Constrained (l-)-S-adenosyl-l-homocysteine (SAH) analogues as DNA methyltransferase inhibitors

Isakovic, Ljubomir; Saavedra, Oscar M.; Llewellyn, David B.; Claridge, Stephen; Zhan, Lijie; Bernstein, Naomy; Vaisburg, A. F.; Elowe, Nadine H.; Petschner, Andrea J.; Rahil, Jubrail; Beaulieu, Norman; MacLeod, A. Robert; Delorme, Daniel; Besterman, Jeffrey M.; Wahhab, Amal

doi:10.1016/j.bmcl.2009.03.132

Cited by 47 publications

(31 citation statements)

References 46 publications

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“…Under these conditions, the enzymatic activity of DNMT1 was not affected by nanaomycin A. To our knowledge, this is the first report of a non-SAH (S-adenosyl-L-homocysteine) analogue acting as a DNMT3B-selective inhibitor (34,35).…”

Section: Resultsmentioning

confidence: 73%

Nanaomycin A Selectively Inhibits DNMT3B and Reactivates Silenced Tumor Suppressor Genes in Human Cancer Cells

Kuck

Caulfield

Lyko

et al. 2010

Molecular Cancer Therapeutics

150

116

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Enzymes involved in the epigenetic regulation of the genome represent promising starting points for therapeutic intervention by small molecules, and DNA methyltransferases (DNMT) are emerging targets for the development of a new class of cancer therapeutics. In this work, we present nanaomycin A, initially identified by a virtual screening for inhibitors against DNMT1, as a compound inducing antiproliferative effects in three different tumor cell lines originating from different tissues. Nanaomycin A treatment reduced the global methylation levels in all three cell lines and reactivated transcription of the RASSF1A tumor suppressor gene. In biochemical assays, nanaomycin A revealed selectivity toward DNMT3B. To the best of our knowledge, this is the first DNMT3B-selective inhibitor identified to induce genomic demethylation. Our study thus establishes the possibility of selectively inhibiting individual DNMT enzymes. Mol Cancer Ther; 9(11); 3015-23.

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Section: Resultsmentioning

confidence: 73%

Nanaomycin A Selectively Inhibits DNMT3B and Reactivates Silenced Tumor Suppressor Genes in Human Cancer Cells

Kuck

Caulfield

Lyko

et al. 2010

Molecular Cancer Therapeutics

150

116

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“…We used the well-known DNMT inhibitor (altough structurally unrelated) S-adenosyl-L-homocysteine (SAH)(54, 55) as the standard which showed IC 50 = 2 μM on DNMT1. For comparison purposes, we also used the parent stilbene resveratrol, which showed inhibition on DNMT3B (IC 50 = 65 μM) and DNMT3A (IC 50 = 105 μM), but no activity on DNMT1 (IC 50 higher than 300 μM, Table 1).…”

Section: Resultsmentioning

confidence: 99%

Resveratrol-salicylate derivatives as selective DNMT3 inhibitors and anticancer agents

Aldawsari

Aguayo‐Ortiz

Kapilashrami

et al. 2015

Journal of Enzyme Inhibition and Medicinal Chemistry

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Resveratrol is a natural polyphenol with plethora of biological activities. Resveratrol has previously shown to decrease DNA methyltransferase (DNMT) enzymes expression and to reactivate silenced tumor suppressor genes. Currently, it seems that no resveratrol analogues have been developed as DNMT inhibitors. Recently, we reported the synthesis of resveratrol-salicylate derivatives and by examining the chemical structure of these analogues, we proposed that these compounds could exhibit DNMT inhibition especially that they resembled NSC 14778, a compound we previously identified as DNMT inhibitor by virtual screening. Indeed, using in vitro DNMT inhibition assay, some of the resveratrol-salicylate analogues we screened in this work showed selective inhibition against DNMT3 enzymes which was greater than resveratrol. A molecular docking study revealed key binding interactions with DNMT3A and DNMT3B enzymes. Additionally, the most active analogues, 10 showed considerable cytotoxicity against three human cancer cells; HT-29, HepG2 and SK-BR-3 which was greater than resveratrol. Further studies are needed to understand the anticancer mechanisms of these derivatives.

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“…The synthetic intermediate 4-acetylsulfanyl-piperidine-1-carboxylic acid tert-butyl ester ( 4 ) was synthesized by using the method of Plettenburg et al 32 in which potassium thioacetate and 4-bromo-piperidine ( 3 ) were heated in DMF. According to a modified procedure based on an existing protocol, 33 4 reacted with sodium methoxide to form the thiol, followed by the reaction with 2 to give 4-[6-(6-amino-purin-9-yl)-2,2-dimethyl-tetrahydro-furo[3,4-d][1,3]dioxol-4-ylmethylsulfanyl]-piperidine-1-carboxylic acid tert-butyl ester ( 5 ). Under the TFA/DCM condition, cleavage of the BOC protection group yielded 9-[2,2-dimethyl-6-(piperidin-4-ylsulfanylmethyl)-tetrahydro-furo[3,4-d][1,3]dioxol-4-yl]-9 H -purin-6-ylamine ( 6 ) and the subsequent reaction of 6 with (2-bromo-ethyl)-carbamic acid tert-butyl ester provided the key intermediate (2-{4-[6-(6-amino-purin-9-yl)-2,2-dimethyl-tetrahydro-furo[3,4-d][1,3]dioxol-4-ylmethylsulfanyl]-piperidin-1-yl}-ethyl)-carbamic acid tert-butyl ester ( 7 ).…”

Section: Resultsmentioning

confidence: 99%

Bisubstrate analogue inhibitors of 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase: New design with improved properties

Shi

Shaw

Liang

et al. 2012

Bioorganic & Medicinal Chemistry

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6-Hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK), a key enzyme in the folate biosynthetic pathway, catalyzes the pyrophosphoryl transfer from ATP to 6-hydroxymethyl-7,8-dihydropterin. The enzyme is essential for microorganisms, is absent from humans, and is not the target for any existing antibiotics. Therefore, HPPK is an attractive target for developing novel antimicrobial agents. Previously, we characterized the reaction trajectory of HPPK-catalyzed pyrophosphoryl transfer and synthesized a series of bisubstrate analog inhibitors of the enzyme by linking 6-hydroxymethylpterin to adenosine through 2, 3, or 4 phosphate groups. Here, we report a new generation of bisubstrate analog inhibitors. To improve protein binding and linker properties of such inhibitors, we have replaced the pterin moiety with 7,7-dimethyl-7,8-dihydropterin and the phosphate bridge with a piperidine linked thioether. We have synthesized the new inhibitors, measured their Kd and IC50 values, determined their crystal structures in complex with HPPK, and established their structure-activity relationship. 6-Carboxylic acid ethyl ester-7,7-dimethyl-7,8-dihydropterin, a novel intermediate that we developed recently for easy derivatization at position 6 of 7,7-dimethyl-7,8-dihydropterin, offers a much high yield for the synthesis of bisubstrate analogs than that of previously established procedure.

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Constrained (l-)-S-adenosyl-l-homocysteine (SAH) analogues as DNA methyltransferase inhibitors

Cited by 47 publications

References 46 publications

Nanaomycin A Selectively Inhibits DNMT3B and Reactivates Silenced Tumor Suppressor Genes in Human Cancer Cells

Nanaomycin A Selectively Inhibits DNMT3B and Reactivates Silenced Tumor Suppressor Genes in Human Cancer Cells

Resveratrol-salicylate derivatives as selective DNMT3 inhibitors and anticancer agents

Bisubstrate analogue inhibitors of 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase: New design with improved properties

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