Kohamaic acid A, a novel sesterterpenic acid, inhibits activities of DNA polymerases from deuterostomes

Mizushina, Yoshiyuki; Murakami, Chikako; Yogi, Kentaro; Ueda, Katsuhiro; Ishidoh, Tomomi; Takemura, Masaharu; Perpelescu, Marinela; Suzuki, Motoshi; Oshige, Masahiko; Yamaguchi, Toshiaki; Saneyoshi, Mineo; Yoshida, Hiromi; Sakaguchi, Kengo

doi:10.1016/s1570-9639(03)00108-0

Cited by 8 publications

(13 citation statements)

References 29 publications

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“…We also analyzed the kinetics of compound 5, and obtained similar results (data not shown). In the kinetic analysis, poly(dA)/oligo(dT) [12][13][14][15][16][17][18] and dTTP were used as the DNA template-primer and nucleotide substrate, respectively. Double-reciprocal plots of the results show that inhibition of pol α activity by compound 6 was noncompetitive with the DNA template and the nucleotide substrate.…”

Section: Resultsmentioning

confidence: 99%

“…Similar results were observed with compound 5: the pol α inhibition was non-competitive with both DNA template-primer and dTTP, but the pol β inhibition was competitive with both DNA template-primer and dTTP. When activated DNA was used as the template-primer DNA instead of synthesized DNA (i.e., poly(dA)/oligo(dT) [12][13][14][15][16][17][18] ), the inhibitory modes of the compounds were unchanged (data not shown). The triterpene acids may interact with or affect both of the binding sites on pol β, thereby decreasing its affinity for the DNA template and substrate, whereas they may bind or interact with a domain distinct from the template or substrate binding sites on pol α.…”

Section: Resultsmentioning

confidence: 99%

“…Activities of DNA polymerases were measured by the methods described previously. 24,25) The substrates of DNA polymerases used were poly(dA)/oligo(dT) [12][13][14][15][16][17][18] and dTTP as template-primer DNA and nucleotide substrate, respectively. One unit of each DNA polymerase activity was defined as the amount of enzyme that catalyzes the incorporation of 1 nmol of deoxyribonucleotide triphosphate (i.e., dTTP) into the synthetic template-primers (i.e., poly(dA)/oligo(dT) [12][13][14][15][16][17][18] , A/T=2/1) in 60 min at 37°C under the normal reaction conditions for each of the enzymes.…”

Section: Methodsmentioning

confidence: 99%

“…Therefore, information concerning the structural characteristics of these inhibitors may provide valuable insight for the design of new anti-cancer agents. [12][13][14][15][16][17][18] were purchased from Amersham Biosciences (Buckinghamshire, UK). Supercoiled pUC19 plasmid DNA was obtained from TaKaRa (Tokyo).…”

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confidence: 99%

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

et al. 2004

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Traditional Chinese medicinal plants are a treasure house for screening novel inhibitors of DNA polymerases and DNA topoisomerases from mammals; in the present study, nine lanostanetype triterpene acids were found in sclerotium of Poria cocos. Among the nine compounds, only dehydroebriconic acid could potently inhibit DNA topoisomerase II (topo II) activity (IC50=4.6 μM), while the compound moderately inhibited the activities of DNA polymerases α, β, γ, δ, ɛ, η, iota;, κ and λ only from mammals, to similar extents. Another compound, dehydrotrametenonic acid, also showed moderate inhibitory effects against topo II (IC50=37.5 μM) and weak effects against all the polymerases tested. Both compounds showed no inhibitory effect against topo I, higher plant (cauliflower) DNA polymerase I (α‐like polymerase) or II (βlike polymerase), calf thymus terminal deoxynucleotidyl transferase, human immunodeficiency virus type‐1 reverse transcriptase, prokaryotic DNA polymerases such as the Klenow fragment of E. coli DNA polymerase I, Taq DNA polymerase and T4 DNA polymerase, or DNA metabolic enzymes such as T7 RNA polymerase, T4 polynucleotide kinase and bovine deoxyribonu‐clease I. These findings suggest that dehydroebriconic acid and dehydrotrametenonic acid should be designated as topo II‐preferential inhibitors, although they also moderately inhibited all the mammalian DNA polymerases tested. Both dehydrotrametenonic acid and dehydroebriconic acid could prevent the growth of human gastric cancer cells, and their LD50 values were 63.6 and 38.4 μM, respectively. The cells were halted at the G1 phase in the cell cycle. The relation between the structure of triterpene acids and their inhibitory activities is discussed.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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

et al. 2004

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“…All synthetic analogs were racemate. Our preliminary results on enzyme inhibition assay according to the previously reported procedure 2,11,12) indicated that diterpene analog 3 was active as a pol inhibitor, even though 3 was considerably less active than 1 (KA-A). On the other hand, 4 and 5 were inactive.…”

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confidence: 71%

Synthetic Studies on Kohamaic Acids: Synthesis of Structurally Simplified Analogs of Kohamaic Acid A

Takikawa¹,

Kamatani²,

Nakanishi³

et al. 2008

Bioscience, Biotechnology, and Biochemistry

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Targeting cancer with sesterterpenoids: the new potential antitumor drugs

Zhang

Liu

2015

J Nat Med

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Cancer remains a major cause of death in the world to date. A variety of anticancer drugs have been used in clinical chemotherapy, acting on the particular oncogenic abnormalities that are responsible for malignant transformation and progression. Interestingly, some of these anticancer drugs are developed from natural sources such as plants, marine organisms, and microorganisms. Over the past decades, a family of naturally occuring molecules, namely sesterterpenoids, has been isolated from different organisms and they exhibit significant potential in the inhibition of tumor cells in vitro, while the molecular targets of these compounds and their functional mechanisms are still obscure. In this review, we summarize and discuss the functions of these sesterterpenoids in the inhibition of cancer cells. Moreover, we also highlight and discuss chemical structure–activity relationships of some compounds, demonstrating their pervasiveness and importance in cancer therapy.

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Kohamaic acid A, a novel sesterterpenic acid, inhibits activities of DNA polymerases from deuterostomes

Cited by 8 publications

References 29 publications

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

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

Synthetic Studies on Kohamaic Acids: Synthesis of Structurally Simplified Analogs of Kohamaic Acid A

Targeting cancer with sesterterpenoids: the new potential antitumor drugs

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