Hypoglycemic Agents. III.<sup>1—3</sup> N<sup>1</sup>-Alkyl- and Aralkylbiguanides

Shapiro, Seymour L.; Parrino, Vincent A.; Freedman, Louis

doi:10.1021/ja01523a060

Cited by 86 publications

(35 citation statements)

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“…A vast selection of guanidine derivatives was then synthesised and evaluated, but enthusiasm was dampened by their lesser glucose-lowering efficacy in non-diabetic animals compared with agents that stimulate insulin secretion [34,35]. However, studies in human maturity-onset diabetes indicated greater glucose-lowering efficacy of phenformin compared with other biguanides and this agent gained global popularity as an alternative to sulfonylureas, especially in the USA [36][37][38].…”

Section: The Biguanide Opportunitymentioning

confidence: 99%

Metformin: historical overview

2017

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Metformin (dimethylbiguanide) has become the preferred first-line oral blood glucose-lowering agent to manage type 2 diabetes. Its history is linked to Galega officinalis (also known as goat's rue), a traditional herbal medicine in Europe, found to be rich in guanidine, which, in 1918, was shown to lower blood glucose. Guanidine derivatives, including metformin, were synthesised and some (not metformin) were used to treat diabetes in the 1920s and 1930s but were discontinued due to toxicity and the increased availability of insulin. Metformin was rediscovered in the search for antimalarial agents in the 1940s and, during clinical tests, proved useful to treat influenza when it sometimes lowered blood glucose. This property was pursued by the French physician Jean Sterne, who first reported the use of metformin to treat diabetes in 1957. However, metformin received limited attention as it was less potent than other glucose-lowering biguanides (phenformin and buformin), which were generally discontinued in the late 1970s due to high risk of lactic acidosis. Metformin's future was precarious, its reputation tarnished by association with other biguanides despite evident differences. The ability of metformin to counter insulin resistance and address adult-onset hyperglycaemia without weight gain or increased risk of hypoglycaemia gradually gathered credence in Europe, and after intensive scrutiny metformin was introduced into the USA in 1995. Long-term cardiovascular benefits of metformin were identified by the UK Prospective Diabetes Study (UKPDS) in 1998, providing a new rationale to adopt metformin as initial therapy to manage hyperglycaemia in type 2 diabetes. Sixty years after its introduction in diabetes treatment, metformin has become the most prescribed glucose-lowering medicine worldwide with the potential for further therapeutic applications.

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Section: The Biguanide Opportunitymentioning

confidence: 99%

Metformin: historical overview

2017

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“…Some of the synthesized compounds are reported in the literature for various medicinal chemistry applications. Shapiro et al have reported the synthesis of several derivatives of N,N-disubstituted biguanide including 8a and 8f (Shapiro et al, 1958(Shapiro et al, , 1959 by fusion of equimolar mixture of amine hydrochloride and cyanoguanidine at 130-150°C for 0.5-2 h. In addition to this, compound 8d is widely used an as starting material for the synthesis of substituted triazines (Angelucci et al, 1961;Kelarev et al, 2003) In our work, we followed protocol reported by Mayer et al for synthesizing disubstituted biguanide derivatives with the slight modification of using HCl as catalysis instead of TMSCl as reported in the literature.…”

Section: Chemistrymentioning

confidence: 99%

Design, synthesis, biological evaluation and toxicity studies of N,N-disubstituted biguanides as quorum sensing inhibitors

et al. 2014

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A series of novel N,N-disubstituted biguanides (8a-8j) have been synthesized using varied secondary amines and cyanoguanidine under microwave irradiation. All the synthesized compounds were evaluated for quorum sensing inhibition (QSI) activity using Chromobacterium violaceum (ATCC12472)-based bioassay. Out of these ten compounds, two compounds 8a and 8g (IC 50 = 179 and 120 lM) showed maximum QSI activity. Decrease in violacein production was observed in the range of 0.2-200 lM concentration for these respective compounds. The molecular docking studies revealed that N,N-disubstituted biguanides shared structural complementarity with CviR domain. Furthermore, TOPKAT analysis on Ames mutagenicity and carcinogenicity models had shown that this class of compounds has least probability (0.000-0.009) of exhibiting toxicity in experimental models.

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“…The MET-Chol were synthesized according to the typical cyano addition reaction between 2-cyanoguanidine and the primary amino group of EDA-Chol. 13 Compared with that of EDA-Chol in 1 H NMR and 13 C NMR analysis ( Figure S1), the new proton and carbon peaks of MET-Chol at 7.85 and 160 ppm were attributed to the imine ones of the guanidine group. These results proved the successful conjugation of biguanide moiety on the cholesterol skeleton.…”

Section: Synthesis Of Cholesterol Derivative Of Metforminmentioning

confidence: 92%

Dual Functional LipoMET Mediates Envelope-type Nanoparticles to Combinational Oncogene Silencing and Tumor Growth Inhibition

et al. 2017

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The success of small interfering RNA (siRNA)-mediated gene silencing for cancer therapy is still limited because of its instability and poor intracellular internalization. Traditional cationic carriers cannot adequately meet the need for clinical application of siRNA. We herein report a dual-functional liposome containing a cholesterol derivative of metformin, i.e., LipoMET, which takes advantage of the fusogenic activity as well as intrinsic tumor apoptosis inducing ability of biguanide moiety to achieve a combinational anti-oncogenic effect. In this study, the vascular endothelial growth factor (VEGF)-specific siRNAs were first electrostatically condensed into a ternary nanocomplex composed of polycation and hyaluronate, which was subsequently enveloped by LipoMET through membrane fusion. In comparison with common cationic control group, the resulting envelope-type nanoparticles (PH@LipoMET nanoparticles [NPs]) showed the ability of rapid cellular internalization and effective endosomal escape of siRNA during intracellular trafficking studies. Systemic administration of the targeted LipoMETs was capable of inducing apoptosis and tumor growth inhibition in the NCI-H460 xenograft model. When carrying VEGF-specific siRNAs, PH@LipoMET NPs remarkably downregulated the expression of VEGF and led to even more tumor suppression in vivo. Thus, LipoMET originated envelope-type nanoparticles may serve as a potential dual-functional siRNA delivery system to improve therapeutic effect of oncogene silencing.

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Hypoglycemic Agents. III.^1—3 N¹-Alkyl- and Aralkylbiguanides

Cited by 86 publications

References 0 publications

Metformin: historical overview

Metformin: historical overview

Design, synthesis, biological evaluation and toxicity studies of N,N-disubstituted biguanides as quorum sensing inhibitors

Dual Functional LipoMET Mediates Envelope-type Nanoparticles to Combinational Oncogene Silencing and Tumor Growth Inhibition

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Hypoglycemic Agents. III.1—3 N1-Alkyl- and Aralkylbiguanides

Cited by 86 publications

References 0 publications

Metformin: historical overview

Metformin: historical overview

Design, synthesis, biological evaluation and toxicity studies of N,N-disubstituted biguanides as quorum sensing inhibitors

Dual Functional LipoMET Mediates Envelope-type Nanoparticles to Combinational Oncogene Silencing and Tumor Growth Inhibition

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Hypoglycemic Agents. III.^1—3 N¹-Alkyl- and Aralkylbiguanides