Sagarkumar Patel1, Rajkumar Patle1, Preethi Parameswaran1, Alok Jain2, Amit Shard3. 1. Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research Ahmedabad, Opposite Air Force Station, Gandhinagar, Gujarat, 382355, India. 2. Department of Biotechnology, National Institute of Pharmaceutical Education and Research Ahmedabad, Opposite Air Force Station, Gandhinagar, Gujarat 382355, India. Electronic address: alokjain@niperahm.ac.in. 3. Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research Ahmedabad, Opposite Air Force Station, Gandhinagar, Gujarat, 382355, India. Electronic address: amit@niperahm.ac.in.
Abstract
BACKGROUND: Abolition of cancer warrants effective treatment modalities directed towards specific pathways dysregulated in tumor proliferation and survival. The antiapoptotic Bcl-2 proteins are significantly altered in several tumor types which position them as striking targets for therapeutic intervention. Here we designed, computationally evaluated, synthesized, and biologically tested structurally optimized thiazole-based small molecules as anticancer agents. METHODS: The virtually designed 200 molecules were subjected to rigorous docking and in silico ADME-Toxicity studies. Out of this, 23 skeletally diverse thiazole-based molecules which passed pan assay interference compounds (PAINS) filter and were synthetically feasible were synthesized in 3 steps using cheap and readily available reagents. The molecules were in vitro evaluated against Bcl-2-Jurkat, A-431 cancerous cell lines and ARPE-19 cell lines. Molecular Dynamics (MD) simulation studies were performed to analyse conformational changes induced by ligand 32 in Bcl-2. Flow cytometry analysis of compound 32 treated Bcl-2 cells was done to check apoptosis. RESULTS: The molecules exhibited appreciable interactions with Bcl-2 and were having acceptable drug like properties as tested in silico. The multi step synthesis yielded 23 skeletally diverse thiazole-based molecules in up to 80% yield. The molecules simultaneously inhibited Bcl-2 Jurkat cells in vitro without causing detectable toxicity to normal cells (ARPE-19 cells). Among them molecules 32, 50, 53, 57 and 59 showed considerable activities against Bcl-2 Jurkat and A-431cell lines at concentrations ranging from 32-46 μM and 34-52 μM, respectively. The standard doxorubicin exhibited IC50 in Bcl-2 Jurkat and A-431cell lines at 45.87 μM and 42.37 μM, respectively. The molecule 32, almost equipotent in both the cell lines was subjected to molecular dynamics (MD) simulation with Bcl-2 protein (4IEH). It was shown that 32 interacted with protein majorly via hydrophobic interactions and few H-bonding interactions. Fluorescence-activated cell sorting (FACS) analysis established that molecule is dragging cancerous cells towards apoptosis. DISCUSSION AND CONCLUSION: The chemical intuition was checked by computation coupled with biological results confirmed that thiazole-based hits have the potential to be developed downstream into potent and safer leads against antiapoptotic Bcl-2 cells.
BACKGROUND:Abolition of cancer warrants effective treatment modalities directed towards specific pathways dysregulated in tumor proliferation and survival. The antiapoptotic Bcl-2 proteins are significantly altered in several tumor types which position them as striking targets for therapeutic intervention. Here we designed, computationally evaluated, synthesized, and biologically tested structurally optimized thiazole-based small molecules as anticancer agents. METHODS: The virtually designed 200 molecules were subjected to rigorous docking and in silico ADME-Toxicity studies. Out of this, 23 skeletally diverse thiazole-based molecules which passed pan assay interference compounds (PAINS) filter and were synthetically feasible were synthesized in 3 steps using cheap and readily available reagents. The molecules were in vitro evaluated against Bcl-2-Jurkat, A-431cancerous cell lines and ARPE-19 cell lines. Molecular Dynamics (MD) simulation studies were performed to analyse conformational changes induced by ligand 32 in Bcl-2. Flow cytometry analysis of compound 32 treated Bcl-2 cells was done to check apoptosis. RESULTS: The molecules exhibited appreciable interactions with Bcl-2 and were having acceptable drug like properties as tested in silico. The multi step synthesis yielded 23 skeletally diverse thiazole-based molecules in up to 80% yield. The molecules simultaneously inhibited Bcl-2Jurkat cells in vitro without causing detectable toxicity to normal cells (ARPE-19 cells). Among them molecules 32, 50, 53, 57 and 59 showed considerable activities against Bcl-2Jurkat and A-431cell lines at concentrations ranging from 32-46 μM and 34-52 μM, respectively. The standard doxorubicin exhibited IC50 in Bcl-2Jurkat and A-431cell lines at 45.87 μM and 42.37 μM, respectively. The molecule 32, almost equipotent in both the cell lines was subjected to molecular dynamics (MD) simulation with Bcl-2 protein (4IEH). It was shown that 32 interacted with protein majorly via hydrophobic interactions and few H-bonding interactions. Fluorescence-activated cell sorting (FACS) analysis established that molecule is dragging cancerous cells towards apoptosis. DISCUSSION AND CONCLUSION: The chemical intuition was checked by computation coupled with biological results confirmed that thiazole-based hits have the potential to be developed downstream into potent and safer leads against antiapoptotic Bcl-2 cells.
Authors: Mohammed F Arshad; Aftab Alam; Abdullah Ayed Alshammari; Mohammed Bader Alhazza; Ibrahim Mohammed Alzimam; Md Anish Alam; Gulam Mustafa; Md Salahuddin Ansari; Abdulelah M Alotaibi; Abdullah A Alotaibi; Suresh Kumar; Syed Mohammed Basheeruddin Asdaq; Mohd Imran; Pran Kishore Deb; Katharigatta N Venugopala; Shahamah Jomah Journal: Molecules Date: 2022-06-21 Impact factor: 4.927
Authors: Iryna Ivasechko; Ihor Yushyn; Piotr Roszczenko; Julia Senkiv; Nataliya Finiuk; Danylo Lesyk; Serhii Holota; Robert Czarnomysy; Olga Klyuchivska; Dmytro Khyluk; Nataliya Kashchak; Andrzej Gzella; Krzysztof Bielawski; Anna Bielawska; Rostyslav Stoika; Roman Lesyk Journal: Molecules Date: 2022-09-21 Impact factor: 4.927