The major goal of this project is to design and synthesize vitamin D3 analogs (deltanoids) having high cancer chemoprotective activities without causing hypercalcemia. These deltanoids are expected to maintain the differentiating ability of cells and thus to prevent them from adopting a proliferative phenotype. To accomplish this goal, first a series of hybrid deltanoids will be prepared combining structural modifications on the A- ring with structural modifications on the side-chain (Aim 4.1). Based on literature precedent, it is expected that the effects of these structural changes on biological activity will be synergistic. Preliminary results indicate that modifications of the A ring will contribute to low calcemic activity, and, based on literature precedent, modifications of the side chain will contribute to high antiproliferative, differentiation-inducing, and cancer chemoprotective activities. The specific side-chain modifications have been chosen to represent the most potent inducers of cell differentiation and of cancer prevention. Preliminary biological evaluation of one example of such analogs in vitro shows that, in murine keratinocytes as well as in human leukemic cell, this compound has antiproliferative potency greater than that of calcitriol, and, significantly, it is essentially non-calcemic. These findings provide strong support for examination of SAR in other structurally modified deltanoids, as proposed here. Second, a series of non-classical deltanoids lacking the natural ring A or D will be prepared (Aim 4.2). A-ring aromatic analogs are targeted because of their rigid structural similarity to natural calcitriol and because of their inability to undergo undesirable previtamin equilibrium. Synthesis of a variety of related A-ring heteroaromatic deltanoids is proposed. These deltanoids will be relatively easy to synthesize. The results of in vitro testing will lead in Years 4 and 5, to larger-scale syntheses to prepare enough material for evaluation of the most promising new deltanoids for protection of animals against cancer (Aim 4.3). Collectively, these studies should provide important structure-activity and mechanistic insights into chemoprotective actions of vitamin D3 analogs.