Design, synthesis, in silico, in vitro and in vivo anticancer potential of sulphonamide- ethylamine-triazole-aryl in against triple negative breast cancer and Dalton lymphoma.
It is suggested that 4c exerts anticancer activity through ROS-mediated mitochondrial apoptosis and cell-cycle disruption, highlighting its promise as an oncotherapeutic candidate for TNBC and Dalton lymphoma.
Abstract
This study aimed to synthesize a novel series of sulphonamide-ethylamine-triazole-aryl derivatives as potential anticancer agents. The compounds were synthesized using an efficient click reaction and characterized by 1H, 13C NMR, HRMS and HPLC. Anticancer potential was tested against human breast cancer SK-BR-3, MDA-MB-231 and MCF-7, along with cervical cancer HeLa and non-oncogenic HEK-293 cells. Among the synthesized derivatives (4a-4o), compound 4c showed the most significant apoptotic activity in MDA-MB-231 cells, with an IC50 of 15μM, while exhibiting minimal toxicity towards non-oncogenic HEK-293 cells. Mechanistic studies revealed that 4c markedly increased intracellular ROS levels, mitochondrial dysfunction (Mito-tracker and JC-1 assay), which may lead to mitochondrial-mediated apoptosis. This was confirmed by AO/EtBr dual staining, which showed characteristic apoptotic features such as chromatin condensation and membrane blebbing, which was again validated through Annexin/V and Caspase-3/7 assay. Flow cytometric cell-cycle analysis further demonstrated that 4c induced G2/M phase arrest, a critical checkpoint dysregulation that may also contribute to its pro-apoptotic effects. In vivo studies showed strong antitumor efficacy of 4c in Dalton lymphoma, comparable to docetaxel, while suppressing tumor progression with reduced toxicity. Molecular docking studies also identified compounds 4a, 4c, 4 h, and 4 m as promising binders towards tyrosine-protein kinase. ADMET and drug-likeness analysis of compounds 4a-4o supported the favourable profile of 4c. Overall, these findings suggest that 4c exerts anticancer activity through ROS-mediated mitochondrial apoptosis and cell-cycle disruption, highlighting its promise as an oncotherapeutic candidate for TNBC and Dalton lymphoma.
Cancer remains a leading cause of mortality worldwide, necessitating the continuous development of more effective and selective therapeutic agents. Among heterocyclic scaffolds, 1,3,4-thiadiazole derivatives have attracted considerable attention due to their diverse pharmacological properties and favorable physicochemical characteristics. In this study, a novel thiadiazole-based compound namely 2-((5-acetamido-1,3,4-thiadiazol-2-yl)thio)-N-(naphthalen-2-yl)acetamide, was successfully synthesized in excellent yield (99%) and high thermal stability and was fully structurally characterized using FT-IR, NMR, and mass spectrometry. The anticancer potential of the synthesized compound was evaluated in vitro against three human cancer cell lines, namely breast adenocarcinoma (MCF-7), colorectal carcinoma (HCT-116), and hepatocellular carcinoma (HepG-2), using the MTT assay. The compound exhibited pronounced cytotoxic activity against MCF-7 and HCT-116 cell lines, with IC50 values of 1.07 ± 0.03 µM and 2.09 ± 0.55 µM, respectively, demonstrating superior potency compared to the reference drug doxorubicin. In contrast, no significant activity was observed against HepG-2 cells, indicating a degree of selectivity. These findings highlight the potential of the 1,3,4-thiadiazole scaffold as a promising platform for the development of novel anticancer agents with enhanced efficacy and selectivity. In silico investigations, including molecular docking, molecular dynamics simulations, and MM/GBSA analysis, revealed stable binding of the synthesized compound within the VEGFR2 active site, supported by favorable binding free energy and key ligand–residue interactions.
Mostafa Sayed, Ehdaa Mohammed, Doha H. Aboubaker et al.· RSC Advances· 0 citations
A series of novel pyrimidine-based benzothiazole/phenyl hybrids was rationally designed and synthesized via molecular hybridization to develop promising anticancer agents. The compounds were evaluated against human lung carcinoma (A549) and breast adenocarcinoma (MCF-7) cell lines, while HEK-293 cells were used to assess selectivity toward normal cells. Among the derivatives, K12, K5, and K4 showed potent activity against A549 cells, with IC50 values of 6.18, 7.01, and 7.54 μM, respectively. K5 and K12 also showed significant activity against MCF-7 cells, with IC50 values of 8.33 and 9.30 μM, respectively. All compounds displayed minimal cytotoxicity toward HEK-293 cells, indicating favorable selectivity for cancer cells. UV-Vis DNA-binding studies suggested a probable intercalative binding mode, while DNA nicking assays demonstrated protection against oxidative DNA damage. K12 showed the strongest DNA-binding affinity and DNA-protective activity. Molecular docking against the VEGFR-2 kinase domain (PDB ID: 4ASD), followed by 501 ns MD simulations, revealed stable protein-ligand complexes, supported by RMSD, RMSF, DCCM, PCA, and free energy landscape analyses. MM/GBSA calculations indicated favorable binding free energies, dominated by van der Waals interactions. Overall, K12 emerged as the most promising lead compound, combining potent antiproliferative activity, high selectivity, efficient DNA-binding characteristics, and robust computational performance, highlighting its potential for further development as a novel anticancer agent.
Karan Kamle, Shreyansh R. Mevada, Reena Hirani et al.· Bioorganic chemistry (Print)· 0 citations
It is demonstrated that benzofuran-furan-pyrano[2,3-c]pyrazole hybrids possess promising multifaceted in vitro anticancer activity by inhibiting cancer cell proliferation, migration, invasion, and clonogenicity while inducing ROS-mediated mitochondrial apoptosis, highlighting these hybrid scaffolds as attractive candidates for further anticancer drug development.
E. Hutanu, Bassam A. Najri, A. Abdelsalam et al.· RSC Advances· 0 citations
Among the synthesized compounds, PBc1 exhibited the greatest in vitro antiproliferative activity against both MDA-MB-231 and SK-OV-3 cell lines, suggesting that PBc1 is a promising compound for further biological and mechanistic investigation.
Prachita Gauns Dessai, Parixit J. Bhandurge, C. Nazareth et al.· Journal of the Iranian Chemi...· 0 citations
A novel series of 2-hydrazono-5-acetyl-[1,3,4]thiadiazole (10-15) and N'-ethylideneethanethiohydrazide (17-21) derivatives were designed and synthesized using robust methodology and tested as anticancer agents against a panel of cancer cell lines, including PC3 (prostate cell line), A549 (lung carcinoma), HepG2 (hepatocellular carcinoma cell line), HCT116 (human colon cancer cell line), and the normal human fibroblast cell line (BJ1). The findings identified compounds coded 10 and 11 as the most promising candidates, with IC₅₀ values of 47 ± 0.24 μM and 50.8 ± 0.41 μM, respectively. Compound 10 exhibited selective cytotoxicity toward HepG2 cells with a selectivity index of 3.19. In contrast, the selectivity index for compound 11 could not be determined because it produced a negative effect on the BJ1 cells at the highest tested concentration. Furthermore, the mechanism of action of the most active compounds against liver cancer was explored through gene expression, DNA damage, and DNA fragmentation. Expression levels of the anti-apoptotic gene BCL-2 increased significantly (1 ± 0.046) in negative samples of liver cancer cell lines relative to the treated cell lines (10: 0.62 ± 0.033, and 11: 0.68 ± 0.038). BCL-2 expression decreased significantly in HepG2 + 10 (62% of control), followed by HepG2 + 11 (68% of control), and reached the lowest levels in HepG2 + Doxo (42% of control). In contrast, DNA damage values increased significantly in treated liver cancer cell line samples exposed to 10 (27.80 ± 1.36) and 11 (25.60 ± 1.29), as well as to the Doxo drug (33.20 ± 1.43). DNA fragmentation rates also increased significantly in treated liver cancer cells treated with 10 (24.48 ± 1.02), 11 (23.08 ± 0.94), and Doxo (29.54 ± 1.25) compared with the negative control.
Ashraf A. Sediek, Eman Sabry, Huda F. Khalil et al.· Bioorganic chemistry (Print)· 0 citations
This study reports an efficient synthesis of 6-(4-methoxyphenyl)-3-aryl-[1,2,4]triazolo[4,3-b]pyridazine derivatives via oxidative cyclization of the corresponding hydrazones using iodobenzene diacetate as a mild and metal-free oxidizing agent. The structures of the synthesized compounds were confirmed by 1H NMR, 13C NMR, FTIR, and mass spectrometry. Their in vitro anticancer activity was evaluated against the MCF-7 breast cancer cell line, where four compounds (7a, 7c, 7d, and 7f) exhibited notable cytotoxic effects. Molecular docking studies suggested favorable binding interactions of these compounds with several cancer-related targets, including human 17β-hydroxysteroid dehydrogenase, topoisomerase IIα, p73 tetramerization domain, Bcl2-xL, EGFR tyrosine kinase, and survivin. Docking of the complete compound series (7a-7j) further supported the observed activity trends. These findings indicate that triazolopyridazine derivatives represent promising scaffolds for further investigation as anticancer agents. IBD was used as an environment friendly reagent for the synthesis of 1,2,4-triazolo[4,3-b]pyridazines by oxidative cyclization of hydrazone derivatives. 1,2,4-Triazoles showed excellent anticancer activity against breast cancer Michigan Cancer Foundation-7 (MCF-7) cells. The molecular docking studies were carried out with several enzymes associated with breast cancer to find the effective binding of the synthesized compounds.
S. Malik, R. Soni, M. Sihag et al.· Discover Chemistry· 0 citations
