Back to Search
Start Over
Non-small cell lung cancer sensitisation to platinum chemotherapy via new thiazole-triazole hybrids acting as dual T-type CCB/MMP-9 inhibitors.
- Source :
-
Journal of enzyme inhibition and medicinal chemistry [J Enzyme Inhib Med Chem] 2024 Dec; Vol. 39 (1), pp. 2388209. Date of Electronic Publication: 2024 Aug 14. - Publication Year :
- 2024
-
Abstract
- Cisplatin remains the unchallenged standard therapy for NSCLC. However, it is not completely curative due to drug resistance and oxidative stress-induced toxicity. Drug resistance is linked to overexpression of matrix metalloproteinases (MMPs) and aberrant calcium signalling. We report synthesis of novel thiazole-triazole hybrids as MMP-9 inhibitors with T-type calcium channel blocking and antioxidant effects to sensitise NSCLC to cisplatin and ameliorate its toxicity. MTT and whole cell patch clamp assays revealed that 6d has a balanced profile of cytotoxicity (IC <subscript>50</subscript> = 21 ± 1 nM, SI = 12.14) and T-type calcium channel blocking activity (⁓60% at 10 μM). It exhibited moderate ROS scavenging activity and nanomolar MMP-9 inhibition (IC <subscript>50</subscript> = 90 ± 7 nM) surpassing NNGH with MMP-9 over -2 and MMP-10 over -13 selectivity. Docking and MDs simulated its receptor binding mode. Combination studies confirmed that 6d synergized with cisplatin (CI = 0.69 ± 0.05) lowering its IC <subscript>50</subscript> by 6.89 folds. Overall, the study introduces potential lead adjuvants for NSCLC platinum-based therapy.
- Subjects :
- Humans
Structure-Activity Relationship
Molecular Structure
Matrix Metalloproteinase Inhibitors pharmacology
Matrix Metalloproteinase Inhibitors chemistry
Matrix Metalloproteinase Inhibitors chemical synthesis
Cisplatin pharmacology
Cisplatin chemistry
Calcium Channels, T-Type metabolism
Carcinoma, Non-Small-Cell Lung drug therapy
Carcinoma, Non-Small-Cell Lung pathology
Carcinoma, Non-Small-Cell Lung metabolism
Lung Neoplasms drug therapy
Lung Neoplasms pathology
Lung Neoplasms metabolism
Antineoplastic Agents pharmacology
Antineoplastic Agents chemistry
Antineoplastic Agents chemical synthesis
Drug Screening Assays, Antitumor
Triazoles chemistry
Triazoles pharmacology
Triazoles chemical synthesis
Matrix Metalloproteinase 9 metabolism
Dose-Response Relationship, Drug
Thiazoles chemistry
Thiazoles pharmacology
Thiazoles chemical synthesis
Cell Proliferation drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1475-6374
- Volume :
- 39
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Journal of enzyme inhibition and medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 39140776
- Full Text :
- https://doi.org/10.1080/14756366.2024.2388209