Development of 7-hydroxy-4-methylcoumarin-cyanoacrylate hybrids with antiproliferative activity against breast cancer cells: from molecular design to in vivo validation.
5 affiliations
- 1Department of Chemistry, Faculty of Science, Port Said University Port Said Egypt [email protected] [email protected] [email protected].
- 2Department of Pharmacology and Toxicology, Faculty of Medicine, Umm Al-Qura University Makkah 21955 Saudi Arabia [email protected].
- 3Department of Pharmaceutical Sciences, College of Pharmacy, Princess Nourah bint Abdulrahman University P.O. Box 84428 Riyadh 11671 Saudi Arabia [email protected].
- 4Chemistry Department, Faculty of Science, Suez Canal University Ismailia 41522 Egypt [email protected].
- 5Institute for Chemistry, Humboldt Universität zu Berlin 12489 Berlin Germany.
Abstract
In the present study, a series of novel 6,8-dibromo-7-hydroxy-4-methylcoumarin-cyanoacrylate hybrids and their corresponding pyrazole derivatives were designed, synthesized, and evaluated for antiproliferative activity against breast cancer cells. Among the tested compounds, cyanoacrylate derivative 8 emerged as the most active analogue against MCF-7 cells (IC₅₀ = 5.9 ± 0.4 µM) and retained antiproliferative activity against MDA-MB-231 cells (IC₅₀ = 11.7 ± 0.4 µM). Compound 8 exhibited weaker cytotoxicity toward the non-cancerous MCF-10A and WI-38 cell lines (IC₅₀ = 46 ± 3 and 37.4 ± 1.3 µM, respectively), although the magnitude of selectivity was cell-context dependent. Mechanistic investigations in MCF-7 cells revealed pronounced G2/M cell-cycle arrest (7.57% to 32.24%), inhibition of tubulin polymerization (IC₅₀ = 4.7 ± 0.2 µM), and EGFR kinase activity (IC₅₀ = 50 ± 3 nM). Flow-cytometric analysis showed an increase in total apoptotic cells from 2.71% to 33.19%, while LDH release increased 2.88-fold, indicating concomitant loss of membrane integrity. qRT-PCR demonstrated upregulation of BAX (7.9-fold), caspase-9 (8.8-fold), and p53 (4.7-fold) and downregulation of BCL-2 (0.27-fold), with corresponding protein-level changes confirmed by ELISA, providing complementary evidence for activation of the intrinsic apoptotic pathway. Molecular docking provided structural hypotheses for potential interactions of compound 8 within the tubulin colchicine-binding region and EGFR ATP-binding site. In vivo, compound 8 significantly suppressed tumor burden in the Ehrlich ascites carcinoma (EAC) mouse model, reducing viable tumor-cell counts by up to 72.4% and ascitic tumor volume by 85.3%. Treatment also ameliorated tumor-associated hepatic and renal dysfunction, oxidative stress, and inflammatory alterations, with histopathological and immunohistochemical findings supporting tissue recovery. Collectively, these findings identify compound 8 as a promising antiproliferative and antitumor lead and support further optimization and evaluation of this scaffold in more clinically relevant breast cancer models.
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BibTeX
@article{elzend2026development,
title = {{Development of 7-hydroxy-4-methylcoumarin-cyanoacrylate hybrids with antiproliferative activity against breast cancer cells: from molecular design to in vivo validation.}},
author = {Manar A El-Zend and Ibrahim M El-Deen and Zeinab Abdelkarim and Ibrahim M Alanazi and Samar Zuhair Alshawwa and Essa M Saied},
journal = {RSC advances},
year = {2026},
month = oct,
doi = {10.1039/d6ra06101j},
url = {https://europepmc.org/article/MED/42948722},
note = {CC BY},
}
RIS
TY - JOUR
TI - Development of 7-hydroxy-4-methylcoumarin-cyanoacrylate hybrids with antiproliferative activity against breast cancer cells: from molecular design to in vivo validation.
AU - Manar A El-Zend
AU - Ibrahim M El-Deen
AU - Zeinab Abdelkarim
AU - Ibrahim M Alanazi
AU - Samar Zuhair Alshawwa
AU - Essa M Saied
PY - 2026
DA - 2026/10/27
JO - RSC advances
DO - 10.1039/d6ra06101j
UR - https://europepmc.org/article/MED/42948722
AB - In the present study, a series of novel 6,8-dibromo-7-hydroxy-4-methylcoumarin-cyanoacrylate hybrids and their corresponding pyrazole derivatives were designed, synthesized, and evaluated for antiproliferative activity against breast cancer cells. Among the tested compounds, cyanoacrylate derivative 8 emerged as the most active analogue against MCF-7 cells (IC₅₀ = 5.9 ± 0.4 µM) and retained antiproliferative activity against MDA-MB-231 cells (IC₅₀ = 11.7 ± 0.4 µM). Compound 8 exhibited weaker cytotoxicity toward the non-cancerous MCF-10A and WI-38 cell lines (IC₅₀ = 46 ± 3 and 37.4 ± 1.3 µM, respectively), although the magnitude of selectivity was cell-context dependent. Mechanistic investigations in MCF-7 cells revealed pronounced G2/M cell-cycle arrest (7.57% to 32.24%), inhibition of tubulin polymerization (IC₅₀ = 4.7 ± 0.2 µM), and EGFR kinase activity (IC₅₀ = 50 ± 3 nM). Flow-cytometric analysis showed an increase in total apoptotic cells from 2.71% to 33.19%, while LDH release increased 2.88-fold, indicating concomitant loss of membrane integrity. qRT-PCR demonstrated upregulation of BAX (7.9-fold), caspase-9 (8.8-fold), and p53 (4.7-fold) and downregulation of BCL-2 (0.27-fold), with corresponding protein-level changes confirmed by ELISA, providing complementary evidence for activation of the intrinsic apoptotic pathway. Molecular docking provided structural hypotheses for potential interactions of compound 8 within the tubulin colchicine-binding region and EGFR ATP-binding site. In vivo, compound 8 significantly suppressed tumor burden in the Ehrlich ascites carcinoma (EAC) mouse model, reducing viable tumor-cell counts by up to 72.4% and ascitic tumor volume by 85.3%. Treatment also ameliorated tumor-associated hepatic and renal dysfunction, oxidative stress, and inflammatory alterations, with histopathological and immunohistochemical findings supporting tissue recovery. Collectively, these findings identify compound 8 as a promising antiproliferative and antitumor lead and support further optimization and evaluation of this scaffold in more clinically relevant breast cancer models.
SN - 2046-2069
ER -