2. Academic Validation
  3. Ligand-based design and synthesis of new trityl histamine and trityl cysteamine derivatives as SIRT2 inhibitors for cancer therapy

Ligand-based design and synthesis of new trityl histamine and trityl cysteamine derivatives as SIRT2 inhibitors for cancer therapy

  • Eur J Med Chem. 2024 Mar 7:269:116302. doi: 10.1016/j.ejmech.2024.116302.
Mostafa M Badran 1,  Samar H Abbas 2,  Hiroshi Tateishi 3,  Yuki Maemoto 4,  Tsugumasa Toma 5,  Akihiro Ito 6,  Mikako Fujita 7,  Masami Otsuka 8,  Mohamed Abdel-Aziz 9,  Mohamed O Radwan 10
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, Faculty of Pharmacy, South Valley University, Qena, 83523, Egypt; Department of Medicinal Chemistry, Faculty of Pharmacy, Minia University, 61519-Minia, Egypt; Medicinal and Biological Chemistry Science Farm Joint Research Laboratory, Faculty of Life Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto, 862-0973, Japan. Electronic address: mostbadran@svu.edu.eg.
  • 2 Department of Medicinal Chemistry, Faculty of Pharmacy, Minia University, 61519-Minia, Egypt. Electronic address: samar_hafez@mu.edu.eg.
  • 3 Medicinal and Biological Chemistry Science Farm Joint Research Laboratory, Faculty of Life Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto, 862-0973, Japan; Research & Development, Hirata Corporation, 111 Hitotsugi Uekimachi, Kita-ku, Kumamoto, 861-0135, Japan. Electronic address: htateishi@kumamoto-u.ac.jp.
  • 4 Laboratory of Cell Signaling, School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, 192-0392, Japan. Electronic address: ymaemoto@toyaku.ac.jp.
  • 5 Medicinal and Biological Chemistry Science Farm Joint Research Laboratory, Faculty of Life Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto, 862-0973, Japan. Electronic address: 205y1021@st.kumamoto-u.ac.jp.
  • 6 Laboratory of Cell Signaling, School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, 192-0392, Japan. Electronic address: aito@toyaku.ac.jp.
  • 7 Medicinal and Biological Chemistry Science Farm Joint Research Laboratory, Faculty of Life Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto, 862-0973, Japan. Electronic address: mfujita@kumamoto-u.ac.jp.
  • 8 Medicinal and Biological Chemistry Science Farm Joint Research Laboratory, Faculty of Life Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto, 862-0973, Japan; Department of Drug Discovery, Science Farm Ltd., Kumamoto, 862-0976, Japan. Electronic address: motsuka@gpo.kumamoto-u.ac.jp.
  • 9 Department of Medicinal Chemistry, Faculty of Pharmacy, Minia University, 61519-Minia, Egypt. Electronic address: abulnil@hotmail.com.
  • 10 Medicinal and Biological Chemistry Science Farm Joint Research Laboratory, Faculty of Life Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto, 862-0973, Japan; Chemistry of Natural Compounds Department, Pharmaceutical and Drug Industries Research Division, National Research Centre, Dokki, Cairo, 12622, Egypt. Electronic address: mohamedosman251@gmail.com.
PMID: 38484678 DOI: 10.1016/j.ejmech.2024.116302
Abstract

The relentless pursuit of novel therapeutic agents against Cancer has led to the identification of multiple molecular targets, among which Sirtuin 2 (SIRT2) has garnered significant attention. This study presents an extensive SAR study of our reported trityl scaffold-based SIRT2 inhibitors. This study encompasses a range of different medicinal chemistry approaches to improve the activity of the lead compounds TH-3 and STCY1. The rationally designed and synthesized structures were confirmed using NMR and high-resolution mass spectroscopy before performing SIRT2 inhibition assay, NCI60 cytotoxicity test, and cell cycle analysis. Indeed, our strategies afforded hitherto unreported SIRT2 inhibitors with high activity, particularly 2a, 4a, 7c, and 7f. Remarkably, the presence of a lipophilic para substitution on the phenyl group of a freely rotating or a locked trityl moiety enhanced activity SIRT2 inhibition. Concomitantly, the synthesized compounds showed prominent activity against different Cancer lines from the NCI60 assay. Of interest, compound 7c stands out as a potent and highly selective antiproliferative agent against leukemia and colon Cancer panels. Furthermore, 7c treatment resulted in cell cycle arrest in MCF-7 cells at G2 phase and did not cause in vitro DNA cleavage.

Keywords

Anticancer activity; Ligand-based drug design; SIRT2 inhibitors; Structure-activity relationship; Trityl cysteamine.

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