Concise and Stereodivergent Synthesis of Carbasugars Reveals Unexpected Structure-Activity Relationship (SAR) of SGLT2 Inhibition

Ng, W. F.; Li, Ho Chuen; Lau, Kin Mang; Chan, Anthony; Lau, Clara Bik San; Shing, Tony K. M.

doi:10.1038/s41598-017-05895-9

Cited by 11 publications

(7 citation statements)

References 39 publications

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“…The basic difference is that canagliflozin has a thienyl moiety bridging the two phenyl rings of the pharmacophore aglycone, whereas dapagliflozin and empagliflozin have a methylene group instead ( Figure 1 ). The latter two also contain a chlorine substitution on their phenyl rings, whose electronegativity (i.e., “pulling” electron pairs from the aromatic π ring electron cloud) further protects against its metabolic degradation [ 6 ]. The chlorine atom also increases the inhibitory potency against SGLT2 [ 5 , 6 ].…”

Section: Introductionmentioning

confidence: 99%

“…The latter two also contain a chlorine substitution on their phenyl rings, whose electronegativity (i.e., “pulling” electron pairs from the aromatic π ring electron cloud) further protects against its metabolic degradation [ 6 ]. The chlorine atom also increases the inhibitory potency against SGLT2 [ 5 , 6 ]. In contrast, canagliflozin has a fluorine substitution on one of its phenyl rings, which is also very electronegative and increases metabolic stability [ 6 , 7 ].…”

Section: Introductionmentioning

confidence: 99%

“…The chlorine atom also increases the inhibitory potency against SGLT2 [ 5 , 6 ]. In contrast, canagliflozin has a fluorine substitution on one of its phenyl rings, which is also very electronegative and increases metabolic stability [ 6 , 7 ]. Finally, empagliflozin, unlike canagliflozin and dapagliflozin, has one additional tetrahydrofuran ring connected via an ether bond to the distant phenyl ring of its pharmacophore ( Figure 1 ).…”

Section: Introductionmentioning

confidence: 99%

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Sympatholytic Mechanisms for the Beneficial Cardiovascular Effects of SGLT2 Inhibitors: A Research Hypothesis for Dapagliflozin’s Effects in the Adrenal Gland

Lymperopoulos

Borges

Cora

et al. 2021

IJMS

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Heart failure (HF) remains the leading cause of morbidity and death in the western world, and new therapeutic modalities are urgently needed to improve the lifespan and quality of life of HF patients. The sodium-glucose co-transporter-2 (SGLT2) inhibitors, originally developed and mainly indicated for diabetes mellitus treatment, have been increasingly shown to ameliorate heart disease, and specifically HF, in humans, regardless of diabetes co-existence. Indeed, dapagliflozin has been reported to reduce cardiovascular mortality and hospitalizations in patients with HF and reduced ejection fraction (HFrEF). This SGLT2 inhibitor demonstrates these benefits also in non-diabetic subjects, indicating that dapagliflozin’s efficacy in HF is independent of blood glucose control. Evidence for the effectiveness of various SGLT2 inhibitors in providing cardiovascular benefits irrespective of their effects on blood glucose regulation have spurred the use of these agents in HFrEF treatment and resulted in FDA approvals for cardiovascular indications. The obvious question arising from all these studies is, of course, which molecular/pharmacological mechanisms underlie these cardiovascular benefits of the drugs in diabetics and non-diabetics alike. The fact that SGLT2 is not significantly expressed in cardiac myocytes (SGLT1 appears to be the dominant isoform) adds even greater perplexity to this answer. A variety of mechanisms have been proposed over the past few years and tested in cell and animal models and prominent among those is the potential for sympatholysis, i.e., reduction in sympathetic nervous system activity. The latter is known to be high in HF patients, contributing significantly to the morbidity and mortality of the disease. The present minireview first summarizes the current evidence in the literature supporting the notion that SGLT2 inhibitors, such as dapagliflozin and empagliflozin, exert sympatholysis, and also outlines the main putative underlying mechanisms for these sympatholytic effects. Then, we propose a novel hypothesis, centered on the adrenal medulla, for the sympatholytic effects specifically of dapagliflozin. Adrenal medulla is responsible for the production and secretion of almost the entire amount of circulating epinephrine and of a significant percentage of circulating norepinephrine in the human body. If proven true experimentally, this hypothesis, along with other emerging experimental evidence for sympatholytic effects in neurons, will shed new light on the pharmacological effects that mediate the cardiovascular benefits of SGLT2 inhibitor drugs, independently of their blood glucose-lowering effects.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Sympatholytic Mechanisms for the Beneficial Cardiovascular Effects of SGLT2 Inhibitors: A Research Hypothesis for Dapagliflozin’s Effects in the Adrenal Gland

Lymperopoulos

Borges

Cora

et al. 2021

IJMS

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“…While recent studies have attempted to dock phlorizin-derived compounds into inward-facing models of hSGLTs 7 , the Wright lab has demonstrated that SGLT2 inhibitors bind from the extracellular solution likely stabilizing a Na + -bound, outward-facing conformation 8 . Thus, a detailed molecular view of this interaction is not possible without a reliable outward-facing model of SGLTs.…”

Section: Introductionmentioning

confidence: 99%

Inhibitor binding mode and allosteric regulation of Na+-glucose symporters

Bisignano

Ghezzi

et al. 2018

Nat Commun

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Sodium-dependent glucose transporters (SGLTs) exploit sodium gradients to transport sugars across the plasma membrane. Due to their role in renal sugar reabsorption, SGLTs are targets for the treatment of type 2 diabetes. Current therapeutics are phlorizin derivatives that contain a sugar moiety bound to an aromatic aglycon tail. Here, we develop structural models of human SGLT1/2 in complex with inhibitors by combining computational and functional studies. Inhibitors bind with the sugar moiety in the sugar pocket and the aglycon tail in the extracellular vestibule. The binding poses corroborate mutagenesis studies and suggest a partial closure of the outer gate upon binding. The models also reveal a putative Na+ binding site in hSGLT1 whose disruption reduces the transport stoichiometry to the value observed in hSGLT2 and increases inhibition by aglycon tails. Our work demonstrates that subtype selectivity arises from Na+-regulated outer gate closure and a variable region in extracellular loop EL5.

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“…In the following four decades, the chemical, biological, and conformational aspects of carbasugars were extensively studied [12,13], resulting in studies on enzyme inhibition, lectin-binding, and even HIV and cancer treatment [14][15][16]. Various strategies have been employed for the synthesis and isolation of carbasugars, mostly starting from simple monosaccharides such as glucosamine and resulting in the corresponding carbasugars [17][18][19]. Other approaches work from simple hexopyranoses to more complex carbafuranoses such as carbaarabinofuranosides [20,21] or even more complex carbasugar derivatives such as fluorinated carbasugars [22].…”

Section: Introductionmentioning

confidence: 99%

Current Synthetic Approaches to the Synthesis of Carbasugars from Non-Carbohydrate Sources

et al. 2022

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Carbasugars are a group of carbohydrate derivatives in which the ring oxygen is replaced by a methylene group, producing a molecule with a nearly identical structure but highly different behavior. Over time, this definition has been extended to include other unsaturated cyclohexenols and carba-, di-, and polysaccharides. Such molecules can be found in bacterial strains and the human body, acting as neurotransmitters (e.g., inositol trisphosphate). In science, there are a wide range of research areas that are affected by, and involve, carbasugars, such as studies on enzyme inhibition, lectin-binding, and even HIV and cancer treatment. In this review article, different methods for synthesizing carbasugars, their derivatives, and similar cyclohexanes presenting comparable characteristics are summarized and evaluated, utilizing diverse starting materials and synthetic procedures.

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Concise and Stereodivergent Synthesis of Carbasugars Reveals Unexpected Structure-Activity Relationship (SAR) of SGLT2 Inhibition

Cited by 11 publications

References 39 publications

Sympatholytic Mechanisms for the Beneficial Cardiovascular Effects of SGLT2 Inhibitors: A Research Hypothesis for Dapagliflozin’s Effects in the Adrenal Gland

Sympatholytic Mechanisms for the Beneficial Cardiovascular Effects of SGLT2 Inhibitors: A Research Hypothesis for Dapagliflozin’s Effects in the Adrenal Gland

Inhibitor binding mode and allosteric regulation of Na+-glucose symporters

Current Synthetic Approaches to the Synthesis of Carbasugars from Non-Carbohydrate Sources

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