone, which is elongated by three atoms (from epoxide). The whole sequence is a homologous Baeyer-Villiger reaction. It is an extremely useful, mild, easy and convenient method of transforming relatively simple molecules into structurally much more complex cyclic systems. As an example, (±)-phoracantholide I was synthesized in 3 steps, representing one of the shortest synthetic sequences to this natural product.