Structure‐Activity Relationship of a Novel Group of Mammalian DNA Polymerase Inhibitors, Synthetic Sulfoquinovosylacylglycerols

Abstract

We reported previously that sulfolipids in the sulfoquinovosylacylglycerol class from a fern and an alga are potent inhibitors of DNA polymerase α α α α and β β β β and potent anti-neoplastic agents. In developing a procedure for chemical synthesis of sulfolipids, we synthesized many derivatives and stereoisomers of sulfoquinovosylmonoacylglycerol (SQMG)/sulfoquinovosyldiacylglycerol (SQDG). Some of these molecules were stronger inhibitors than the SQMG/SQDG originally reported as natural compounds. In this study, we examined 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, although each of the SQMG/SQDG was a much stronger inhibitor than the fatty acid 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-Burk plots of SQMG/SQDG indicated that DNA polymerase α α α α was non-competitively inhibited, but the SQMG/SQDG were effective as antagonists of both template-primer DNA-binding and nucleotide substrate-binding of DNA polymerase β β β β. The SQMG 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 discuss the molecular action of SQMG/SQDG and propose drug design strategies for developing new anti-neoplastic agents.Key words: Sulfoquinovosylmonoacylglycerol (SQMG) -Sulfoquinovosyldiacylglycerol (SQDG) -DNA polymerase -Enzyme inhibitor -Anti-neoplastic agentsAt least seven classes of DNA polymerases (pol. α, β, γ, δ, ε, ζ and η) have been identified in mammalian cells.1-3) Moreover, pol. θ may also be expressed in mammals. Recent studies have revealed the biochemical and structural properties of these polymerases, and some of their genes have been cloned. The in vivo functions of some of these polymerases, especially pol. β, δ, ε, ζ and η, appear to be related to DNA repair and/or recombination. On the other hand, pol. α, γ, δ and ε are mainly involved in nuclear or mitochondrial DNA replication. Our recent studies of the polymerases have focused on understanding the structure and function of these polymerases, especially pol. α and β types, and identifying the factors controlling their activities. For these studies, potent and selective inhibitors are required.1) In screening studies, we found many inhibitors of mammalian DNA polymerases. [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] At present, we are engaged in analyzing the structure and function of the DNA polymerases using these inhibitors from two different viewpoints; to understand the precise role of each polymerase in vivo, and to develop a drug design strategy for cancer chemotherapy agents. Since DNA polymerases are essential enzymes for DNA replication and repair, and thus for cell division, inhibition of the enzymes will le...

A novel DNA topoisomerase inhibitor: dehydroebriconic acid, one of the lanostane‐type triterpene acids from Poria cocos

“…2 and 3). In fact, as described previously, sulfolipids, which inhibit the activities of topo I and II, and eukaryotic DNA polymerases equally, 27,34) were found to be potent anticancer agents in vivo. 35) We have also been engaged in analyz- ing the structure and function of primarily topo II and secondarily mammalian DNA polymerases from two different viewpoints, using dehydrotrametenonic acid and dehydroebriconic acid.…”

Galactosyldiacylglycerol, a Mammalian DNA Polymerase .ALPHA.-Specific Inhibitor from a Sea Alga, Petalonia bingbamiae.

“…Some synthetic sulfoquinovosylacylglycerols were shown to be potent anti-neoplastic agents, 41) and novel agents in the glycolipids group could be a superb anti-cancer drugs for clinical use. The results of the present and our previous studies will be useful for drug design to obtain novel glycolipid inhibitors including derivatives of GDG.…”

“…We have succeeded in systematic chemical synthesis of many kinds of sulfoquinovosylacylglycerols including their stereoisomers and derivatives, [40][41][42] and recently we also synthesized GDG chemically (Hanashima et al in preparation). Some synthetic sulfoquinovosylacylglycerols were shown to be potent anti-neoplastic agents, 41) and novel agents in the glycolipids group could be a superb anti-cancer drugs for clinical use.…”

Inhibitory Effect of Mispyric Acid on Mammalian DNA Polymerases

“…As described previously, sulfo-glycolipids, which inhibited the activity of mammalian pols equally, 11,12) were as effective as anti-cancer agents in vivo. 13,14) Mispyric acid could, therefore, be considered a possible candidate for an anti-cancer agent.…”