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Aiming at exploration for new anti-cancer leads utilizing biologically active natural products as seed principles, several synthetic lead compounds have been disclosed through structure-activity relationship analyses by means of a synthetic approach. 1) The absolute structure of callystatin A, potent cytotoxic polyketide, was established by comparative analysis of the CD spectra of synthetic model compounds and our first total synthesis. Furthermore, structure-activity relationship analysis using synthetic analogs revealed α,β-unsaturated δ-lactone to be pharmacophore functionality. According to the synthetic protocol of callystatin A, the first synthesis of leptomycin B, congeneric anti-tumor polyketide, was achieved to determine its absolute structure. 2) By evaluation for biological potency of synthesized amide analogs of potent cytotoxic depsipeptide arenastatin A, metabolism of 15,20-ester linkage resulted in significant reduction of anti-tumor efficacy in vivo. Modification of this ester linkage gave rise to promising leads with stability in serum as well as moderate cytotoxicity. 3) Synthesis of 4-deacetoxycongener of agosterol A, an MDR modulating polyhydroxysterol, was conducted from readily available ergosterol by way of regioselective reductive-cleavage of epoxy function developed by our group. In addition, 4-deacetoxycongener exhibited MDR modulating activity similar to agosterol A.