Detail Synthesis of (+)-neocarzinostatin chromophore and its analog-mechanistic studies in vivo and in vitro Bibliografi Author: Liang, Jun ; Myers, Andrew G. (Advisor) Topik: CHEMISTRY; ORGANIC Bahasa: (EN )    ISBN: 0-599-77672-2     Penerbit: Harvard University Press     Tahun Terbit: 2000     Jenis: Theses - Dissertation Fulltext: 9972363.pdf (0.0B; 0 download) Abstract A convergent, enantioselective synthesis of neocarzinostatin chromophore (1), the chromophore component of the natural antitumor antibiotic neocarzinostatin (NCS), is described. Coupling of the epoxydiyne 11 and the enone dimethyl acetal 12 initiated a sequence of 18 synthetic steps (87% average yield per step, 9% overall yield) leading to neocarzinostatin chromophore aglycone (7). Glycosylation of 7 with the N-methylfucosamine-derived trichloroacetimidate 79, containing a free N-methylamino group, formed the α-glycoside 85 selectively. Subsequent removal of protective groups under mild conditions furnished the highly labile chromophore component (1). To date, this is the only reported preparation of any chromoprotein chromophore. The synthetic route was modified to prepare tritium-labeled 1, which was employed in studies to determine the mechanism of action of NCS in vivo. Incubation of HeLa cells with NCS formed by reconstitution of apo-NCS with radiolabeled 1 was shown to produce the NCS chromophore-glutathione adduct, as determined by BPLC comparison with an authentic standard, prepared in vitro. The α-D-fucosyl NCS chromophore analog 52 , in which the 2′-N-methylamino group of 1 is replaced with a 2'-hydroxyl group, was synthesized to evaluate the importance of the methylamino group of 1 as an internal base in thiol activation. In organic solvents, analog 52 was shown to be inert to thiol activation in the absence of an external base such as triethylamine. Additionally, the efficiency and rate of thiol-induced DNA cleavage in aqueous solution by 52 was found to be diminished relative to 1, whereas the sequence selectivity of DNA cleavage by both compounds is similar. Thus, the methylamino group of NCS chromophore appears to play a primary role in thiol activation, but not in DNA recognition.* *Please refer to dissertation for diagrams. Opini Anda Klik untuk menuliskan opini Anda tentang koleksi ini! Lihat Sejarah Pengadaan  Konversi Metadata   Kembali

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