Current status of N-, O-, S-heterocycles as potential alkaline phosphatase inhibitors: a medicinal chemistry overview (original) (raw)
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RSC Advances, 2023
Heterocycles are a class of compounds that have been found to be potent inhibitors of alkaline phosphatase (AP), an enzyme that plays a critical role in various physiological processes such as bone metabolism, cell growth and differentiation, and has been linked to several diseases such as cancer and osteoporosis. AP is a widely distributed enzyme, and its inhibition has been considered as a therapeutic strategy for the treatment of these diseases. Heterocyclic compounds have been found to inhibit AP by binding to the active site of the enzyme, thereby inhibiting its activity. Heterocyclic compounds such as imidazoles, pyrazoles, and pyridines have been found to be potent AP inhibitors and have been studied as potential therapeutics for the treatment of cancer, osteoporosis, and other diseases. However, the development of more potent and selective inhibitors that can be used as therapeutics for the treatment of various diseases is an ongoing area of research. Additionally, the study of the mechanism of action of heterocyclic AP inhibitors is an ongoing area of research, which could lead to the identification of new targets and new therapeutic strategies. The enzyme known as AP has various physiological functions and is present in multiple tissues and organs throughout the body. This article presents an overview of the
Inhibition of Alkaline Phosphatase: An Emerging New Drug Target
Bentham Science Publishers
Alkaline phosphatase (AP, EC 3.1.3.1.) is a metalloenzyme that belongs to a family of ectonucleotidases. The other members of ectonucleotidase family are ecto-nucleoside triphosphate diphosphohydrolases (E-NTPDases), ecto-nucleotide pyrophosphatase/phosphodiesterases (E-NPPs) and ecto-5ʹ-nucleotidase (e5ʹNT). These ectonucleotidases are responsible for hydrolyzing extracellular nucleotides to nucleosides including adenosine. Many of these extracellular nucleotides and adenosine are important signaling molecules that act on their respective receptors (adenosine activated P1 receptor; nucleotide activated P2 receptor, each having many sub-types) and are therefore responsible for triggering cellular responses that lead to important physiological and immunological changes. A dedicated, concerted cohort of ectonucleotidases is responsible for controlling the availability of these extracellular signaling molecules at their respective receptors. Inhibitors of these ectonucleotidases provide the means by which these cellular processes can be modulated. This mini review has been written in the wake of mounting evidence of potential therapeutic benefits associated with inhibition of alkaline phosphatases and aims to provide prolific leads to design more potent and selective AP inhibitors.
Diabetes is a metabolic disorder wherein blood glucose level is increased along with some other abnormal conditions like polyuria, polydipsia and polyphagia. As per WHO estimation, 380 million people will become diabetic by 2025. Tyrosine residues are selectively dephosphorylated by Protein tyrosine phosphatases (PTPs) and thus a wide variety of cellular processes are regulated by their action. Protein tyrosine phosphatase 1B (PTP1 B) has shown to be a negative regulator in the insulin signaling pathways. Recent gene knockout studies carried out on mice portrays PTP1B as an effective target for drug discovery process related to anti-diabetic and anti-obese agents. PTPs are also involved in several other disorders like cancer. The structure of compounds synthesized by the present method were confirmed by TLC, IR, NMR and Mass spectroscopy. The anti-diabetic activity of the synthesized compounds were tested against PTP1B enzyme by using Calbiochem® PTP1B colorimetric assay kit. Among all synthesized compounds 4c, 4d, 4e, 4f had shown promising anti-diabetic activity, while other compounds have shown lesser potency as anti-diabetic agent.
European journal of medicinal chemistry, 2018
Chalcones and 1,2-benzothiazines are two important classes of bioactive compounds, each scaffold endowed with diverse pharmacological activities. Combining both of these pharmacophores in a single molecule was aimed to yield multi-modal agents. Herein, we report a series of hybrid compounds 3a-3o derived from chalcones and 1,2-benzothiazine cores. They were synthesized from commercially available sodium saccharin, and the resulting 1,2-benzothiazine-derived ketone was then condensed with aromatic aldehydes in an aldol condensation to obtain the respective chalcones. The compounds were characterized using different analytical techniques including FT-IR, NMR spectroscopy, mass spectrometry and X-ray crystallography. Some synthesized chalcones revealed potent and/or selective inhibitory properties towards alkaline phosphatase isozymes transiently expressed in COS-7 cells. A detailed structure-activity and selectivity study was carried out with regard to the effect of different substitu...
Bioorganic Chemistry, 2019
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Sodium Phosphaethynolate as a Building Block for Heterocycles
Angewandte Chemie International Edition, 2014
Phosphorus-containing heterocycles have evolved from laboratory curiosities to functional components, such as ligands in catalytically active metal complexes or molecular constituents in electronic devices. The straightforward synthesis of functionalized heterocycles on a larger scale remains a challenge. Herein, we report the use of the phosphaethynolate (OCP) À anion as a building block for various sterically unprotected and functionalized hydroxy substituted phosphorus heterocycles. Because the resulting heterocycles are themselves anions, they are building blocks in their own right and allow further facile functionalization. This property may be of interest in coordination chemistry and material science.
Synthesis and evaluation of thiophenyl derivatives as inhibitors of alkaline phosphatase
Bioorganic & Medicinal Chemistry Letters, 2011
Pathological calcifications induced by deposition of basic phosphate crystals or hydroxyapatite (HA) on soft tissues are a large family of diseases comprising of ankylosing spondylitis (AS), end-stage osteoarthritis (OA) and vascular calcification. High activity of tissue non-specific alkaline phosphatase (TNAP) is a hallmark of pathological calcifications induced by HA deposition. The use of TNAP inhibitor is a possible therapeutic option to address calcific diseases produced by HA deposition on soft tissues. We report the synthesis of a series of thiopheno-imidazo[2,1-b]thiazole derivatives which were evaluated as potential inhibitors of TNAP displaying a large range of IC 50 at pH 10.4 (from 42 ± 13 lM to more than 800 lM). Ó 2011 Published by Elsevier Ltd.