Search for inhibitors of cell cycle and development for natural molecular probe

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In search of new pharmaceutically valuable substances from marine organisms, we have been engaged in chemical studies on the bioactive substances, which was isolated from marine invertebrates on the guidance of new practical bioassay.a)Differentiation inducer against leukemia cells and neuroblastoma1)Long-chain acetylene alcohol (lembehyne A) : Lembehyne A(LB-A), isolated from marine sponge of Haliclona sp., induced neuronal cell differentiation in a neuroblastoma cell line, Neuro 2A. Furthermore, the cell cycle of Neuro 2A cell was found to be specifically blocked at the G1 phase by LB-A. The total synthesis of LB-A was achieved, and the several analogues were synthesized from suitable fatty acids. The structure-activity relationship study revealed that the carbon-chain length and 3R configuration are important for neuritogenic activity. To identify the target protein for LB-A, a radioactive photoaffinity probe was synthesized, and the in situ photoaffinity labeling was succeeded in t … More he detection of a protein of Mr 30 kDa. 2)Sesquiterpene aminoquinone (smenospongine) : A new sesquiterpene aminoquinone, 5-epi-smenospongorine, together with nine known sesquiterpene quinone/phenols, was isolated from the marine sponge Dactylospongia elegans as differentiation-inducing substances to K562 cells into erythroblast. Smenospongine increased hemoglobin production in K562 cells and showed increase of glycophorin A expression. The structure-activity relationship study of these compounds clarified that the quinone skeleton is indispensable and the amino group plays an important role.b)Modulator of multi-drug resistance against anti-tumor drugs (inhibitor of P-gp) :Kendarimide A, a novel modulator of multi-drug resistance(MDR) in tumor cells mediated by P-glycoprotein(P-gp) was isolated from a marine sponge of Haliclona sp. The chemical structure of kendarimide A was characterized to be a linear peptide composed of N-methylpyroglutamic acid (pyroMeGlu), N-methylated eight-membered cysteinyl-cysteine (ox-[MeCys-MeCys]) together with many N-methyl amino acid residues, and the absolute stereostructure was determined by comparison with synthetic model compounds. Less