فهرست نشریات علمی دسترسی آزاد ایران

Triple-negative breast cancer (TNBC), which lacks ER, PR, and HER2 expression, remains challenging to treat due to the absence of targeted therapeutic options and frequent chemoresistance. Cyclosenegalin A, a cyclic heptapeptide, offers a compact β-turn scaffold amenable to selective receptor engagement but displays only moderate native activity. In this study, computational modeling, chemical synthesis, and cell-based evaluation were integrated to develop cyclosenegalin-derived peptides as anticancer candidates. A 29-member analog panel was sketched in ChemDraw, converted to 3D in Chem3D, and subjected to geometry and frequency optimization using Gaussian (DFT B3LYP/3-21G) to afford electronically stable conformers. Molecular docking with AutoDock Vina against ERα (PDB: 3ERT), PR (2OVH), EGFR kinase (2ITY), and the IκBα/NF-κB complex (1NFI) identified two multi-target leads, A14 and A21, which exhibited consistently lower predicted binding free energies and extensive hydrogen-bond and hydrophobic contact networks at key pocket residues. Both peptides were synthesized via Fmoc-based solid-phase assembly, macrocyclized under dilute conditions, purified by RP-HPLC to >95% purity, and structurally confirmed by ESI-MS (calcd/obs: A14, 757.89 Da / [M+H]⁺ 761–762; A21, 762.87 Da / [M+H]⁺ 762). Antiproliferative activity evaluated using the MTT assay against luminal T-47D and TNBC MDA-MB-231 cells showed that A21 was the most potent analog, with IC₅₀ values of 387.99 ± 10.2 µg/mL (T-47D) and 143.15 ± 6.4 µg/mL (MDA-MB-231), outperforming A14 (710.28 ± 12.4 µg/mL and 220.05 ± 8.6 µg/mL, respectively). Both peptides demonstrated preferential cytotoxicity toward the TNBC subtype, with A21 offering a favorable balance of potency and subtype selectivity. Collectively, these findings validate a docking-led design pipeline for cyclosenegalin-based cyclic peptides and identify A21 as a tractable lead for further optimization, mechanistic studies focused on EGFR/NF-κB pathway modulation, and future in vivo investigations.