دورية أكاديمية
أعرض في EDS

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

التفاصيل البيبلوغرافية
العنوان: Ligand-based design and synthesis of new trityl histamine and trityl cysteamine derivatives as SIRT2 inhibitors for cancer therapy.
المؤلفون: Badran MM; 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., Abbas SH; Department of Medicinal Chemistry, Faculty of Pharmacy, Minia University, 61519-Minia, Egypt. Electronic address: samar_hafez@mu.edu.eg., Tateishi H; 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., Maemoto Y; 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., Toma T; 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., Ito A; 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., Fujita M; 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., Otsuka M; 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., Abdel-Aziz M; Department of Medicinal Chemistry, Faculty of Pharmacy, Minia University, 61519-Minia, Egypt. Electronic address: abulnil@hotmail.com., Radwan MO; 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.
المصدر: European journal of medicinal chemistry [Eur J Med Chem] 2024 Apr 05; Vol. 269, pp. 116302. Date of Electronic Publication: 2024 Mar 07.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Editions Scientifiques Elsevier Country of Publication: France NLM ID: 0420510 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1768-3254 (Electronic) Linking ISSN: 02235234 NLM ISO Abbreviation: Eur J Med Chem Subsets: MEDLINE
أسماء مطبوعة: Publication: Paris : Editions Scientifiques Elsevier
Original Publication: Paris, S.E.C.T. [etc.]
مواضيع طبية MeSH: Antineoplastic Agents*/chemistry , Neoplasms*, Humans ; Structure-Activity Relationship ; Sirtuin 2 ; Histamine ; Cysteamine ; Ligands ; Molecular Structure ; Cell Proliferation ; Drug Screening Assays, Antitumor
مستخلص: 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.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier Masson SAS. All rights reserved.)
فهرسة مساهمة: Keywords: Anticancer activity; Ligand-based drug design; SIRT2 inhibitors; Structure-activity relationship; Trityl cysteamine
المشرفين على المادة: EC 3.5.1.- (Sirtuin 2)
820484N8I3 (Histamine)
5UX2SD1KE2 (Cysteamine)
0 (Ligands)
0 (Antineoplastic Agents)
EC 3.5.1.- (SIRT2 protein, human)
تواريخ الأحداث: Date Created: 20240314 Date Completed: 20240408 Latest Revision: 20240408
رمز التحديث: 20240408
DOI: 10.1016/j.ejmech.2024.116302
PMID: 38484678
قاعدة البيانات: MEDLINE
الوصف
تدمد:1768-3254
DOI:10.1016/j.ejmech.2024.116302