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

Takikawa, Hirosato; Kamatani, N.; Nakanishi, Koki; Tashiro, Takuya; Sasaki, Makoto; Yoshida, Hiromi; Mizushina, Yoshiyuki

doi:10.1271/bbb.80629

Cited by 7 publications

(8 citation statements)

References 19 publications

(16 reference statements)

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“…The effect on cell division was suggested to proceed via a block or inhibition of sea urchin replication-essential DNA polymerases. More detailed analysis of KA-A and a series of analogs [88, 89] revealed broad spectrum inhibition of human DNA polymerases α, β, δ and γ, suggesting a possible universal mechanism of inhibition of DNA polymerases but a clear lack of specificity for Polβ. The structure of the natural compound KA-A and the most effective derivative [Compound #11; (1S*, 4aS*, 8aS*)−17-(1,4,4a,5,6,7,8,8a–octahydro-2,5,5,8a–tetramethylnaphthalen-1-yl)heptanoic acid] [88] is shown in Fig.…”

Section: Ka-amentioning

confidence: 99%

Targeting DNA Polymerase ß for Therapeutic Intervention

Goellner

Svilar²,

Almeida³

et al. 2012

CMP

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DNA damage plays a causal role in numerous disease processes. Hence, it is suggested that DNA repair proteins, which maintain the integrity of the nuclear and mitochondrial genomes, play a critical role in reducing the onset of multiple diseases, including cancer, diabetes and neurodegeneration. As the primary DNA polymerase involved in base excision repair, DNA polymerase β (Polβ) has been implicated in multiple cellular processes, including genome maintenance and telomere processing and is suggested to play a role in oncogenic transformation, cell viability following stress and the cellular response to radiation, chemotherapy and environmental genotoxicants. Therefore, Polβ inhibitors may prove to be effective in cancer treatment. However, Polβ has a complex and highly regulated role in DNA metabolism. This complicates the development of effective Polβ-specific inhibitors useful for improving chemotherapy and radiation response without impacting normal cellular function. With multiple enzymatic activities, numerous binding partners and complex modes of regulation from post-translational modifications, there are many opportunities for Polβ inhibition that have yet to be resolved. To shed light on the varying possibilities and approaches of targeting Polβ for potential therapeutic intervention, we summarize the reported small molecule inhibitors of Polβ and discuss the genetic, biochemical and chemical studies that implicate additional options for Polβ inhibition. Further, we offer suggestions on possible inhibitor combinatorial approaches and the potential for tumor specificity for Polβ-inhibitors.

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Section: Ka-amentioning

confidence: 99%

Targeting DNA Polymerase ß for Therapeutic Intervention

Goellner

Svilar²,

Almeida³

et al. 2012

CMP

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“…As briefly described in the Introduction, we found and reported that KA-A (compound 1 ) is an inhibitor of pols only from the deuterostome branch in the phylogenetic tree, including mammals [ 2 ]. The purpose of this study was to investigate the inhibitory mechanism more precisely using eleven chemically synthesized derivatives of KA-A (compounds 2 – 12 ), which were prepared as described previously [ 10 ]. The chemical structures of KA-A and its analogs are shown in Figure 1 .…”

Section: Resultsmentioning

confidence: 99%

“…These inhibitors are not only molecular tools for analyzing pols, but are also potentially useful for cancer chemotherapy. Subsequently, we found that KA-A (compound 1 ) was a potentially useful agent [ 2 ], and synthesized KA-A derivatives (compounds 2 – 12 ) [ 10 ]. The inhibitory effect of compound 11 on both mammalian pol activity and human cancer cell growth was strongest of all compounds tested ( Figure 2 and Figure 3 ), and this compound inhibited enzyme activity at an IC 50 of 4.21 μM for pol α and 5.50 μM for pol β ( Table 1 ).…”

Section: Resultsmentioning

confidence: 99%

“…It has also been reported that primary mesenchyme cells undergo mitotic divisions after they have been shed into the blastocoel [ 9 ]. This indirect evidence suggests that KA-A is useful for investigating the relationship between sea urchin pols and the cleavage of fertilized sea urchin eggs, and that KA-A may induce inhibition of the first cleavage of fertilized sea urchin eggs by inhibiting DNA replication [ 2 ]; subsequently, we succeeded in chemically synthesizing KA-A (compound 1 ) and its eleven derivatives (compounds 2 – 12 ) ( Figure 1 ) [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

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The Inhibitory Action of Kohamaic Acid A Derivatives on Mammalian DNA Polymerase β

et al. 2008

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We previously isolated a novel natural product, designated kohamaic acid A (KA-A, compound 1), as an inhibitor of the first cleavage of fertilized sea urchin eggs, and found that this compound could selectively inhibit the activities of mammalian DNA polymerases (pols). In this paper, we investigated the structure and bioactivity of KA-A and its chemically synthesized 11 derivatives (i.e., compounds 2–12), including KA-A - fatty acid conjugates. The pol inhibitory activity of compound 11 [(1S*,4aS*,8aS*)-17-(1,4,4a,5,6,7,8,8a-octahydro-2,5,5,8a-tetramethyl-naphthalen-1-yl)heptadecanoic acid] was the strongest among the synthesized compounds, and the range of IC50 values for mammalian pols was 3.22 to 8.76 μM; therefore, the length of the fatty acid side chain group of KA-A is important for pol inhibition. KA-A derivatives could prevent human cancer cell (promyelocytic leukemia cell line, HL-60) growth with the same tendency as the inhibition of mammalian pols. Since pol β is the smallest molecule, we used it to analyze the biochemical relationship with KA-A derivatives. From computer modeling analysis (i.e., docking simulation analysis), these compounds bound selectively to four amino acid residues (Leu11, Lys35, His51 and Thr79) of the N-terminal 8-kDa domain of pol β, and the binding energy between compound 11 and pol β was largest in the synthesized compounds. The relationship between the three-dimensional molecular structures of KA-A-related compounds and these inhibitory activities is discussed.

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“…Inspired by its interesting biological profiles, we initiated studies toward the synthesis of 1 as a continuation of our synthetic studies on pol inhibitors [4,5]. Here, we report the first synthesis of (S)-(+)-1.…”

mentioning

confidence: 99%