Epidithiodiketopiperazine as a pharmacophore for protein lysine methyltransferase G9a inhibitors: Reducing cytotoxicity by structural simplification

Fujishiro, Shinya; Dodo, Kosuke; Iwasa, Eriko; Teng, Yuou; Sohtome, Yoshihiro; Hamashima, Yoshitaka; Ito, Akihiro; Yoshida, Minoru; Sodeoka, Mikiko

doi:10.1016/j.bmcl.2012.11.087

Cited by 40 publications

(45 citation statements)

References 28 publications

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“…Certainly we wanted to defer the sulfidation step until a late stage of the synthesis. Precedent from the Movassaghi, 13 Sodeoka 18 and our 19 groups suggested that the installation of methylthio or epidithio substituents by thiol trapping of N -acyliminium ions derived from intermediate 15 should be possible and likely stereoselective. However, forming the bridging trisulfide functionality of plectosphaeroic acid C ( 3 ) by a short sequence was less certain.…”

Section: Resultsmentioning

confidence: 90%

Enantioselective Total Syntheses of Plectosphaeroic Acids B and C

Jabri

Overman

2013

J. Org. Chem.

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Evolution of the synthetic strategy that culminated in the first total syntheses of the structurally unique plectosphaeroic acids B (2) and C (3) is described. The successful enantioselective route to (+)-2 and (+)-3 proceeds in 6 and 11 steps from the known hexahydro-2H-pyrazinopyrrolo[2,3-b]indole-1,4-dione 39, which in turn are available in enantiomerically pure form by chemical synthesis. The central challenge in this synthesis endeavor was uniting the hexahydro-2H-pyrazinopyrrolo[2,3-b]indole-1,4-dione and cinnabarinic acid fragments of these marine alkaloids. Critical for achieving this successful C–N bond formation was the use of an iodocinnabarinic acid diester in which the amino group was masked with two Boc substituents, a Cu(I) carboxylate complex, and the weak base KOAc. The highly congested C–N bond generated in this coupling, in conjunction with the delicate nature of the densely functionalized coupling partners, provide striking testament to the power of modern copper-mediated amination methods. Two approaches, one stereoselective, for introducing the methylthio substituents of (+)-plectosphaeroic acid B were developed. The epitrisulfide ring of (+)-plectosphaeroic acid C was formed by ring expansion of an epidisulfide precursor.

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Section: Resultsmentioning

confidence: 90%

Enantioselective Total Syntheses of Plectosphaeroic Acids B and C

Jabri

Overman

2013

J. Org. Chem.

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“…Nevertheless, the modularity of our synthetic strategy enabled us to compile a small but useful collection of derivatives for SAR profiling. Our synthetic investigations of some of these ETPs have already been reported, so herein we will highlight the results of SAR studies on ETPs focusing on G9a‐inhibitory activity (Tables and ) . G9a (also known as EHMT2: euchromatic histone‐lysine N‐methyltransferase 2) is a histone methyltransferase, which catalyzes mono‐ and di‐methylations of histone H3 at lysine residues 9 and 27 .…”

Section: Chaetocin Analogues As Pmt Inhibitorsmentioning

confidence: 99%

“…Since then, some structural development work to improve the selectivity of 1 for HKMT and/or to increase the PMT‐inhibitory activity has been reported, in part because chaetocin has recognized as a highly toxic reagent that reacts with proteins, including G9a, in a non‐selective manner ,. In this section, we mainly describe how we identified less toxic PKMT inhibitors on the basis of structure‐activity relationship (SAR) studies on 1 , focusing on G9a‐inhibitory activity in vitro …”

Section: Chaetocin Analogues As Pmt Inhibitorsmentioning

confidence: 99%

“…The primary objective of the SAR study was to understand the roles of the functional groups in 1 in the HKMT‐inhibitory activity, with the aim of obtaining more potent derivatives ,. However, in the case of chaetocin ( 1 ), this is not easy because of its structural complexity ,.…”

Section: Chaetocin Analogues As Pmt Inhibitorsmentioning

confidence: 99%

“…In this vein, we focused on the total synthesis of chaetocin ( 1 ), which was reported by Imhof and coworkers in 2005 as the first HKMT (histone lysine methyltransferases) inhibitor . In this Personal Account, we provide brief overviews of our recent progress on structural development of chaetocin ( 1 ) to obtain PMT inhibitors with reduced cytotoxicity, and on the application of ProSeAM ( 2 ) as a PMT substrate detector (Figure )…”

Section: Introductionmentioning

confidence: 99%

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Development of Chaetocin and S‐Adenosylmethionine Analogues as Tools for Studying Protein Methylation

Sohtome

Sodeoka

2018

The Chemical Record

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Physiological regulatory mechanisms of protein, RNA, and DNA functions include small chemical modifications, such as methylation, which are introduced or removed in a highly chemo‐, regio‐, and site‐selective manner by methyltransferases and demethylases, respectively. However, mimicking or controlling these modifications by using labeling reagents and inhibitors remains challenging. In this Personal Account, we introduce our nascent interdisciplinary collaboration between chemists and biologists aimed at developing a basic strategy to analyse and control the methylation reactions regulated by protein methyltransferases (PMTs). We focus in particular on the structural development of chaetocin and S‐adenosylmethionine to obtain PMT inhibitors and PMT substrate detectors.

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Cross‐Coupling Reaction of Dimer‐Derived Persistent Tertiary‐Carbon‐Centered Radicals with Azo Compounds

et al. 2019

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Cross-coupling reactions using tertiary carboncentered radicals are an important class of transformations for constructing C(sp 3 )À C(sp 3 ) bonds, but the use of dimers as precursors of the persistent radicals is quite rare. Herein, we describe a radical-based cross-coupling reaction between dimers (prepared from 2-oxindoles and benzofuranones) and azo compounds that proceeds simply upon heating the reaction mixture. We present a conformational analysis of the dimers and we characterize the generation of a persistent radical via cleavage of the elongated C(3)À C(3') σ-bond. The behavior of the dimers in solution was characterized by spectroscopic analysis, helping to provide a basis for expanding the substrate scope of the cross-coupling reaction.

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Epidithiodiketopiperazine as a pharmacophore for protein lysine methyltransferase G9a inhibitors: Reducing cytotoxicity by structural simplification

Cited by 40 publications

References 28 publications

Enantioselective Total Syntheses of Plectosphaeroic Acids B and C

Enantioselective Total Syntheses of Plectosphaeroic Acids B and C

Development of Chaetocin and S‐Adenosylmethionine Analogues as Tools for Studying Protein Methylation

Cross‐Coupling Reaction of Dimer‐Derived Persistent Tertiary‐Carbon‐Centered Radicals with Azo Compounds

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