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Synthesis, Modification And Bioactivity Evaluation Of Bromophenols Isolated From Alga

Posted on:2011-02-09Degree:DoctorType:Dissertation
Country:ChinaCandidate:S J GuoFull Text:PDF
GTID:1100360305473575Subject:Marine Chemistry
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Type 2 diabetes, is a complex metabolic disease characterized by insulin resistance, hyperglycemia and hyperinsulinemia. Evidence from biochemistry and genetic studies supported that PTP1B, a key negative regulator of insulin signal transduction, was a major target for a novel therapeutic strategy for the treatment of diabetes and obesity.The family Rhodomelaceae, distributed widely in China, Japan, and Korean Peninsula, are known to contain bromophenols. Four bromophenols isolated from Rhodomela confervoides collected at the coast of Qingdao, China, showed potent Protein tyrosine phosphatase 1B (PTP1B) inhibitory activity, especially the compound named 3,4-dibromo-5-(2-bromo-6-(ethoxymethyl)- 3,4-dihydroxybenzyl)benzene -1,2–diol (BPN)(IC50=0.84μmol/L). In order to further study its hypoglycemic activity in vivo, the compound BPN was synthesized.1. 9.9 g BPN and 7 bromophenols were isolated from EtOAc-soluble portion of 50kg red alga R. confervoides by chromatography including normal phase silica gel, Sephadex LH-20 gel and recrystallization. However, it is hard to isolate BPN from R. confervoides, because constituent of R. confervoides makes separation and purification process of BPN taking a lot of money and time.2. The targeting compound BPN was synthesized in 8 steps with an overall yield of 14.4%, employing bromination, Wolff-Kishner-Huang reduction and Friedel-Crafts reaction as key steps. A practical approach was established after the optimization of each reaction. 35 g BPN was synthesized via this synthetic route. 3. 31 compounds (including 26 new compounds) were synthesized and the structures of these compounds were elucidated by spectroscopic methods including 1HNMR, 13CNMR, EIMS and HRESIMS.4. Based on the inhibition of these compounds, the preliminary structure-activity relationships of the screened compounds were revealed as followed:(a). Bromo-diphenyl methane (one) structural unit is necessary for the compounds to behave the PTP1B inhibitory activity. Once the structure is destroyed, the inhibitory activity will disappear.(b). The length of R3 plays an important role in structure-activity relationship of the screened compounds.(c). The increasing of bromine number on benzyl ring could upgrade potency of PTP1B inhibitory activity.5. The acute toxicity test in mice was carried out, and the compound showed no obvious acute toxicity. The oral antihyperglycemic effects of BPN were investigated on streptozotocin-induced experimental diabetes in rats. Oral administration of BPN resulted in a reduction in blood glucose.
Keywords/Search Tags:3,4-dibromo-5-(2-bromo-6-(ethoxymethyl)-3,4-dihydroxybenzyl) benzene-1,2–diol, Diabetes mellitus, Protein tyrosine phosphatase 1B,, Bromophenol derivatives, Antihyperglycemic in vivo, STZ-DM rats
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