Jul 2026· European journal of medicinal chemistry· Vol 318, pp.
119163
· 0 citations· 34 references
Medicine
TL;DR
Camptothecin (CPT) and its derivatives are clinically validated topoisomerase I (Topo I) inhibitors with broad-spectrum antitumor activity and modification at the 10-position of the CPT scaffold represents a promising strategy to enhance binding affinity.
Abstract
Camptothecin (CPT) and its derivatives are clinically validated topoisomerase I (Topo I) inhibitors with broad-spectrum antitumor activity. Based on the stabilization of the covalent DNA-Topo I complex, modification at the 10-position of the CPT scaffold represents a promising strategy to enhance binding affinity. Herein, the rational design, synthesis, and biological evaluation of novel 10-substituted CPT derivatives guided by molecular dynamics (MD) simulations are presented. A total of 45 derivatives were synthesized and evaluated for their antiproliferative activity against three human cancer cell lines (A549, HCT116, HepG2). Structure-activity relationship (SAR) studies demonstrated that the carbonylmethylene linker and 3-methoxy-4-methylphenyl substitution afforded optimal potency. The most promising compound C6 showed exceptional cytotoxicity against HCT116 cells with an IC50 value of 0.001 μM, 16-fold more potent than that of compound SN-38. Mechanistic studies confirmed that C6 induced S-phase cell cycle arrest and apoptosis in HCT116 cells, suppressed cell migration and invasion, and downregulated Topo I protein expression in a concentration-dependent fashion. Furthermore, compound C6 exhibited significant in vivo antitumor efficacy in an HCT116 xenograft model with a favorable safety profile. Pharmacokinetic evaluation in rats confirmed moderate absolute bioavailability and a reasonable half-life. Collectively, compound C6 was identified as a potent Topo I inhibitor with promising antitumor activity.
The epidermal growth factor receptor (EGFR) is a key regulator of malignant cell growth and survival, making it an attractive target for cancer therapy. In this study, a new series of thiazole derivatives was rationally designed and synthesized as potential EGFR inhibitors and evaluated for their antiproliferative activity against two human colon cancer cell lines (HCT-116 and HT29). Several compounds exhibited potent anticancer activity, with compound 4j showing the highest potency, displaying half-maximal inhibitory concentration (IC50) values of 2.10 and 1.91 µM against HCT-116 and HT29 cells, respectively. Owing to its superior antiproliferative activity, compound 4j was further evaluated for EGFR inhibitory activity and demonstrated remarkable potency with an IC50 value of 0.27 µM. In addition, 4j exhibited a favorable selectivity index toward normal WI38 cells and effectively induced apoptosis through modulation of Bax, Bcl-2, and p53 expression. Molecular docking demonstrated strong binding interactions of 4j within the EGFR active site, while its ADME predictions supported its favorable drug-like profile. Overall, compound 4j represents a promising lead candidate for the development of novel EGFR-targeted anticancer agents.
Amani M. R. Alsaedi, Alaa M. Abu Alnjaa, Amel S. Younes et al.· Future Medicinal Chemistry· 0 citations
Mechanistic studies and structure–activity relationship analysis identify compound 11b as a valuable scaffold for further development of novel anticancer agents targeting CRC, and reduce intracellular ROS levels and attenuated mTOR signaling.
Pedro J. M. Sobral, Rita Oliveira, Silvia Marín et al.· RSC Medicinal Chemistry· 0 citations
A novel set of imidazo[2,1-b]thiazolediones 4a,b and 5a-d, with anticipated EGFR and IDO1 inhibition activities, was designed and prepared. These novel derivatives were evaluated in the NCI 60 cell line panel in which the superior compounds 5b and 5d were chosen for further evaluation of their five dose cytotoxicity toward the most sensitive cancer cells namely non-small cell lung cancer EKVX and HOP-92, breast HS 578 T, and normal WI-38 cells. The presence of a substituted benzylidene moiety at position-2 of the imidazothiazole scaffold in compounds 5a-d positively influences anticancer activity, with the phenylallylidene moiety at position-6 exhibiting superior cytotoxic effects compared to the 2-thienylidene moiety. Among the examined hybrids, 5d showed significant antiproliferative effect against HS 578 T tumor cell. To explore the underlying cell-death mechanisms, secondary biological evaluations were conducted, including cell-free EGFR and IDO1 enzymatic inhibition, apoptosis assay, and cell cycle analysis. In cell-free biochemical assays, the most active derivatives demonstrated a promising potential dual inhibitory profile against EGFR and IDO1, with compound 5d exhibiting sub-micromolar activity against both target enzymes, providing a plausible biochemical rationale for its potent cell killing. Furthermore, compound 5d induced cell cycle arrest at the G2/M phase and triggered apoptosis in HS 578 T cells, as supported by the up-regulation of Caspase-3 and Bax accompanied by the down-regulation of Bcl-2. In-silico ADMET profiling and molecular docking simulations further supported the favorable drug-like properties and binding modes of the key compounds within the target active sites. Overall, these findings highlight compound 5d as a promising lead candidate for further optimization and cellular mechanistic validation in anti-cancer drug discovery.
M. Sarg, Fatma G. Abdulrahman, Yasmin S. Sheta et al.· Bioorganic & Medicinal Chemi...· 0 citations
The current study devised and synthesized a novel class of pyrazole derivatives based on indole as possible inhibitors of cyclin‐dependent kinase‐2 (CDK‐2). 1H NMR, 13C NMR, NOESY, HMQC, and elemental analysis were used to confirm the structural integrity of the synthesized compounds. Promising CDK‐2 inhibitory activity was observed in biological assays, and numerous compounds exhibited sub‐micromolar IC50 values. Compound 5 d outperformed the reference inhibitor Roscovitine (IC50 = 0.716 µM) as the most potent inhibitor (IC50 = 0.536 µM), followed by compound 9 g (IC50 = 0.675 µM). SAR analysis showed that the observed activity was significantly influenced by the electronic nature of the added substituents as well as the orientation of the indole bond, with brominated derivatives exhibiting greater potency. The antiproliferative activity of the most potent compounds against the cancer cell lines HepG2, HCT‐116, and MCF‐7 was further assessed. In addition to having an enhanced selectivity index for normal MCF‐10A cells (SI = 8.00 vs. 4.96 for Roscovitine), compound 5 d had the greatest activity against MCF‐7 cells (IC50 = 6.78 µM), surpassing Roscovitine (IC50 = 8.11 µM). According to mechanistic investigations, compound 5 d significantly reduced the S‐phase population, markedly promoted apoptosis, and caused G1 and G2/M cell‐cycle arrest. Additionally, the consistent binding of compound 5 d within the ATP‐binding pocket of CDK‐2 was confirmed by molecular docking and molecular dynamics simulations, and attractive drug‐like and pharmacokinetic features, similar to those of Roscovitine, were demonstrated by in silico ADMET predictions. All of these results point to compound 5 d as a promising lead scaffold for developing potent CDK‐2‐targeted anticancer agents.
Wagdy M. Eldehna, Zainab M Elsayed, Mohamed R. Elnagar et al.· Drug development research (P...· 0 citations
The limited efficacy and resistance associated with current anticancer therapies necessitate the development of novel agent, particularly for aggressive malignancies. In this study, a series of fluorine-substituted isoindolinone-amino acid conjugates was designed and evaluated for antiproliferative activity using a phenotypic screening approach. A library of 24 compounds was screened against lung, breast and skin cancer cell lines, among which 11 derivatives demonstrated promising antiproliferative activity with IC50 values ranging from 7.36 to 41.99 µM. SAR analysis revealed that incorporation of trifluoromethoxy (-OCF3) substitution with Trp, Tyr, and Phe conjugation significantly enhances activity relative to trifluoromethyl (-CF3) and mono-fluoro analogues. The lead compounds 9c, 9d, 9e, and 10c markedly inhibited cancer cell proliferation, clonogenic survival, and migration, while inducing apoptosis and a pronounced S-phase cell-cycle arrest. Network pharmacology identified CDK2 and GSK3B as key hub genes associated with cell-cycle regulation. Mechanistic studies demonstrated downregulation of CDK2 and PCNA, activation of p53-p21 signaling pathway, and increased γ-H2AX expression, indicating replicating-associated damage. Molecular docking predicted favorable interactions with the CDK2 catalytic pocket, which was further validated by an in vitro CDK2/CyclinA2 kinase inhibition and reduced CDK2 protein expression determined by western blot analysis, collectively implicating CDK2 as a key molecular target. Furthermore, compounds 9c, 9d, 9e and 10c exhibited significant tumor growth inhibition (TGI) values of 53.50%, 79.47%, 64.50% and 69.14% respectively, in the 4T1 murine breast cancer model without evident systemic toxicity. Collectively, these findings identify fluorinated isoindolinone-amino acid conjugates as promising anticancer leads targeting CDK2-associated cell-cycle signaling against triple-negative breast cancer.
Soma Mandal, Rajat Choudhary, A.A.I. Parvaj Laskar et al.· Biomedicine & pharmacotherap...· 0 citations
A rational pharmacophore-guided strategy was employed to design and synthesize a series of novel coumarin derivatives as potential dual cyclin-dependent kinase 6 (CDK6) and vascular endothelial growth factor receptor-2 (VEGFR-2) inhibitors. Following structural characterization, the synthesized compounds were evaluated for their anticancer activity against MCF-7, MDA-MB-231, HepG-2, and HCT-116 cancer cell lines, together with normal WI-38 and WISH cells. Among the tested derivatives, compound 7e exhibited the highest potency, with IC50 values ranging from 3.80 to 6.35 µM, while demonstrating superior selectivity toward cancer cells compared with sorafenib. Enzymatic assays confirmed potent dual inhibition of VEGFR-2 (IC50 = 0.3905 µM) and CDK6 (IC50 = 0.3380 µM). Mechanistic studies revealed that compound 7e induced significant apoptosis, promoted S-phase cell cycle arrest, and effectively inhibited cell migration in HCT-116 cells. Computational studies, including molecular docking, molecular dynamics simulations, and binding free energy calculations, supported its stable interactions with both kinase targets. Furthermore, in silico ADMET analysis predicted favorable pharmacokinetic and safety profiles. Collectively, these findings identified compound 7e as a promising dual VEGFR-2/CDK6 inhibitor with potent and selective anticancer activity, warranting further preclinical investigation.
Hazem Elkady, Walid E. Elgammal, I. Eissa et al.· RSC Advances· 0 citations
