Journal Article

(E)-4-(4-Acrylamidophenoxy)-N-Methylpicolinamides as b-Raf/VEGFR-2 Inhibitors with Antiangiogenic Activity in HUVEC and Zebrafish Model

Telukutla, Srinivasa Reddy, Plebanski, Magdalena, Vankudoth, Jayaram, Velma, Ganga Reddy, Wlodkowic, Donald, Akunuri, Ravikumar, Privér, Steven, Kamal, Ahmed, Yedla, Poornachandra, Bhargava, Suresh K., Grewal, Ajmer Singh, Pabbaraja, Srihari

2026

Overview

Pharmacophore hybridization is a well-established strategy for developing novel anticancer agents with improved biological profiles. In this study, a new series of (E)-4-(4-acrylamidophenoxy)-N-methylpicolinamide derivatives has been rationally designed by hybridizing key structural features of sorafenib with cinnamide pharmacophores and subsequently synthesized. The antiproliferative activities of the synthesized compounds were evaluated against a panel of human cancer cell lines, including A549 (lung), DU-145 (prostate), SKOV3 (ovarian), and HepG2 (liver), along with non-cancerous Hek293T cells. In comparison with the standard drug sorafenib, most of the (E)-4-(4-acrylamidophenoxy)-N-methylpicolinamides demonstrated significant antiproliferative activity, with specificity toward the HepG2 (liver cancer) cell line, and no effect on the noncancerous cells (Hek293T). Among them, compound 5f, the derivative containing a trifluoromethyl-substituted cinnamoyl moiety was identified as the lead candidate, exhibiting an IC50 of 5.3 µM towards HepG2 (liver) cancer cells, comparable to the reference drug sorafenib. Enzyme inhibition studies showed that compound 5f inhibited both b-Raf and VEGFR-2 with IC50 values of 1.45 and 0.37 µM, respectively. Furthermore, compound 5f suppressed angiogenesis in vitro and in vivo, as evidenced by the tube formation assay using HUVECs and in transgenic zebrafish Tg(fli1a:EGFP) models, respectively. Mechanistic studies indicated that compound 5f induced apoptosis in HepG2 cells through mitochondrial membrane depolarization and increased ROS generation. Molecular docking studies supported experimental findings and showed that 5f can interact with catalytically active residues via hydrogen-bonding interactions. Overall, these results highlight the potential of compound 5f as a promising dual target therapeutic lead with dual direct anticancer and antiangiogenic properties.

• Publisher: MDPI AG,Multidisciplinary Digital Publishing Institute (MDPI)
• Subject: Angiogenesis / Angiogenesis - drug effects / Angiogenesis Inhibitors - chemical synthesis / Angiogenesis Inhibitors - chemistry / Angiogenesis Inhibitors - pharmacology / Animals / anticancer / Antidiabetics / Antineoplastic Agents - chemical synthesis / Antineoplastic Agents - chemistry / Antineoplastic Agents - pharmacology / apoptosis / Apoptosis - drug effects / b-Raf inhibitors / Cell growth / Cell Line, Tumor / Cell Proliferation - drug effects / Cytotoxicity / Drug resistance / Enzymes / Growth factors / HEK293 Cells / Hep G2 Cells / Human Umbilical Vein Endothelial Cells - drug effects / Humans / Kinases / Liver cancer / Molecular Docking Simulation / Ovarian cancer / Picolinic Acids - chemical synthesis / Picolinic Acids - chemistry / Picolinic Acids - pharmacology / Protein Kinase Inhibitors - chemical synthesis / Protein Kinase Inhibitors - chemistry / Protein Kinase Inhibitors - pharmacology / Proto-Oncogene Proteins B-raf - antagonists & inhibitors / Proto-Oncogene Proteins B-raf - metabolism / Sorafenib - pharmacology / Structure-Activity Relationship / Toxicity / Vascular Endothelial Growth Factor Receptor-2 - antagonists & inhibitors / Vascular Endothelial Growth Factor Receptor-2 - metabolism / VEGFR-2 inhibitors / Zebrafish