We have located links that may give you full text access.
A New Series of Triazolothiadiazines as Potential Anticancer Agents for Targeted Therapy of Non-small Cell Lung and Colorectal Cancers: Design, Synthesis, In Silico and In Vitro Studies Providing Mechanistic Insight into Their Anticancer Potencies.
Medicinal Chemistry 2020 October 22
BACKGROUND: Targeted therapies acting on specific molecular targets in cancer cells with better curative efficacy and lower toxicity have come into prominence for the management of non-small cell lung cancer (NSCLC) and colorectal cancer (CRC). COX-2 stands out as a plausible target for anticancer agents due to its pivotal role in tumor initiation, progression and invasion.
OBJECTIVES: Due to the importance of triazolothiadiazine scaffold in targeted anticancer drug discovery, the aim of this work is the design of new triazolothiadiazines as potential anticancer agents for the targeted therapy of NSCLC and CRC.
METHODS: New triazolo[3,4-b]-1,3,4-thiadiazines (2a-g) were synthesized via the ring closure reactions of 2-bromo-1- arylethanones with 4-amino-5-((5-methoxy-2-methyl-1H-indol-3-yl)methyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione (1), which was obtained via the solvent-free reaction of 5-methoxy-2-methyl-3-indoleacetic acid with thiocarbohydrazide. MTT assay was performed to determine their cytotoxic effects on A549 human lung adenocarcinoma, Caco-2 human colorectal adenocarcinoma and CCD-19Lu human lung fibroblast cells. The most potent compounds were evaluated for their effects on apoptosis, caspase-3, mitochondrial membrane potential, cell cycle, ultrastructural morphological changes and COX-2 in A549 and Caco-2 cells. In silico docking and Absorption, Distribution, Metabolism and Excretion (ADME) studies were also performed using Schrödinger's Maestro molecular modeling package.
RESULTS: 6-(4-Chlorophenyl)-3-[(5-methoxy-2-methyl-1H-indol-3-yl)methyl]-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine (2e) was the most potent and selective anticancer agent in this series against A549 and Caco-2 cell lines. Compound 2e induced early apoptosis, caused mitochondrial membrane depolarization and arrested cell cycle at G0/G1 phase in A549 cells. On the other hand, compound 2e triggered intrinsic apoptotic pathway involving caspase-3 activation in Caco-2 cells. Compound 2e caused apoptotic morphological changes in both cancer cell lines. The cytotoxic and apoptotic effects of this compound on CRC were found to be related to its selective COX-2 inhibitory activity. According to molecular docking studies, compound 2e showed good affinity to the active site of COX-2 (PDB code: 4COX). Based on in silico ADME studies, the compound is predicted to possess a favorable ADME profile.
CONCLUSION: According to in vitro and in silico studies, compound 2e was identified as a potential orally bioavailable anticancer agent for COX-2-targeted therapy of CRC.
OBJECTIVES: Due to the importance of triazolothiadiazine scaffold in targeted anticancer drug discovery, the aim of this work is the design of new triazolothiadiazines as potential anticancer agents for the targeted therapy of NSCLC and CRC.
METHODS: New triazolo[3,4-b]-1,3,4-thiadiazines (2a-g) were synthesized via the ring closure reactions of 2-bromo-1- arylethanones with 4-amino-5-((5-methoxy-2-methyl-1H-indol-3-yl)methyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione (1), which was obtained via the solvent-free reaction of 5-methoxy-2-methyl-3-indoleacetic acid with thiocarbohydrazide. MTT assay was performed to determine their cytotoxic effects on A549 human lung adenocarcinoma, Caco-2 human colorectal adenocarcinoma and CCD-19Lu human lung fibroblast cells. The most potent compounds were evaluated for their effects on apoptosis, caspase-3, mitochondrial membrane potential, cell cycle, ultrastructural morphological changes and COX-2 in A549 and Caco-2 cells. In silico docking and Absorption, Distribution, Metabolism and Excretion (ADME) studies were also performed using Schrödinger's Maestro molecular modeling package.
RESULTS: 6-(4-Chlorophenyl)-3-[(5-methoxy-2-methyl-1H-indol-3-yl)methyl]-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine (2e) was the most potent and selective anticancer agent in this series against A549 and Caco-2 cell lines. Compound 2e induced early apoptosis, caused mitochondrial membrane depolarization and arrested cell cycle at G0/G1 phase in A549 cells. On the other hand, compound 2e triggered intrinsic apoptotic pathway involving caspase-3 activation in Caco-2 cells. Compound 2e caused apoptotic morphological changes in both cancer cell lines. The cytotoxic and apoptotic effects of this compound on CRC were found to be related to its selective COX-2 inhibitory activity. According to molecular docking studies, compound 2e showed good affinity to the active site of COX-2 (PDB code: 4COX). Based on in silico ADME studies, the compound is predicted to possess a favorable ADME profile.
CONCLUSION: According to in vitro and in silico studies, compound 2e was identified as a potential orally bioavailable anticancer agent for COX-2-targeted therapy of CRC.
Full text links
Related Resources
Trending Papers
Challenges in Septic Shock: From New Hemodynamics to Blood Purification Therapies.Journal of Personalized Medicine 2024 Februrary 4
Molecular Targets of Novel Therapeutics for Diabetic Kidney Disease: A New Era of Nephroprotection.International Journal of Molecular Sciences 2024 April 4
The 'Ten Commandments' for the 2023 European Society of Cardiology guidelines for the management of endocarditis.European Heart Journal 2024 April 18
A Guide to the Use of Vasopressors and Inotropes for Patients in Shock.Journal of Intensive Care Medicine 2024 April 14
Get seemless 1-tap access through your institution/university
For the best experience, use the Read mobile app
All material on this website is protected by copyright, Copyright © 1994-2024 by WebMD LLC.
This website also contains material copyrighted by 3rd parties.
By using this service, you agree to our terms of use and privacy policy.
Your Privacy Choices
You can now claim free CME credits for this literature searchClaim now
Get seemless 1-tap access through your institution/university
For the best experience, use the Read mobile app