Antidiabetic and antimalarial biguanide drugs are metal-interactive antiproteolytic agents

Sweeney, Deacon; Raymer, Michael L.; Lockwood, Tom

doi:10.1016/s0006-2952(03)00338-1

Cited by 64 publications

(74 citation statements)

References 40 publications

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“…These findings support the notion that since transporters involved in uptake and extrusion of metformin were designed by nature for endogenous substrates, the metabolic effects of metformin might involve substrate competition phenomena with metabolites or nutrients (Glossmann & Reider, 2013). Metformin and related biguanides are known to bind endogenous metals such as Zn 2+ , Cu 2+ , Fe 3+ that independently inhibit pro‐inflammatory proteases (Glossmann & Reider, 2013; Lockwood, 2010; Logie et al., 2012; Sweeney et al., 2003; Thorne & Lockwood, 1991). Accordingly, our systematic chemoinformatics approach confirmed that metallopeptidases and proteins with transition metal ion‐binding properties were significantly overrepresented among the predicted targets for metformin.…”

Section: Discussionmentioning

confidence: 99%

“…These findings lend weight to the notion that metal‐interactive regulation of protein functioning should be viewed as a central mechanism of action of metformin and, consequently, that zinc, copper, iron, and other metals might be viewed as primary targets of metformin. The metal‐binding properties of metformin appear to be involved not only in its capacity to regulate a number of proteases (Lockwood, 2010; Sweeney et al., 2003), but also to interact with and regulate the activity of a significant number of aging‐ and cancer‐related DNA/chromatin‐interacting enzymes. Interestingly, our systematic chemoinformatics approach coupled to confirmatory experimental testing revealed for the first time that metformin can directly target the chromatin‐modifying activity of aging‐related histone demethylases such as KMD6A/UTX.…”

Section: Discussionmentioning

confidence: 99%

“…Although approved as an insulin‐lowering agent for type 2 diabetes or other hyperinsulinemic conditions, the ongoing use of metformin has led to the discovery of unanticipated and multifaceted actions in several chronic conditions. Indeed, metformin is an archetypical example of an approved drug that has been clinically exploited without a complete understanding of its precise therapeutic targets or chemical determinants (Sweeney, Raymer & Lockwood, 2003). Here, using a systematic chemoinformatics approach (Figure S1B) coupled to laboratory‐based confirmatory testing, we sought to computationally predict and experimentally validate new biomolecular targets through which metformin might operate as a polytherapeutic tool capable of targeting the biological machinery of aging.…”

Section: Introductionmentioning

confidence: 99%

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Metformin directly targets the H3K27me3 demethylase KDM6A/UTX

et al. 2018

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SummaryMetformin, the first drug chosen to be tested in a clinical trial aimed to target the biology of aging per se, has been clinically exploited for decades in the absence of a complete understanding of its therapeutic targets or chemical determinants. We here outline a systematic chemoinformatics approach to computationally predict biomolecular targets of metformin. Using several structure‐ and ligand‐based software tools and reference databases containing 1,300,000 chemical compounds and more than 9,000 binding sites protein cavities, we identified 41 putative metformin targets including several epigenetic modifiers such as the member of the H3K27me3‐specific demethylase subfamily, KDM6A/UTX. AlphaScreen and AlphaLISA assays confirmed the ability of metformin to inhibit the demethylation activity of purified KDM6A/UTX enzyme. Structural studies revealed that metformin might occupy the same set of residues involved in H3K27me3 binding and demethylation within the catalytic pocket of KDM6A/UTX. Millimolar metformin augmented global levels of H3K27me3 in cultured cells, including reversion of global loss of H3K27me3 occurring in premature aging syndromes, irrespective of mitochondrial complex I or AMPK. Pharmacological doses of metformin in drinking water or intraperitoneal injection significantly elevated the global levels of H3K27me3 in the hepatic tissue of low‐density lipoprotein receptor‐deficient mice and in the tumor tissues of highly aggressive breast cancer xenograft‐bearing mice. Moreover, nondiabetic breast cancer patients receiving oral metformin in addition to standard therapy presented an elevated level of circulating H3K27me3. Our biocomputational approach coupled to experimental validation reveals that metformin might directly regulate the biological machinery of aging by targeting core chromatin modifiers of the epigenome.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Metformin directly targets the H3K27me3 demethylase KDM6A/UTX

et al. 2018

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“…The biological activity of biguanides and their metal complexes is well known and intensely studied, some of them being used as antihyperglycemic, antimalarial, antibacterial and antifungal agents [1][2][3][4].…”

Section: Introductionmentioning

confidence: 99%

Synthesis and characterization of new copper(II) complex compounds with chlorhexidine. Part I

et al. 2010

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“…This feature provides better control of postprandial glycemia. Metglinides are characterized by a slight decrease of the glycohemoglobin content (HbA1C, approximately 0.5-0.8 %), the risk of body weight gain, that is also typical for sulfonylureas and decrease of efficacy during long-term using despite the effectiveness of meglitinides [3,4]. The solution of this problem can be as following: the creation of more effective drugs among different classes of heterocyclic compounds, the combination of drugs, or drugs, that would contain known antidiabetic «pharmacophorе» fragments able to provide a long-term hypoglycemic effect and having a polyvectoral mechanism 6 Yu.…”

Section: Introductionmentioning

confidence: 99%

Targeted search of hypoglycemic agents among N-substituted isoindoline-1,3-diones and its analogues

Martynenko

Kazunin

Antypenko

et al. 2018

Current Issues in Pharmacy and Medicine: Science and Practice

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It is known, that increasing of glucose level in the blood is an important factor at the risk of vascular complications in diabetes mellitus type 2 development. Taking this into account, short-acting priming regulators of glycemia (meglitinides) are designed, such as tableted sugar-reducing drugs with short acting insulin secretion stimulation. They are characterized by a slight decrease of glycohemoglobin content, the risk of body weight gain and decrease of efficacy during long-term usage despite their effectiveness. The solution of this problem can be as following: the creation of more effective drugs, which would contain known antidiabetic "pharmacophore" fragments able to provide a long-term hypoglycemic effect and having a polyvectoral mechanism of activity and effect both on symptoms of the disease and on disease etiology.The aim of the work is targeted search of hypoglycemic isoindoline-1,3-dione derivatives and its hydrogenated analogues based on rational design, structural similarity to metglitinides, molecular docking and traditional pharmacological screening.Materials and methods: laboratory utensils and organic solvents, "Stuart Scientific SMP30" melting point apparatus, ELEMENTAR vario EL Cube elemental analyzer, Bruker ALPHA FT-IR spectrometer, Varian-Mercury 400 1 H NMR spectrometer, Agilent 1100 Series liquid chromatograph, Marvin Sketch 17.21, AutoDockTools-1.5.6, Discovery Studio 4.0.Results. The targeted search of hypoglycemic agents among N-substituted isoindoline-1,3-diones and its analogues based on the structural similarity with existing active pharmaceutical ingredients, using molecular docking and traditional pharmacological screening was performed in the work. Mentioned compounds were synthesized by the refluxing of phthalic anhydride and its analogs with aminoalkyl-(alkaryl-,aryl-) carboxylic acids in the medium of the acetic acid. It was shown, that refluxing of 3a,4,7,7a-tetrahydro-4,7-epoxyisobenzofuran-1,3-dione with glycine under the given conditions resulted the retro Diels-Alder reaction and formation of (Z)-4-((carboxymethyl)amino)-4-oxobut-2-enoic acid. Elemental analysis, chromatomass-, IR-and 1 H-NMR spectral methods were used to prove the structure and individuality of the synthesized compounds. Conclusion.A number of compounds were synthesized and chemically modified. Research of their hypoglycemic activity was carried out, that raveled a number of high active substances. Certain "structure -activity relations" were established and the perspective directions of their further chemical modification were substantiated. Відомо, що підвищення рівня глюкози у крові -важливий чинник ризику розвитку судинних ускладнень при цукровому діабеті 2 типу. Враховуючи це, розробили регулятори глікемії (меглітиніди) -цукрознижувальні засоби, механізм дії котрих спрямований на стимулювання секреції інсуліну протягом короткого проміжку часу. Незважаючи на ефективність, для них характерне не-значне зменшення вмісту глікогемоглобіну, ризик набору маси тіла та зниження ефективності під час трив...

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Antidiabetic and antimalarial biguanide drugs are metal-interactive antiproteolytic agents

Cited by 64 publications

References 40 publications

Metformin directly targets the H3K27me3 demethylase KDM6A/UTX

Metformin directly targets the H3K27me3 demethylase KDM6A/UTX

Synthesis and characterization of new copper(II) complex compounds with chlorhexidine. Part I

Targeted search of hypoglycemic agents among N-substituted isoindoline-1,3-diones and its analogues

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