ChemInform Abstract: Design, Synthesis, Inhibitory Activity, and Binding Mode Study of Novel DNA Methyltransferase 1 Inhibitors.

Suzuki, Takayoshi; Tanaka, Rikako; Hamada, Shohei; Nakagawa, Hidehiko; Miyata, Naoki

doi:10.1002/chin.201038206

Cited by 5 publications

(12 citation statements)

References 1 publication

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“…56 Compound 11 was further studied and was shown to inhibit in vitro bacterial C5 DNA methyltransferase M.SssI and to demethylate certain promoters in several cancer cells (Table 1). 57,58 Subsequently, 15 (maleimide derivatives of 11), 59 a benzoylpyrrolidine analog, and a thionitropyridine analog 50 were synthesized, conferring increased inhibitory properties in enzymatic assays (Figure 2). These studies highlighted that, depending on the experimental conditions of the enzymatic assay (the choice of the C5 DNA methyltransferase, the concentration of the cofactor, the concentration and nature of the DNA duplex, and the method of detection), the inhibitory potency can vary greatly for the same compound.…”

Section: ■ Introductionmentioning

confidence: 99%

Targeting DNA Methylation with Small Molecules: What’s Next?

et al. 2014

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DNA methylation is a mammalian epigenetic mark that is involved in defining where and when genes are expressed, both in normal cells and in the context of diseases. Like other epigenetic marks, it is reversible and can be modulated by chemical agents. Because it plays an important role in cancer by silencing certain genes, such as tumor suppressor genes, and by reactivating other regions, such as repeated elements, it is a promising therapeutic target. Two compounds are already approved to treat hematological cancers. Many efforts have been carried out to discover new molecules that are able to efficiently inhibit DNA methylation in cancer cells. We will briefly overview the foremost of these efforts by focusing on what we have learned to this point on non-nucleoside inhibitors and on what we consider to be the features of an ideal inhibitor.

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Section: ■ Introductionmentioning

confidence: 99%

Targeting DNA Methylation with Small Molecules: What’s Next?

et al. 2014

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“…30 More recently, maleimide derivatives of 1 were designed to trap DNMT1 through addition of the catalytic thiol of the enzyme to the maleimide moiety (Figure 1). 38 Herein, we conducted a structure−activity relationship (SAR) study to understand the important features of 1 and its interaction in the DNMT active site in order to improve its activity. We synthesized a small library of analogues of 1 shown in Figure 2.…”

Section: ■ Introductionmentioning

confidence: 99%

Synthesis and Evaluation of Analogues of N-Phthaloyl-l-tryptophan (RG108) as Inhibitors of DNA Methyltransferase 1

et al. 2014

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DNA methyltransferases (DNMT) are promising drug targets in cancer provided that new, more specific, and chemically stable inhibitors are discovered. Among the non-nucleoside DNMT inhibitors, N-phthaloyl-l-tryptophan 1 (RG108) was first identified as inhibitor of DNMT1. Here, 1 analogues were synthesized to understand its interaction with DNMT. The indole, carboxylate, and phthalimide moieties were modified. Homologated and conformationally constrained analogues were prepared. The latter were synthesized from prolinohomotryptophan derivatives through a methodology based amino-zinc-ene-enolate cyclization. All compounds were tested for their ability to inhibit DNMT1 in vitro. Among them, constrained compounds 16-18 and NPys derivatives 10-11 were found to be at least 10-fold more potent than the reference compound. The cytotoxicity on the tumor DU145 cell line of the most potent inhibitors was correlated to their inhibitory potency. Finally, docking studies were conducted in order to understand their binding mode. This study provides insights for the design of the next-generation of DNMT inhibitors.

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“…As analyzed above, the improved potency of compound DC_517 can be attributed to the cation−π interaction between its outward carbazolyl and R1576, which has been highlighted as an important residue that interacts with other non-nucleoside DNMT inhibitors. 3,24,25 However, from a ligand efficiency (LE) perspective, DC_517 (LE = 0.21) is slightly inferior to DC_05 (LE = 0.24), which suggests that the increased hydrophobic and cation−π interactions are weak intermolecular forces and only lead to a less significant gain in affinity. To achieve a more effective interaction with R1576, the carbazolyl of DC_517 should be replaced by smaller groups, such as phenyl or other small negatively charged groups.…”

Section: ■ Introductionmentioning

confidence: 99%

“…2 In mammals, DNA methylation occurs at the 5-position of cytosine, almost as in the context of CpG dinucleotides that are clustered in CpG islands. 1,3 In cancer cells, alterations in DNA methylation can lead to promoter hypermethylation at CpG islands and then silence tumor suppressor genes. 4 Unlike genetic origins, aberrations in DNA methylation are reversible, thus allowing cancer cells to revert to their normal state.…”

Section: ■ Introductionmentioning

confidence: 99%

“…As shown in Figure 4F, one carbazolyl of DC_517 is located in the hydrophobic pocket of the SAM pocket, which resembles DC_05 binding, and the other carbazolyl stretches outside the SAM pocket and interacts with R1576, which has been shown to be an important residue that forms interactions with DNMT1 inhibitors. 3,24,25 Because R1576 is less than 4 Å away and has a carbazolyl group outside the SAM pocket, the improved potency observed in DC_517 can therefore be ascribed to the gain of a cation−π interaction with R1576. In addition, the hydroxyl group of DC_517 forms hydrogen bonds with E1171, and the imino group interacts with the primary chain oxygen of F1148.…”

Section: ■ Introductionmentioning

confidence: 99%

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Identifying Novel Selective Non-Nucleoside DNA Methyltransferase 1 Inhibitors through Docking-Based Virtual Screening

et al. 2014

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The DNA methyltransferases (DNMTs) found in mammals include DNMT1, DNMT3A, and DNMT3B and are attractive targets in cancer chemotherapy. DNMT1 was the first among the DNMTs to be characterized, and it is responsible for maintaining DNA methylation patterns. A number of DNMT inhibitors have been reported, but most of them are nucleoside analogs that can lead to toxic side effects and lack specificity. By combining docking-based virtual screening with biochemical analyses, we identified a novel compound, DC_05. DC_05 is a non-nucleoside DNMT1 inhibitor with low micromolar IC50 values and significant selectivity toward other AdoMet-dependent protein methyltransferases. Through a process of similarity-based analog searching, compounds DC_501 and DC_517 were found to be more potent than DC_05. These three potent compounds significantly inhibited cancer cell proliferation. The structure-activity relationship (SAR) and binding modes of these inhibitors were also analyzed to assist in the future development of more potent and more specific DNMT1 inhibitors.

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ChemInform Abstract: Design, Synthesis, Inhibitory Activity, and Binding Mode Study of Novel DNA Methyltransferase 1 Inhibitors.

Cited by 5 publications

References 1 publication

Targeting DNA Methylation with Small Molecules: What’s Next?

Targeting DNA Methylation with Small Molecules: What’s Next?

Synthesis and Evaluation of Analogues of N-Phthaloyl-l-tryptophan (RG108) as Inhibitors of DNA Methyltransferase 1

Identifying Novel Selective Non-Nucleoside DNA Methyltransferase 1 Inhibitors through Docking-Based Virtual Screening

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