Structure optimization and molecular dynamics studies of new tumor-selective s-triazines targeting DNA and MMP-10/13 for halting colorectal and secondary liver cancers
A series of triazole-tethered triazines bearing pharmacophoric features of DNA-targeting agents and non-hydroxamate MMPs inhibitors were synthesized and screened against HCT-116, Caco-2 cells, and normal colonocytes by MTT assay. 7a and 7g surpassed doxorubicin against HCT-116 cells regarding potenc...
Saved in:
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Taylor & Francis Group
2024-12-01
|
| Series: | Journal of Enzyme Inhibition and Medicinal Chemistry |
| Subjects: | |
| Online Access: | https://www.tandfonline.com/doi/10.1080/14756366.2024.2423174 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850119820447580160 |
|---|---|
| author | Christine A. Morcos Nesreen S. Haiba Rafik W. Bassily Marwa M. Abu-Serie Amira F. El-Yazbi Omar A. Soliman Sherine N. Khattab Mohamed Teleb |
| author_facet | Christine A. Morcos Nesreen S. Haiba Rafik W. Bassily Marwa M. Abu-Serie Amira F. El-Yazbi Omar A. Soliman Sherine N. Khattab Mohamed Teleb |
| author_sort | Christine A. Morcos |
| collection | DOAJ |
| description | A series of triazole-tethered triazines bearing pharmacophoric features of DNA-targeting agents and non-hydroxamate MMPs inhibitors were synthesized and screened against HCT-116, Caco-2 cells, and normal colonocytes by MTT assay. 7a and 7g surpassed doxorubicin against HCT-116 cells regarding potency (IC50 = 0.87 and 1.41 nM) and safety (SI = 181.93 and 54.41). 7g was potent against liver cancer (HepG-2; IC50 = 65.08 nM), the main metastatic site of CRC with correlation to MMP-13 expression. Both derivatives induced DNA damage at 2.67 and 1.87 nM, disrupted HCT-116 cell cycle and triggered apoptosis by 33.17% compared to doxorubicin (DNA damage at 0.76 nM and 40.21% apoptosis induction). 7g surpassed NNGH against MMP-10 (IC50 = 0.205 μM) and MMP-13 (IC50 = 0.275 μM) and downregulated HCT-116 VEGF related to CRC progression by 38%. Docking and MDs simulated ligands-receptors binding modes and highlighted SAR. Their ADMET profiles, drug-likeness and possible off-targets were computationally predicted. |
| format | Article |
| id | doaj-art-9ba7052bfe054249a160cf6cfa89a7b8 |
| institution | OA Journals |
| issn | 1475-6366 1475-6374 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Journal of Enzyme Inhibition and Medicinal Chemistry |
| spelling | doaj-art-9ba7052bfe054249a160cf6cfa89a7b82025-08-20T02:35:33ZengTaylor & Francis GroupJournal of Enzyme Inhibition and Medicinal Chemistry1475-63661475-63742024-12-0139110.1080/14756366.2024.2423174Structure optimization and molecular dynamics studies of new tumor-selective s-triazines targeting DNA and MMP-10/13 for halting colorectal and secondary liver cancersChristine A. Morcos0Nesreen S. Haiba1Rafik W. Bassily2Marwa M. Abu-Serie3Amira F. El-Yazbi4Omar A. Soliman5Sherine N. Khattab6Mohamed Teleb7Chemistry Department, Faculty of Science, Alexandria University, Alexandria, EgyptDepartment of Physics and Chemistry, Faculty of Education, Alexandria University, Alexandria, EgyptChemistry Department, Faculty of Science, Alexandria University, Alexandria, EgyptMedical Biotechnology Department, Genetic Engineering and Biotechnology Research Institute, City of Scientific Research and Technological Applications (SRTA-City), New Borg El-Arab, EgyptDepartment of Pharmaceutical Analytical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria, EgyptDepartment of Human Genetics, Medical Research Institute, Alexandria University, Alexandria, EgyptChemistry Department, Faculty of Science, Alexandria University, Alexandria, EgyptDepartment of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria, EgyptA series of triazole-tethered triazines bearing pharmacophoric features of DNA-targeting agents and non-hydroxamate MMPs inhibitors were synthesized and screened against HCT-116, Caco-2 cells, and normal colonocytes by MTT assay. 7a and 7g surpassed doxorubicin against HCT-116 cells regarding potency (IC50 = 0.87 and 1.41 nM) and safety (SI = 181.93 and 54.41). 7g was potent against liver cancer (HepG-2; IC50 = 65.08 nM), the main metastatic site of CRC with correlation to MMP-13 expression. Both derivatives induced DNA damage at 2.67 and 1.87 nM, disrupted HCT-116 cell cycle and triggered apoptosis by 33.17% compared to doxorubicin (DNA damage at 0.76 nM and 40.21% apoptosis induction). 7g surpassed NNGH against MMP-10 (IC50 = 0.205 μM) and MMP-13 (IC50 = 0.275 μM) and downregulated HCT-116 VEGF related to CRC progression by 38%. Docking and MDs simulated ligands-receptors binding modes and highlighted SAR. Their ADMET profiles, drug-likeness and possible off-targets were computationally predicted.https://www.tandfonline.com/doi/10.1080/14756366.2024.2423174Colorectal cancerDNA targetingMMP-10/13 inhibition1,2,3-triazole-tethered s-triazinesmolecular dynamics |
| spellingShingle | Christine A. Morcos Nesreen S. Haiba Rafik W. Bassily Marwa M. Abu-Serie Amira F. El-Yazbi Omar A. Soliman Sherine N. Khattab Mohamed Teleb Structure optimization and molecular dynamics studies of new tumor-selective s-triazines targeting DNA and MMP-10/13 for halting colorectal and secondary liver cancers Journal of Enzyme Inhibition and Medicinal Chemistry Colorectal cancer DNA targeting MMP-10/13 inhibition 1,2,3-triazole-tethered s-triazines molecular dynamics |
| title | Structure optimization and molecular dynamics studies of new tumor-selective s-triazines targeting DNA and MMP-10/13 for halting colorectal and secondary liver cancers |
| title_full | Structure optimization and molecular dynamics studies of new tumor-selective s-triazines targeting DNA and MMP-10/13 for halting colorectal and secondary liver cancers |
| title_fullStr | Structure optimization and molecular dynamics studies of new tumor-selective s-triazines targeting DNA and MMP-10/13 for halting colorectal and secondary liver cancers |
| title_full_unstemmed | Structure optimization and molecular dynamics studies of new tumor-selective s-triazines targeting DNA and MMP-10/13 for halting colorectal and secondary liver cancers |
| title_short | Structure optimization and molecular dynamics studies of new tumor-selective s-triazines targeting DNA and MMP-10/13 for halting colorectal and secondary liver cancers |
| title_sort | structure optimization and molecular dynamics studies of new tumor selective s triazines targeting dna and mmp 10 13 for halting colorectal and secondary liver cancers |
| topic | Colorectal cancer DNA targeting MMP-10/13 inhibition 1,2,3-triazole-tethered s-triazines molecular dynamics |
| url | https://www.tandfonline.com/doi/10.1080/14756366.2024.2423174 |
| work_keys_str_mv | AT christineamorcos structureoptimizationandmoleculardynamicsstudiesofnewtumorselectivestriazinestargetingdnaandmmp1013forhaltingcolorectalandsecondarylivercancers AT nesreenshaiba structureoptimizationandmoleculardynamicsstudiesofnewtumorselectivestriazinestargetingdnaandmmp1013forhaltingcolorectalandsecondarylivercancers AT rafikwbassily structureoptimizationandmoleculardynamicsstudiesofnewtumorselectivestriazinestargetingdnaandmmp1013forhaltingcolorectalandsecondarylivercancers AT marwamabuserie structureoptimizationandmoleculardynamicsstudiesofnewtumorselectivestriazinestargetingdnaandmmp1013forhaltingcolorectalandsecondarylivercancers AT amirafelyazbi structureoptimizationandmoleculardynamicsstudiesofnewtumorselectivestriazinestargetingdnaandmmp1013forhaltingcolorectalandsecondarylivercancers AT omarasoliman structureoptimizationandmoleculardynamicsstudiesofnewtumorselectivestriazinestargetingdnaandmmp1013forhaltingcolorectalandsecondarylivercancers AT sherinenkhattab structureoptimizationandmoleculardynamicsstudiesofnewtumorselectivestriazinestargetingdnaandmmp1013forhaltingcolorectalandsecondarylivercancers AT mohamedteleb structureoptimizationandmoleculardynamicsstudiesofnewtumorselectivestriazinestargetingdnaandmmp1013forhaltingcolorectalandsecondarylivercancers |