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Design, synthesis and evaluation of novel indirubin-based N-hydroxybenzamides, N-hydroxypropenamides and N-hydroxyheptanamides as histone deacetylase inhibitors and antitumor agents.

التفاصيل البيبلوغرافية
العنوان: Design, synthesis and evaluation of novel indirubin-based N-hydroxybenzamides, N-hydroxypropenamides and N-hydroxyheptanamides as histone deacetylase inhibitors and antitumor agents.
المؤلفون: Anh DT; Hanoi University of Pharmacy, 13-15 Le Thanh Tong, Hanoi, Viet Nam., Hai PT; Hanoi University of Pharmacy, 13-15 Le Thanh Tong, Hanoi, Viet Nam., Dung DTM; Hanoi University of Pharmacy, 13-15 Le Thanh Tong, Hanoi, Viet Nam., Dung PTP; Hanoi University of Pharmacy, 13-15 Le Thanh Tong, Hanoi, Viet Nam., Huong LT; Hanoi University of Pharmacy, 13-15 Le Thanh Tong, Hanoi, Viet Nam., Park EJ; College of Pharmacy, Chungbuk National University, 194-31, Osongsaengmyung-1, Heungdeok, Cheongju, Chungbuk 28160, Republic of Korea., Jun HW; College of Pharmacy, Chungbuk National University, 194-31, Osongsaengmyung-1, Heungdeok, Cheongju, Chungbuk 28160, Republic of Korea., Kang JS; Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju, Chungbuk, Republic of Korea., Kwon JH; Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju, Chungbuk, Republic of Korea., Tung TT; Faculty of Pharmacy, PHENIKAA University, Hanoi 12116, Viet Nam; PHENIKAA Institute for Advanced Study (PIAS), PHENIKAA University, Hanoi 12116, Viet Nam., Han SB; College of Pharmacy, Chungbuk National University, 194-31, Osongsaengmyung-1, Heungdeok, Cheongju, Chungbuk 28160, Republic of Korea. Electronic address: shan@chungbuk.ac.kr., Nam NH; Hanoi University of Pharmacy, 13-15 Le Thanh Tong, Hanoi, Viet Nam. Electronic address: namnh@hup.edu.vn.
المصدر: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2020 Nov 15; Vol. 30 (22), pp. 127537. Date of Electronic Publication: 2020 Sep 08.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Elsevier Science Ltd Country of Publication: England NLM ID: 9107377 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1464-3405 (Electronic) Linking ISSN: 0960894X NLM ISO Abbreviation: Bioorg Med Chem Lett Subsets: MEDLINE
أسماء مطبوعة: Publication: Oxford : Elsevier Science Ltd
Original Publication: Oxford ; New York : Pergamon Press, c1991-
مواضيع طبية MeSH: Amides/*pharmacology , Antineoplastic Agents/*pharmacology , Histone Deacetylase 2/*antagonists & inhibitors , Histone Deacetylase 6/*antagonists & inhibitors , Histone Deacetylase Inhibitors/*pharmacology, Amides/chemical synthesis ; Amides/chemistry ; Antineoplastic Agents/chemical synthesis ; Antineoplastic Agents/chemistry ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Dose-Response Relationship, Drug ; Drug Design ; Drug Screening Assays, Antitumor ; Histone Deacetylase 2/metabolism ; Histone Deacetylase 6/metabolism ; Histone Deacetylase Inhibitors/chemical synthesis ; Histone Deacetylase Inhibitors/chemistry ; Humans ; Indoles/chemistry ; Indoles/pharmacology ; Molecular Structure ; Structure-Activity Relationship
مستخلص: Several novel indirubin-based N-hydroxybenzamides, N-hydropropenamides and N-hydroxyheptanamides (4a-h, 7a-h, 10a-h) were designed using a fragment-based approach with structural features extracted from several previously reported HDAC inhibitors, such as SAHA (vorinostat), MGCD0103 (mocetinostat), nexturastat A and PXD-101 (belinostat). The biological results reveal that our compounds showed excellent cytotoxicity toward three common human cancer cell lines (SW620, PC-3 and NCI-H23) with IC 50 values ranging from 0.09 to 0.007 µM. The cytotoxicity of the compounds was equipotent or even up to 10-times more potent than adriamycin and up to 205-times more potent than SAHA. Among the series of N-hydroxypropenamides, compounds 10a-d were the most potent HDAC inhibitors as well as cytotoxicity toward the cell lines tested. In addition, the strong inhibitory activites toward HDAC of our compounds were observed with IC 50 values of below-micromolar range. Especially, compound 4a inhibited HDAC6 with an IC 50 value of 29-fold lower than that against HDAC2 isoform. Representative compounds 4a and 7a were found to significantly arrest SW620 cells at G0/G1 phase. Compounds 7a and 10a were found to strongly induce apoptosis in SW620 cells. Docking studies revealed some important features affecting the selectivity against HDAC6 isoform. The results clearly demonstrate the potential of the indirubin-hydroxamic acid hybrids and these compounds should be very promising for further development.
(Copyright © 2020 Elsevier Ltd. All rights reserved.)
فهرسة مساهمة: Keywords: ADMET profiling; Docking simulation; Histone deacetylase (HDAC) inhibitors; Hydroxamic acids; N-hydroxybenzamide; N-hydroxypropenamide
المشرفين على المادة: 0 (Amides)
0 (Antineoplastic Agents)
0 (Histone Deacetylase Inhibitors)
0 (Indoles)
EC 3.5.1.98 (HDAC2 protein, human)
EC 3.5.1.98 (HDAC6 protein, human)
EC 3.5.1.98 (Histone Deacetylase 2)
EC 3.5.1.98 (Histone Deacetylase 6)
V86L8P74GI (indirubin)
تواريخ الأحداث: Date Created: 20200911 Date Completed: 20210622 Latest Revision: 20210622
رمز التحديث: 20221213
DOI: 10.1016/j.bmcl.2020.127537
PMID: 32916298
قاعدة البيانات: MEDLINE
الوصف
تدمد:1464-3405
DOI:10.1016/j.bmcl.2020.127537