Discovery of Covalent Inhibitors of Glyceraldehyde-3-phosphate Dehydrogenase, A Target for the Treatment of Malaria

Bruno, Stefano; Pinto, Andrea; Paredi, Gianluca; Tamborini, Lucia; Micheli, Carlo De; Pietra, Valeria La; Marinelli, Luciana; Novellino, Ettore; Conti, Paola; Mozzarelli, Andrea

doi:10.1021/jm500747h

Cited by 55 publications

(73 citation statements)

References 32 publications

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“…35 Further experiments to confirm this peculiar mechanism of action are ongoing, and we shall report results for this in due course.…”

Section: Library Synthesismentioning

confidence: 81%

“…Then, in the combinatorial derivatization we incorporated at position 2 of the 2-Br-1,4-quinones (30)(31)(32)(33)(34)(35) different phenoxy groups via a nucleophilic substitution reaction involving phenols 36-40.…”

Section: Library Synthesismentioning

confidence: 99%

“…In this field, we have reported on the natural-inspired 2-phenoxy-1,4-naphthoquinone (B6; 1 in Scheme 1) as an attractive phenotypic hit, showing a remarkable activity against Trypanosoma 5-hydroxy-1,4-naphthoquinone (juglone) and 5-methoxy-1,4-naphthoquinone as well as the corresponding 2-bromo derivatives (32)(33)(34)(35) have been investigated by some of us for their cytotoxic effects against various tumor cell lines. 21 In addition, intriguing similarities between some of the basic biological aspects of parasitism and cancer have been highlighted.…”

Section: Introductionmentioning

confidence: 99%

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2-Phenoxy-1,4-naphthoquinones: From a Multitarget Antitrypanosomal to a Potential Antitumor Profile

et al. 2015

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A small library of 2-phenoxy-1,4-naphthoquinone and 2-phenoxy-1,4-anthraquinone derivatives was initially developed to optimize the antitrypanosomatid profile of the multitarget hit compound B6 (1). The whole series was evaluated against the three most important human trypanosomatid pathogens (Trypanosoma brucei rhodesiense, Trypanosoma cruzi, and Leishmania donovani), and two compounds (14 and 21) showed good activity, despite a concomitant mammalian cytotoxicity. Furthermore, a subset also inhibited the glycolytic TbGAPDH enzyme in vitro. In light of these results and aware of the antitumor properties of quinones, the anticancer potential of some selected derivatives was investigated. Intriguingly, the tested compounds displayed antitumor activity, while being less toxic against noncancerous cells. The observed cytotoxic potency was ascribed to a multitarget mechanism of action accounting for hGAPDH inhibition and mitochondrial toxicity. Overall, the development of further derivatives, able to finely modulate multiple pathways of cancer or parasite cell metabolism, might lead to more effective treatments against these devastating diseases.

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“…35 Further experiments to confirm this peculiar mechanism of action are ongoing, and we shall report results for this in due course.…”

Section: Library Synthesismentioning

confidence: 81%

Section: Library Synthesismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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2-Phenoxy-1,4-naphthoquinones: From a Multitarget Antitrypanosomal to a Potential Antitumor Profile

et al. 2015

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“…General reactivity of library compounds against thiol groups can be detected by incubation with CoA or glutathione (GSH) and subsequent LC-MS analysis of adduct formation, [55] or through specifically developed, thiol-containing fluorescent probes. [61] On the other hand, the catalytic cysteine of Plasmodium falciparum glyceraldehyde-3-phosphate dehydrogenase has been targeted deliberately (also using MS-based measurements), [62] which demonstrates that a compound's mode of action needs to be assessed in the context of a specific lead finding campaign and warns against premature generalizations.…”

Section: Covalent Inhibitorsmentioning

confidence: 99%

Non-stoichiometric inhibition in integrated lead finding – a literature review

Klumpp

2015

Expert Opinion on Drug Discovery

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Over the last few years, awareness of non-stoichiometric inhibitors within screening libraries and HTS hit lists has considerably increased, not only in the pharmaceutical industry but also in the academic drug discovery community. This has resulted in a variety of methods to detect and handle such compounds. These range from in silico approaches to flag suspicious compounds, and counterassays to measure non-stoichiometric inhibition, to biophysical methods that positively demonstrate stoichiometric binding. In addition, novel technologies to verify target engagement within cells are becoming available. While still a time- and resource-consuming nuisance, non-stoichiometric inhibitors therefore do not fundamentally jeopardize the discovery of low molecular weight lead and drug candidates. Rather, they should be viewed as a manageable issue that with appropriate expertise can be overcome through integration of the above-mentioned approaches.

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“…The rationale for using the 3-Br-isoxazoline as a warhead is based on our previous findings showing that the 3-Br-isoxazoline ring can indeed react with a nucleophilic amino acid residue, such as Cys, when the moiety is correctly positioned into the active site of a target enzyme [20][21][22] . Moreover, a favorable reactivity of 3-bromoisoxazolines toward amines, to generate the corresponding 3-amino-isoxazolines, has been reported 23 .…”

Section: Introductionmentioning

confidence: 99%

Bicyclic γ-amino acids as inhibitors of γ-aminobutyrate aminotransferase

Pinto

Tamborini

Pennacchietti

et al. 2015

Journal of Enzyme Inhibition and Medicinal Chemistry

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The g-aminobutyrate (GABA)-degradative enzyme GABA aminotransferase (GABA-AT) is regarded as an attractive target to control GABA levels in the central nervous system: this has important implications in the treatment of several neurological disorders and drug dependencies. We have investigated the ability of newly synthesized compounds to act as GABA-AT inhibitors. These compounds have a unique bicyclic structure: the carbocyclic ring bears the GABA skeleton, while the fused 3-Br-isoxazoline ring contains an electrophilic warhead susceptible of nucleophilic attack by an active site residue of the target enzyme. Out of the four compounds tested, only the one named (+)-3 was found to significantly inhibit mammalian GABA-AT in vitro. Docking studies, performed on the available structures of GABA-AT, support the experimental findings: out of the four tested compounds, only (+)-3 suitably orients the electrophilic 3-Br-isoxazoline warhead towards the active site nucleophilic residue Lys329, thereby explaining the irreversible inhibition of GABA-AT observed experimentally.

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Discovery of Covalent Inhibitors of Glyceraldehyde-3-phosphate Dehydrogenase, A Target for the Treatment of Malaria

Cited by 55 publications

References 32 publications

2-Phenoxy-1,4-naphthoquinones: From a Multitarget Antitrypanosomal to a Potential Antitumor Profile

2-Phenoxy-1,4-naphthoquinones: From a Multitarget Antitrypanosomal to a Potential Antitumor Profile

Non-stoichiometric inhibition in integrated lead finding – a literature review

Bicyclic γ-amino acids as inhibitors of γ-aminobutyrate aminotransferase

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