The primary overall goal of the proposed research in this revised NCCP grant is to synthesize, evaluate and identify analogs of vitamin D which induce differentiation and inhibit proliferation of leukemia and pre- leukemia cells without inducing toxic hypercalcemia. Under specific aim (1.0), the plan is to design analogs with rigid side chains to restrict rotations as a means of identifying target molecules. In this connection, there is described a method of analysis using a molecular mechanics, computational based approach. Under specific aim (2.0), based on lead results already in hand as well as the new target molecules identified under specific aim (1.0), novel side chain analogs of 1alpha,25- dihydroxyvitamin D3 (1,25-(OH)2D3) will be synthesized and submitted for biological evaluation. New leads, as they emerge, will dictate the course of future studies. Exploratory studies to improve upon chemical synthetic approaches to the analogs will be carried out to a limited degree. Finally, aim (3.0) of the previous version of this application, namely the chemical synthesis of analogs modified structurally in the A-ring, triene and/or the CD ring which emerge from Okamura's DK-16595 grant, which specifically excludes support for syntheses of side chain modified analogs, has been deleted since it would overburden the biological assay resources available.