Biguanides drugs: Past success stories and promising future for drug discovery

Grytsai, Oleksandr; Myrgorodska, Iuliia; Rocchi, Stéphane; Ronco, Cyril; Benhida, Rachid

doi:10.1016/j.ejmech.2021.113726

Cited by 30 publications

(20 citation statements)

References 371 publications

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“…Metformin displays antitumor activity on GSCs [ 27 , 28 ], encouraged its possible repositioning for GBM treatment, at least as molecular lead for new derivatives. Several molecular targets have been proposed for metformin (and other biguanides) antitumor effects [ 28 , 33 , 71 , 72 ], but the inhibition of CLIC1, whose activity is highly correlated to GSC proliferation [ 6 , 38 ], is one of the promising options.…”

Section: Discussionmentioning

confidence: 99%

“…The prototype of non-oncology drugs repurposed as anticancer agent is metformin, a first-line anti-hyperglycemic drug for type-2 diabetes [ 26 ]. Metformin inhibits GSC proliferation in vitro [ 27 ] and in vivo [ 28 ], as well as GSCs self-renewal, metabolic processes, migration, and angiogenesis [ 29 – 32 ] via both direct and indirect molecular mechanisms, which include: (i) modulation of insulin/insulin-like growth factor-1, mitogen-activated protein kinase, and AMP-activated protein kinase regulated pathways; (ii) inhibition of mitochondrial energy metabolism; (iii) interference with ROS and transforming growth factor-β signaling [ 33 ]. However, the relative relevance of all these mechanisms in metformin antitumor activity is still not completely clarified.…”

Section: Introductionmentioning

confidence: 99%

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Chloride intracellular channel 1 activity is not required for glioblastoma development but its inhibition dictates glioma stem cell responsivity to novel biguanide derivatives

Barbieri

Bosio

Pattarozzi

et al. 2022

J Exp Clin Cancer Res

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Background Chloride intracellular channel-1 (CLIC1) activity controls glioblastoma proliferation. Metformin exerts antitumor effects in glioblastoma stem cells (GSCs) inhibiting CLIC1 activity, but its low potency hampers its translation in clinical settings. Methods We synthesized a small library of novel biguanide-based compounds that were tested as antiproliferative agents for GSCs derived from human glioblastomas, in vitro using 2D and 3D cultures and in vivo in the zebrafish model. Compounds were compared to metformin for both potency and efficacy in the inhibition of GSC proliferation in vitro (MTT, Trypan blue exclusion assays, and EdU labeling) and in vivo (zebrafish model), migration (Boyden chamber assay), invasiveness (Matrigel invasion assay), self-renewal (spherogenesis assay), and CLIC1 activity (electrophysiology recordings), as well as for the absence of off-target toxicity (effects on normal stem cells and toxicity for zebrafish and chick embryos). Results We identified Q48 and Q54 as two novel CLIC1 blockers, characterized by higher antiproliferative potency than metformin in vitro, in both GSC 2D cultures and 3D spheroids. Q48 and Q54 also impaired GSC self-renewal, migration and invasion, and displayed low systemic in vivo toxicity. Q54 reduced in vivo proliferation of GSCs xenotransplanted in zebrafish hindbrain. Target specificity was confirmed by recombinant CLIC1 binding experiments using microscale thermophoresis approach. Finally, we characterized GSCs from GBMs spontaneously expressing low CLIC1 protein, demonstrating their ability to grow in vivo and to retain stem-like phenotype and functional features in vitro. In these GSCs, Q48 and Q54 displayed reduced potency and efficacy as antiproliferative agents as compared to high CLIC1-expressing tumors. However, in 3D cultures, metformin and Q48 (but not Q54) inhibited proliferation, which was dependent on the inhibition dihydrofolate reductase activity. Conclusions These data highlight that, while CLIC1 is dispensable for the development of a subset of glioblastomas, it acts as a booster of proliferation in the majority of these tumors and its functional expression is required for biguanide antitumor class-effects. In particular, the biguanide-based derivatives Q48 and Q54, represent the leads to develop novel compounds endowed with better pharmacological profiles than metformin, to act as CLIC1-blockers for the treatment of CLIC1-expressing glioblastomas, in a precision medicine approach.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Chloride intracellular channel 1 activity is not required for glioblastoma development but its inhibition dictates glioma stem cell responsivity to novel biguanide derivatives

Barbieri

Bosio

Pattarozzi

et al. 2022

J Exp Clin Cancer Res

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“…Furthermore, it shows no effects on hepatic metabolism or peripheral oxidative metabolism ( Figure 2 ). As far as buformin is concerned, there are few available data on its pharmacokinetics and pharmacodynamics [ 1 ].…”

Section: Introductionmentioning

confidence: 99%

Metformin: When Should We Fear Lactic Acidosis?

Mauro

Filippello

Scamporrino

et al. 2022

IJMS

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Metformin, a molecule belonging to the biguanide family, represents one of the most commonly prescribed medications for the treatment of diabetes mellitus in the world. Over the sixty years during which it has been used, many benefits have been described, which are not limited to the treatment of diabetes mellitus. However, since metformin is similar to other members of the same drug family, there is still much concern regarding the risk of lactic acidosis. This article aims to highlight the correlation between the use of metformin and the onset of renal damage or lactic acidosis. Metformin-associated lactic acidosis exists; however, it is rare. The appropriate use of the drug, under safe conditions, induces benefits without risks.

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“…Recently many studies have been conducted to evaluate the potential of metformin to treat Covid‐19 [14–17] . The pharmacological activities and therapeutic applications of guanylguanidines have been extensively reviewed in literature [17,18] …”

Section: Introductionmentioning

confidence: 99%

“…[14][15][16][17] The pharmacological activities and therapeutic applications of guanylguanidines have been extensively reviewed in literature. [17,18] Owing to its electron rich nature, monoprotonated states of guanylguanidines have been usually employed in medicinal chemistry. Various studies on structure analysis have been done to predict its stable tautomeric form to avoid its misrepresentation.…”

Section: Introductionmentioning

confidence: 99%

Guanylguanidines: Catalyst and Ligand for Organic Transformations

Bankar¹,

Kathuria

2022

ChemistrySelect

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Guanylguanidines are well known for their wide range of therapeutic applications such as antidiabetic, anticancer, antifilarial, antitrypanosomal, antiaging, etc. Apart from this, they have been explored in the field of crystal engineering, organic synthesis as substrate, non‐linear optics etc. Their metal complexation ability and superbasic nature has paved their way in the field of organocatalysis. In the recent past, various guanylguanidine derivatives have been synthesized and have proven to be excellent catalysts in several organic reactions which include transesterification, C−C and C−N coupling, oxidation, reduction, Beckmann rearrangement etc. However, the limited studies call for more focused research in this direction to fasten the process of development of environmental‐friendly methods. In this review, a comprehensive and systematic discussion of guanylguanidine based catalysts and their applications in various organotransformations has been compiled and discussed meticulously. This review aims to highlight guanylguanidine moiety as a potential catalyst that can be utilized for design and development of novel guanylguanidine based catalysts.

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Biguanides drugs: Past success stories and promising future for drug discovery

Cited by 30 publications

References 371 publications

Chloride intracellular channel 1 activity is not required for glioblastoma development but its inhibition dictates glioma stem cell responsivity to novel biguanide derivatives

Chloride intracellular channel 1 activity is not required for glioblastoma development but its inhibition dictates glioma stem cell responsivity to novel biguanide derivatives

Metformin: When Should We Fear Lactic Acidosis?

Guanylguanidines: Catalyst and Ligand for Organic Transformations

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