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1.
Bioorg Chem ; 113: 104982, 2021 08.
Article in English | MEDLINE | ID: mdl-34020277

ABSTRACT

ERK1/2 inhibitors have attracted special attention concerning the ability of circumventing cases of innate or log-term acquired resistance to RAF and MEK kinase inhibitors. Based on the 4-aminoquinazoline pharmacophore of kinases, herein we describe the synthesis of 4-aminoquinazoline derivatives bearing a 1,2,3-triazole stable core to bridge different aromatic and heterocyclic rings using copper-catalysed azide-alkyne cycloaddition reaction (CuAAC) as a Click Chemistry strategy. The initial screening of twelve derivatives in tumoral cells (CAL-27, HN13, HGC-27, and BT-20) revealed that the most active in BT-20 cells (25a, IC50 24.6 µM and a SI of 3.25) contains a more polar side chain (sulfone). Furthermore, compound 25a promoted a significant release of lactate dehydrogenase (LDH), suggesting the induction of cell death by necrosis. In addition, this compound induced G0/G1 stalling in BT-20 cells, which was accompanied by a decrease in the S phase. Western blot analysis of the levels of p-STAT3, p-ERK, PARP, p53 and cleaved caspase-3 revealed p-ERK1/2 and p-STA3 were drastically decreased in BT-20 cells under 25a incubation, suggesting the involvement of these two kinases in the mechanisms underlying 25a-induced cell cycle arrest, besides loss of proliferation and viability of the breast cancer cell. Molecular docking simulations using the ERK-ulixertinib crystallographic complex showed compound 25a could potentially compete with ATP for binding to ERK in a slightly higher affinity than the reference ERK1/2 inhibitor. Further in silico analyses showed comparable toxicity and pharmacokinetic profiles for compound 25a in relation to ulixertinib.


Subject(s)
Antineoplastic Agents/pharmacology , Extracellular Signal-Regulated MAP Kinases/antagonists & inhibitors , Molecular Docking Simulation , Protein Kinase Inhibitors/pharmacology , Quinazolines/pharmacology , Triazoles/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Extracellular Signal-Regulated MAP Kinases/metabolism , Humans , Molecular Structure , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Quinazolines/chemistry , Structure-Activity Relationship , Triazoles/chemistry
2.
Bioorg Med Chem ; 28(22): 115746, 2020 11 15.
Article in English | MEDLINE | ID: mdl-33007558

ABSTRACT

Human T cell lymphotropic virus type 1 (HTLV-1) is a human retrovirus that infects approximately 10-20 million people worldwide and causes an aggressive neoplasia (adult T-cell leukemia/lymphoma - ATL). Therapeutic approaches for the treatment of ATL have variable effectiveness and poor prognosis, thus requiring strategies to identify novel compounds with activity on infected cells. In this sense, we initially screened a small series of 25 1,2,3-triazole derivatives to discover cell proliferation inhibitors and apoptosis inducers in HTLV-1-infected T-cell line (MT-2) for further assessment of their effect on viral tax activity through inducible-tax reporter cell line (Jurkat LTR-GFP). Eight promising compounds (02, 05, 06, 13, 15, 21, 22 and 25) with activity ≥70% were initially selected, based on a suitable cell-based assay using resazurin reduction method, and evaluated towards cell cycle, apoptosis and Tax/GFP expression analyses through flow cytometry. Compound 02 induced S phase cell cycle arrest and compounds 05, 06, 22 and 25 promoted apoptosis. Remarkably, compounds 22 and 25 also reduced GFP expression in an inducible-tax reporter cell, which suggests an effect on Tax viral protein. More importantly, compounds 02, 22 and 25 were not cytotoxic in human hepatoma cell line (Huh-7). Therefore, the discovery of 3 active and non-cytotoxic compounds against HTLV-1-infected cells can potentially contribute, as an initial promising strategy, to the development process of new drugs against ATL.


Subject(s)
Antiviral Agents/pharmacology , Gene Products, tax/antagonists & inhibitors , Heterocyclic Compounds/pharmacology , Human T-lymphotropic virus 1/drug effects , Triazoles/pharmacology , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Cell Cycle Checkpoints/drug effects , Cell Survival/drug effects , Cells, Cultured , Dose-Response Relationship, Drug , Gene Products, tax/metabolism , Heterocyclic Compounds/chemistry , Humans , Molecular Structure , Structure-Activity Relationship , Triazoles/chemistry
3.
Curr Med Chem ; 26(23): 4403-4434, 2019.
Article in English | MEDLINE | ID: mdl-28748757

ABSTRACT

Neglected Diseases (NDs) affect million of people, especially the poorest population around the world. Several efforts to an effective treatment have proved insufficient at the moment. In this context, triazole derivatives have shown great relevance in medicinal chemistry due to a wide range of biological activities. This review aims to describe some of the most relevant and recent research focused on 1,2,3- and 1,2,4-triazolebased molecules targeting four expressive NDs: Chagas disease, Malaria, Tuberculosis and Leishmaniasis.


Subject(s)
Antiprotozoal Agents/therapeutic use , Chagas Disease/drug therapy , Leishmaniasis/drug therapy , Malaria/drug therapy , Triazoles/therapeutic use , Tuberculosis/drug therapy , Animals , Antiprotozoal Agents/chemistry , Humans , Triazoles/chemistry
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