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1.
J Biomol Struct Dyn ; 42(6): 2859-2871, 2024 Apr.
Article in English | MEDLINE | ID: mdl-37254302

ABSTRACT

Management of type 2 diabetes mellitus (T2DM) using dipeptidyl peptidase IV (DPP IV) inhibitors is gaining precedence as this enzyme plays an indispensable role in cleaving and inactivating peptides, such as glucagon-like peptide-1 (GLP-1), incretin hormones, and glucose-dependent insulinotropic polypeptide (GIP). There are several DPP IV inhibitors used to treat T2DM, but limited by side effects such as disturbed GIT, flu-like symptoms, etc. Thus, there is an urgent need for the development of novel and better DPP IV inhibitors for the management of the same. In the present study, we investigated the effect of new boronic acid-based thiazole compounds as DPP IV inhibitors. We used substituted anilines that were progressively modified through a multi-step synthesis and then chemically characterised. These molecules have good binding affinity and molecular interactions at the active site of the DPP IV enzyme. Two boronic acid-based molecules, i.e. PC06R58 and PC06R108, were used for the assessment of their in-vitro enzymatic activities. Both molecules (PC06108 and PC06R58) exhibited potent uncompetitive DPP IV enzyme inhibition at two different concentrations of 90.9 and 15.6 nM, respectively, compared to sitagliptin having an IC50 of 17.3 nM. Furthermore, the oral glucose tolerance test suggested significantly reduced blood glucose levels at 20 mg/kg of the body weight upon administration of PC06R58 and PC06R108 molecules in rats after glucose ingestion (2 g/kg of the body weight). The compounds showed satisfactory DPP IV inhibition. Furthermore, DPP IV inhibitory activity and acceptable pre-ADME/Tox profile indicate it is a lead compound in this novel class of DPP IV inhibitors.Communicated by Ramaswamy H. Sarma.


Subject(s)
Diabetes Mellitus, Type 2 , Dipeptidyl-Peptidase IV Inhibitors , Hyperglycemia , Rats , Animals , Dipeptidyl-Peptidase IV Inhibitors/pharmacology , Dipeptidyl-Peptidase IV Inhibitors/therapeutic use , Glucose , Diabetes Mellitus, Type 2/drug therapy , Hyperglycemia/drug therapy , Hyperglycemia/chemically induced , Gastric Inhibitory Polypeptide/metabolism , Gastric Inhibitory Polypeptide/therapeutic use , Body Weight , Blood Glucose/metabolism , Hypoglycemic Agents/pharmacology , Hypoglycemic Agents/therapeutic use
2.
Gene ; 822: 146354, 2022 May 15.
Article in English | MEDLINE | ID: mdl-35189247

ABSTRACT

Glandular cancers have a significant share of the total cancer patients all over the world. In the case of adrenocortical carcinomas (ACCs), although the benign form is more frequent and common, the malignant form provides a very less percentage of patients with five or more than five years of survival rate. There are gene alterations that are involved as a crucial factor behind the occurrence of ACCs. Out of these, the most prominent genetic alterations (PRKAR-1A, CTNNB1, ZNRF3, TP53, CCNE1 and TERF2 genes) are linked with a glycolytic enzyme pyruvate kinase M2 (PKM2), which converts phosphoenolpyruvate (PEP) to pyruvate in the glycolytic pathway. The involvementof PKM2 renders a cumulative effect through different pathways that may result in the onset of ACCs. Thus, this review aims to establish a link between ACCs, alterations of specific genes and PKM2.


Subject(s)
Adrenal Cortex Neoplasms/genetics , Adrenocortical Carcinoma/genetics , Carrier Proteins/genetics , Membrane Proteins/genetics , Thyroid Hormones/genetics , Gene Expression Regulation, Neoplastic , Gene Regulatory Networks , Glycolysis , Humans , Survival Analysis , Thyroid Hormone-Binding Proteins
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