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Inhibitors of human DNA polymerase lambda

- Resveratrol, a natural compound found in many dietary plants and in red wine, plays an important role in the prevention of many humanpathological processes, including inflammation, atherosclerosis and carcinogenesis. Here, we present the first detailed biochemical investigation on the mechanism of action of resveratrol towards mammalian pols. Our results suggest that specific structural determinants of the resveratrol molecule are responsible for selective inhibition of different mammalian pols, such as the family B pol a and the family X pol.

Moreover, the resveratrol derivative trans-3,5-dimethoxy-4-hydroxystilbene, can inhibit pols and also suppress the in vitro SV40 DNA replication. The potency of inhibition is similar to that of aphidicolin, an inhibitor of the three replicative pols a, d and e. Our findings establish the necessary background for the synthesis of resveratrol derivatives having more selective and potent antiproliferative activity.

- More than 90% of leukemic cells in acute lymphocytic leukemia and approximately 30% of leukemic cells in the chronic myelogenous leukemia crisis show elevated TDT activity. This finding is connected to a poor prognosis and response to chemotherapy and reduced survival time. On the other hand, recent data indicated that TDT is not the only terminal deoxyribonucleotidyl transferase in mammalian cells. Its close relative, DNA polymerase l, can synthesize DNA both in a template-dependent (polymerase) and template-independent (terminal deoxyribonucleotidyl transferase) fashion. DNA polymerase l might be involved in the nonhomologous end-joining recombinational repair pathway of DNA double-strand breaks. Here, we report the characterization of the mechanism of action of three diketo hexenoic acid (DKHA) derivatives, which proved to be extremely selective for the terminal deoxyribonucleotidyl transferase activity of DNA polymerase l and TDT. They seem to be the first non nucleoside-specific inhibitors of mammalian terminal transferases reported. Moreover, the DKHA analog 6-(1-phenylmethyl- 1H-indol-3-yl)-2,4-dioxo-5-hexenoic acid (RDS2119) was not toxic toward HeLa cells (CC50 >100 mM), whereas it showed significant cytotoxicity against the TDT+ leukemia cell line MOLT-4 (CC50 = 14.9mM), thus having the potential to be further developed as a novel antitumor agent.

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