Structure-activity relationship of a novel group of mammalian DNA polymerase inhibitors, synthetic sulfoquinovosylacylglycerols

We reported previously that sulfolipids in the sulfoquinovosylacylglycerol class from a fern and an alga are potent inhibitors of DNA polymerase alpha and beta and potent anti-neoplastic agents. In developing a procedure for chemical synthesis of sulfolipids, we synthesized many derivatives and ster eoisomers of sulfoquinovosylmonoacylglycerol (SQMG)/sulfoquinovosyldiacylgl ycerol (SQDG), Some of these molecules were stronger inhibitors than the SQ MG/SQDG originally reported as natural compounds. In this study, we examine d the structure-inhibitory function relationship of synthetic SQMG/SQDG and its relationship to cytotoxic activity. The inhibitory effect is probably mainly dependent on the fatty acid effect, which we reported previously, al though each of the SQMG/SQDG was a much stronger inhibitor than the fatty a cid alone that was present in the SQMG/SQDG, The inhibitory effect could be influenced by the chain size of fatty acids in the SQMG/SQDG, The sulfate moiety in the quinovose was also important for the inhibition. Lineweaver-B urk plots of SQMG/SQDG indicated that DNA polymerase a was non-competitivel y inhibited, but the SQMG/SQDG were effective as antagonists of both templa te-primer DNA-binding and nucleotide substrate-binding of DNA polymerase be ta. The SQMC had an cytotoxic effect, but the SQDG tested did not. The SQDG might not be able to penetrate into cells. Based on these results, we disc uss the molecular action of SQMG/SQDG and propose drug design strategies fo r developing new anti-neoplastic agents.