55(P19) 高等生物DNAポリメラーゼ阻害物質の合成研究(ポスター発表の部)

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Since DNA polymerases (pol.) are essential enzymes as DNA replication, repair and cell division, the studies on these enzymes invoked specific inhibitors. We have been reported that the inhibitors have been isolated and their structures have been determined by spectroscopic means. Among these compounds, sulfoquinovosyl diacyl glyceride (SQDG) (1-5) and sulfoquinovosyl monoacyl glyceride (SQMG) (6) inhibited activities of pol. α and pol. β. Several significant biological activities of these compounds were published. Now we aimed to synthesize these compounds (7-15) from D-glucose, and to determine the absolute configurations of the natural products by synthesis of optical pure SQDGs (26, 27) Synthetic routes were represented in Scheme 1 and Scheme 2. In Scheme 1, 1-O-Allyl-4, 6-O-benzylidene glucose 16 was lead to 18a, 18b via 4-6 steps, and dihydroxylation by osmium tetraoxide or AD-mix provided 19a and 19b. After esteration with fatty acid, 20a and 20b were oxidized with OXONE in acetic acid followed by deprotection in catalytic hydrogenation with Pd-C or hydrolysis under acidic condition afforded SQDG 11 or SQMG 15. Compounds 7-15 have been synthesized in the same manner. Optical pure SQDG 26, which has 2(S) configuration, was prepared as shown in Scheme 2. Compound 17a was deallylated, and then tosyl group was converted to thioacetyl group by S_<N2> reaction to afford 23. Glycosyl donor 24 was afforded from 23 with CCl_3CN and DBU, followed by glycosylation with the accepter 28 by TMSOTf as Lewis acid yielded compound 25. After 2steps shown in Scheme 1 afforded 2(5)-α-SQDG 26. 2(R)-α-SQDG 27 was synthesized with the same method. Inhibition against DNA polymerase a and β with SQDGs and SQMGs were shown in Figure 2 and 3. According to our structure-activity analysis, fatty acid moiety at Cl and sulfon group at C6' were essential structures to exhibit inhibition.
天然有機化合物討論会の論文
1999-09-01

55(P19) 高等生物DNAポリメラーゼ阻害物質の合成研究(ポスター発表の部)

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