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1.
ChemMedChem ; 18(19): e202200693, 2023 10 04.
Article in English | MEDLINE | ID: mdl-37442809

ABSTRACT

Kinases are prominent drug targets in the pharmaceutical and research community due to their involvement in signal transduction, physiological responses, and upon dysregulation, in diseases such as cancer, neurological and autoimmune disorders. Several FDA-approved small-molecule drugs have been developed to combat human diseases since Gleevec was approved for the treatment of chronic myelogenous leukemia. Kinases were considered "undruggable" in the beginning. Several FDA-approved small-molecule drugs have become available in recent years. Most of these drugs target ATP-binding sites, but a few target allosteric sites. Among kinases that belong to the same family, the catalytic domain shows high structural and sequence conservation. Inhibitors of ATP-binding sites can cause off-target binding. Because members of the same family have similar sequences and structural patterns, often complex relationships between kinases and inhibitors are observed. To design and develop drugs with desired selectivity, it is essential to understand the target selectivity for kinase inhibitors. To create new inhibitors with the desired selectivity, several experimental methods have been designed to profile the kinase selectivity of small molecules. Experimental approaches are often expensive, laborious, time-consuming, and limited by the available kinases. Researchers have used computational methodologies to address these limitations in the design and development of effective therapeutics. Many computational methods have been developed over the last few decades, either to complement experimental findings or to forecast kinase inhibitor activity and selectivity. The purpose of this review is to provide insight into recent advances in theoretical/computational approaches for the design of new kinase inhibitors with the desired selectivity and optimization of existing inhibitors.


Subject(s)
Phosphotransferases , Protein Kinase Inhibitors , Humans , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Protein Kinase Inhibitors/chemistry , Phosphotransferases/metabolism , Signal Transduction , Binding Sites , Adenosine Triphosphate/metabolism
2.
Bioorg Med Chem Lett ; 30(24): 127613, 2020 12 15.
Article in English | MEDLINE | ID: mdl-33075488

ABSTRACT

Type I Interferon (IFN) signaling plays an important role in the immune defense system against virus infection and in the innate immune response, thus IFNs are widely used as anti-viral agents and treatment for immune disorder or cancer. However, there is a growing demand for novel small-molecule IFN inducer due to tolerance, toxicity, or short duration of action following direct administration of IFNs. In this study, we assessed arylpiperazine (ARP) as a new core skeleton of IFN inducer. To investigate structure-activity relationship, we designed and synthesized a series of ARP analogues and evaluated the ability to stimulate IFN response in THP-1 human monocyte cells. Compound 5i was identified as a potent type I IFN inducer as it significantly increased cytokine secretion and increased expression of various IFN-stimulating genes which are representative biomarkers of type I IFN pathway. Our results suggested a beneficial therapeutic potential of 5i as an anti-viral agent.


Subject(s)
Interferon Inducers/chemistry , Interferon Inducers/pharmacology , Monocytes/drug effects , Piperazines/chemistry , Piperazines/pharmacology , Drug Design , Humans , Immunity, Innate/drug effects , Interferon Inducers/chemical synthesis , Interferon Type I/agonists , Interferon Type I/immunology , Monocytes/immunology , Piperazines/chemical synthesis , THP-1 Cells
3.
Org Biomol Chem ; 12(24): 4186-91, 2014 Jun 28.
Article in English | MEDLINE | ID: mdl-24824863

ABSTRACT

First asymmetric decarboxylative cyanomethylation of isatins is reported herewith using bifunctional thiourea derived from l-proline in good yields and enantioselectivities. This strategy enables the construction of various 3-cyanomethylene substituted 3-hydroxyoxindoles in enantioselective manner. Enantioselective synthesis of CPC-1 alkaloid has been accomplished in fewer steps.


Subject(s)
Isatin/chemical synthesis , Proline/chemistry , Thiourea/chemistry , Catalysis , Decarboxylation , Isatin/chemistry , Methylation , Stereoisomerism
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