Advanced Journal of Chemistry, Section A
5.9(Q2)
CiteScore
31
h-index

Structure-Based Design and Characterization of Cyclosenegalin Derivatives as Novel Breast Cancer Therapeutics

Document Type : Original Research Article

Authors

Jajang Japar Sodik 1
Kania Fajarwati 2
Farandina Suarantika 3
Taufik Muhammad Fakih 4
Rani Maharani 5
Dhania Novitasari 6

1 Department of Pharmaceutical Analysis and Medicinal Chemistry, Faculty of Pharmacy, Universitas Bhakti Kencana, Jalan Soekarno-Hatta No.754, Bandung, 40614, Indonesia

2 Department of Pharmaceutical Biology, Faculty of Pharmacy, Universitas Bhakti Kencana, Jalan Soekarno-Hatta No.754, Bandung, 40614, Indonesia

3 Pharmacist Professional Education Study Program (PPSP), Faculty of Mathematics and Natural Sciences, Universitas Islam Bandung, Jalan Batik Halus, Bandung, 40123, Indonesia

4 Department of Pharmacy, Faculty of Mathematics and Natural Sciences, Universitas Islam Bandung, Jalan Ranggagading, Bandung, 40116, Indonesia

5 Department of Pharmaceutical Analysis and Medicinal Chemistry, Faculty of Pharmacy, Universitas Padjadjaran, Jalan Raya Bandung Sumedang KM 21, Sumedang, 45363, Indonesia

6 Department of Chemistry, Faculty of Mathematics and Natural Sciences, Universitas Padjadjaran, Jalan Raya Bandung Sumedang KM 21, Sumedang, 45363, Indonesia

https://doi.org/10.48309/ajca.2026.560035.1971
Abstract
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.

Graphical Abstract

Structure-Based Design and Characterization of Cyclosenegalin Derivatives as Novel Breast Cancer Therapeutics

Keywords

Cyclosenegalin A
Solid-phase peptide synthesis
Molecular docking
MTT assay
Antiproliferative activity

Subjects

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Advanced Journal of Chemistry, Section A
Volume 9, Issue 6
June 2026
Pages 1048-1074

  • Receive Date 16 November 2025
  • Revise Date 06 December 2025
  • Accept Date 05 January 2026

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