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.
Abstract
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.
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
Histone deacetylase (HDAC) inhibitors are important epigenetic anticancer agents that regulate gene expression, induce cell cycle arrest, and promote apoptosis. In this study, a novel series of 2-oxoindoline-capped hydroxamic acids was designed, synthesized and evaluated for their capacity to inhibit histone deacetylases and suppress cancer cell proliferation. The screening panel incorporated multiple cancer models spanning different organ systems, including colorectal adenocarcinoma (SW620, HCT116), triple-negative breast cancer (MDA-MB-231), non-small cell lung carcinoma (A549), and prostate cancer (PC-3). Comparative assessment against non-transformed fibroblasts (MRC-5) enabled evaluation of selectivity and tolerability profiles. Several derivatives exhibited potent HDAC inhibition at submicromolar concentrations, with compounds 7c, 10b, and 10c showing stronger activity than the reference inhibitor SAHA. Among them, compound 10c demonstrated broad antiproliferative effects while maintaining relatively low toxicity toward normal cells. Mechanistic investigations revealed that 10c induced S-phase cell cycle arrest and promoted apoptosis in SW620 colorectal cancer cells. Molecular docking studies against multiple HDAC isoforms supported the experimental findings by revealing favorable zinc coordination and key interactions within the catalytic pocket. To further elucidate the binding behavior and dynamic features of the most active derivatives, molecular dynamics simulations were performed for HDAC complexes with 7c, 10b, and 10c. The simulations revealed stable protein–ligand interactions without perturbation of the overall protein structure, while highlighting distinct binding dynamics among the compounds, with 10c exhibiting the highest binding persistence, followed by 7c and 10b. In addition, in silico ADME and toxicity predictions were carried out for compound 10c as a representative highly active derivative, indicating acceptable drug-like properties and a favorable safety profile. Overall, 2-oxoindoline-based hydroxamic acids, particularly those bearing extended alkyl linkers, represent promising scaffolds for further development of HDAC-targeted anticancer agents.
Huong Thi Lan Tran, Hwa Kyung Kim, Thai Anh Nguyen et al.· RSC Advances· 0 citations
Compound 4v emerged as a leading candidate, showing EGFR kinase inhibitory activity comparable to Erlotinib, and computational analysis of 4v and EGFR molecular binding suggests that it serves as a superior binder to the inactive EGFR conformation.
Amr Elagamy, Mohamed S. Nafie, Ahmed Elnahrawy et al.· European journal of medicina...· 0 citations
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
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
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.
Yixuan Zhang, Hong Wang, Feilong Zhou et al.· European journal of medicina...· 0 citations