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Syntheses of Dehydroaltenusin, a Selective Inhibitor of Mammalian DNA Polymerase α

[ Vol. 8 , Issue. 1 ]

Author(s):

Kouji Kuramochi, Isoko Kuriyama, Masahito Mori, Shinji Kamisuki, Shunya Takahashi, Kazunori Tsubaki, Fumio Sugawara, Kengo Sakaguchi, Hiromi Yoshida and Yoshiyuki Mizushina   Pages 134 - 144 ( 11 )

Abstract:


Dehydroaltenusin has been isolated from Alternaria tenuis and other fungal species. It exhibits various biological activities such as growth inhibition of wood-damaging fungi, inhibition of calmodulin-dependent myosin light chain kinase, anti-HIV activity, and inhibition of mammalian DNA polymerase α (pol α). These significant biological activities, as well as the unique structural properties of dehydroaltenusin, have stimulated considerable interest in its synthesis. In this review, we summarize the synthesis and structural analysis of dehydroaltenusin and its derivatives. We also focus on the structure-activity relationships of dehydroaltenusin as a mammalian pol α inhibitor. Dehydroaltenusin specifically inhibits mammalian pol α, an enzyme that plays an important role in DNA replication and cell division. The human genome encodes 14 pols that control cellular DNA synthesis, and synthetic dehydroaltenusin derivatives, which are specific inhibitors of mammalian pol α, are useful tools and molecular probes for distinguishing pols and for clarifying their biological and in vivo functions. Moreover, these compounds might be potentially useful as anti-cancer chemotherapeutic drugs for in vivo studies.

Keywords:

Dehydroaltenusin, DNA polymerase, enzyme inhibitor, structure-activity relationship, anti-cancer drug, Mammalian, Alternaria tenuis, fungal species, A. kikuchiana, X ray crystallographic analysis, Cladosporium sphaerospermum, leukemia cells, calmodulin-dependent phosphodiesterase, protein kinase, cytopathic ef-fects, HIV infection, proliferation, Aspergillus fumigates, A. niger, Candida albi-cans, C. neoformans, mycotoxins, trifluoromethanesulfonic anhydride, pyridine, triflate, halogen, boronation, triisopropyl borate, Suzuki coupling, (triphenylphosphine) palladium, potassium phosphate, dioxane afforded, Alkaline hydrolysis, pinacolato, fer-rocene]palladium, methoxydehydroaltenusin, methyl alternariolate tetramethyl ether, tautomers

Affiliation:

Laboratory of Food&Nutritional Sciences, Department of Nutritional Science, Kobe-Gakuin University, 518 Arise, Ikawadani-cho, Nishi-ku, Kobe, Hyogo 651-2180, Japan.



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