TL;DR
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.
The results revealed that the synthesised derivative 3h has potential binding affinity hence blocking the activity, and the synthesised piperazine derivatives are identified as promising lead compounds for further anticancer optimization.
Findings identify compound 7e as a promising VEGFR-2-targeted anticancer lead with strong enzymatic inhibition, potent cytotoxicity, and a well-supported mechanistic profile integrating experimental and computational evidence.
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 continuing to present a serious global health threat, creating an urgent demand for new and effective anticancer candidates. In this study, several novel acridone derivatives were synthesized and characterized by 1H NMR, 13C NMR, HRMS and FT‐IR, and their in vitro anticancer activity was evaluated combined with systematic theoretical calculations. Of these derivatives, 6a demonstrated antiproliferative activity against the HGC‐27 gastric cancer cell line (IC50 = 4.86 µM) in comparison with the HeLa cervical cancer cell line and the HCT116 colon carcinoma cell line. Furthermore, morphological assessment under an inverted microscope revealed that it induced apoptosis like morphological changes. Density functional theory calculations were employed to gain insight into the electronic structure and intramolecular interactions of these compounds. Molecular docking studies revealed that compound 6a binds to the gastric cancer target protein (4OUM) through hydrogen bonds with Arg1106 and Asn1057, which contribute to its enhanced binding affinity (−5.59 kcal/mol). This binding energy is consistent with its potent antiproliferative activity, establishing a correlation between the computational prediction and the experimental observation. Taken together, these results indicate that compound 6a represents a promising lead for the development of novel anticancer agents.
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.
This study aimed to develop novel CDK2 inhibitors with potent antimelanoma activity. Accordingly, a series of 2‐thioxothiazolyl pyrazoles (2–11) was rationally designed through molecular hybridization and synthesized using efficient and straightforward synthetic procedures. The structures of the synthesized compounds were confirmed by IR, NMR, mass spectrometry, and elemental analyses. All compounds were evaluated by the NCI, USA, against the 60‐human cancer cell line panel at a single dose (10 µM). The preliminary screening revealed promising antiproliferative activity, particularly against melanoma cell lines, with compound 11 exhibiting the highest growth inhibition against LOX‐IMVI and MALME‐3 M cells (21.60% and 49.41%, respectively). Based on these results, compounds 2, 4, and 11 were further evaluated by the MTT assay. Compound 11 exhibited the greatest cytotoxicity, with IC 50 values of 3.82 and 2.52 µM against LOX‐IMVI and MALME‐3 M cells, respectively, superior to doxorubicin and 5‐fluorouracil, together with excellent selectivity (SI = 12.14 and 18.40). Moreover, compound 11 potently inhibited CDK2 (IC 50 = 1.07 µM), approaching the activity of roscovitine (IC 50 = 0.84 µM), and induced cell cycle arrest at G1‐phase, besides promoting intrinsic apoptosis (23‐ to 40‐fold) in MALME‐3 M cells. These findings identify compound 11 as a promising selective CDK2‐targeted lead for melanoma therapy.