It is demonstrated that dolutegravir-based 1,2,3-triazole derivatives possess promising anti-hepatocellular carcinoma activity and identify compound 3b as a potential lead candidate for further anticancer drug development.
Abstract
Drug repurposing through structural modification of marketed drugs is a well-established strategy for the discovery of novel therapeutic agents, benefiting from known safety profiles and clinical relevance. Dolutegravir, a widely used HIV integrase inhibitor featuring a nitrogen–oxygen heterocycle, provides an attractive scaffold for exploring new pharmacological activities. In this study, a series of novel dolutegravir derivatives bearing 1,2,3-triazole moieties were synthesized via click chemistry and evaluated for their antitumor activity against hepatocellular carcinoma (HCC). Among them, compounds 3b and 3i exhibited potent antiproliferative activity against HepG2 cells, with IC50 values of 7.89 µM and 15.07 µM, respectively. Both compounds also showed significant inhibitory activity against Huh7 cells, with IC50 values of 2.94 µM for 3b and 4.69 µM for 3i. Further biological studies demonstrated that compounds 3b and 3i significantly induced apoptosis in HepG2 cells, inhibited cell migration in wound-healing assays, and suppressed colony formation. Mechanistic investigations in Huh7 cells further revealed that compound 3b induced concentration-dependent cell death and apoptosis, accompanied by enhanced autophagy and DNA damage. These antitumor effects were associated with significant alterations in apoptosis- and migration-related protein expression. Collectively, these findings demonstrate that dolutegravir-based 1,2,3-triazole derivatives possess promising anti-hepatocellular carcinoma activity and identify compound 3b as a potential lead candidate for further anticancer drug development.
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.
A. Hassan, S. El‐Sebaey, Moshira A. El Deeb et al.· ChemistrySelect· 0 citations
These findings highlight benzimidazole derivatives, particularly 16a and 17b and their nanoparticle formulations, as promising anticancer candidates, driven primarily by strong cellular potency and favorable safety, substantiating their potential as lead candidates for further optimization and therapeutic development.
Mai Montaser Abdullah, R. Hathout, Reham S. Elezaby et al.· RSC Medicinal Chemistry· 0 citations
Chromone derivatives are acknowledged as a privileged scaffold, recognized for their diverse pharmacological activities, including anti-cancer properties, although comprehensive investigations in this domain have been limited. This research addresses the design, synthesis, and biological evaluation of a new series of C-2 anilinated chromone derivatives. Compounds 4v, 4x, and 4y exhibited significant in vitro cytotoxicity against hepatocellular carcinoma (HepG-2) and breast adenocarcinoma (MCF-7) cell lines. Importantly, all three compounds exceeded the cytotoxicity of Erlotinib against MCF-7 and HepG-2 cancer cells. Compound 4v emerged as a leading candidate, showing EGFR kinase inhibitory activity (IC50 = 60.7 nM) comparable to Erlotinib. It prompted cellular apoptosis and initiated cell cycle arrest at the G2/M phase. Mechanistic studies indicated that compound 4v upregulated essential pro-apoptotic factors, including P53, Bax, PUMA, and caspases-7, -8, and -9. In vivo experiments utilizing a xenograft SEC model demonstrated similar tumor growth inhibition and volume reduction between 4v and erlotinib. Computational analysis of 4v and EGFR molecular binding, considering both the active (PDB ID: 1M17) and inactive (PDB ID: 4HJO) forms, suggests that it serves as a superior binder to the inactive EGFR conformation. These results collectively underscore C-2 anilinated chromone derivatives, particularly 4v as a lead, as promising candidates for the advancement of effective anti-cancer therapeutics.
Amr Elagamy, Mohamed S. Nafie, Ahmed Elnahrawy et al.· European journal of medicina...· 0 citations
The development of new therapeutic agents for glioblastoma and hepatocellular carcinoma (HCC) remains a priority due to poor prognosis, limited treatment options, and high recurrence rates. Herein, we report a one‐pot synthesis of aromatic aminopropyl lactams (ArAPLs) via hydrolysis of bicyclic amidines (DBN, DBU), followed by reductive amination with aromatic aldehydes. These compounds were designed to target histamine H3 receptors (H3R), which are often overexpressed in these malignancies. Docking studies suggested that compounds 3a and 4a may act as H3R antagonists, showing favorable binding through hydrophobic and hydrogen‐bonding interactions. Biological evaluation identified 3a and 4a as the most promising compounds, exhibiting micromolar antiproliferative activity in glioblastoma and HCC cell models. Compound 3a showed the best balance between potency and selectivity, including activity in 3D spheroid models and modulation of cell cycle‐related markers. In coculture systems, spheroids displayed reduced size and density, although a slight increase in viability was observed, particularly with 4a. Variations in peripheral cell layers suggest a role for macrophage behavior. Overall, these findings support the cytotoxic potential of ArAPLs, although further studies are required to confirm their role as H3R antagonists.
M. Martins, Ruben Valente, Ruben Amaro et al.· ChemMedChem· 0 citations
The benzanilide scaffold is well known for its biological activities, such as antifungal, antibacterial, herbicide, and anti-tumor activity. Benzanilides with halogen substitution were computationally designed and screened against EGFR kinase, with erlotinib as a reference compound, using molecular docking. Two compounds were synthesized by the Schotten-Baumann reaction and confirmed based on FT-IR spectrophotometry, TLC, and sharp, narrow-range melting point analyses. The synthesized compounds were tested for antiproliferative activity and acute toxicity using the MTT assay with the (MCF-7) human breast cancer cell line. The effect of the compounds on non-cancerous cells in the human body was tested using blood lymphocytes. The mechanism of action evaluated by an in vitro cytotoxicity study revealed IC50 values of compound A = 75.54 ± 4.7 μM and compound B = 178.5 ± 9.0 μM (mean ± SEM, n = 3), showing promising growth-inhibitory cytotoxic actions with increasing concentrations against EGFR in breast cancer. Docking studies revealed that synthesized compounds interacted with a similar enzyme and ATP binding site of EGFR-TK in the reference drug erlotinib, along with additional strong interactions indicating efficacy and potency. To predict better tolerability and late failure, toxicity predictions were made for the synthesized compounds. Therefore, this research aimed to demonstrate the activity of several promising benzanilide molecules.
M. Parab, Pramodkumar P. Gupta, S. Shetty et al.· Biotechnology Notes· 0 citations
In this study, a series of oridonin (ORI 1) derivatives were synthesized, and their antiproliferative activities were evaluated against colorectal cancer (CRC) cell lines. Structure–activity relationship (SAR) analysis revealed that aromatic and heteroaromatic substitutions significantly enhanced the antiproliferative potency compared to the parent compound. Among the synthesized derivatives, difuroate enmein-type compound 11b emerged as the most interesting candidate (IC50 = 0.49 μM), displaying a favorable balance between anticancer activity and cytotoxicity toward normal colon cells. Mechanistic studies revealed that compound 11b significantly inhibited the proliferation of SW620 cells, increased the doubling time, and induced S and G2/M cell cycle arrest. In addition, treatment with this compound reduced intracellular ROS levels, decreased the expression of CDK1 and CDK6, and attenuated mTOR signaling. Collectively, these findings identify compound 11b as a valuable scaffold for further development of novel anticancer agents targeting CRC.
Pedro J. M. Sobral, Rita Oliveira, Silvia Marín et al.· RSC Medicinal Chemistry· 0 citations