From Nature to Synthetic Compounds: Novel 1(N),2,3 Trisubstituted-5-oxopyrrolidines Targeting Multiple Myeloma Cells.

Publisher: MDPI Country of Publication: Switzerland NLM ID: 101092791 Publication Model: Electronic Cited Medium: Internet ISSN: 1422-0067 (Electronic) Linking ISSN: 14220067 NLM ISO Abbreviation: Int J Mol Sci Subsets: MEDLINE

Original Publication: Basel, Switzerland : MDPI, [2000-

Multiple Myeloma*/drug therapy ; Antineoplastic Agents*/therapeutic use; Humans ; Proteasome Endopeptidase Complex/metabolism ; Cell Line, Tumor ; Proteasome Inhibitors/pharmacology ; Proteasome Inhibitors/chemistry ; Esters

The insurgence of drug resistance in treating Multiple Myeloma (MM) still represents a major hamper in finding effective treatments, although over the past decades new classes of drugs, such as proteasome inhibitors and immunomodulatory drugs, have been discovered. Recently, our research team, within a Nature-Aided Drug Discovery project, isolated from Hibiscus Sabdariffa L. calyces the secondary metabolite called Hib-ester which possesses antiproliferative properties against human multiple myeloma RPMI 8226 cells, reduces migration and cell invasion and inhibits proteasome without neurotoxic effects. In the present study, we explored the chemical spaces of the hit compound Hib-ester. We explored the structure-activity relationships (SAR), and we optimized the scaffold through sequentially modifying Hib-ester subunits. Compound screening was performed based on cytotoxicity against the RPMI 8226 cells to assess the potential efficacy toward human MM. The ability of the most effective molecules to inhibit the proteasome was evaluated and the binding mode of the most promising compounds in the proteasome chymotrypsin binding pocket was deciphered through molecular modeling simulations. Compounds 13 and 14 are more potent than Hib-ester, demonstrating that our strategy was suitable for the identification of a novel chemotype for developing possible drug candidates and hopefully widening the drug armamentarium against MM.
Competing Interests: This work was performed without any commercial or financial relationships that could be interpreted as a conflict of interest.

Semin Oncol. 2016 Dec;43(6):676-681. (PMID: 28061985)
Cancers (Basel). 2018 Jun 04;10(6):. (PMID: 29867053)
Blood. 2012 Oct 4;120(14):2817-25. (PMID: 22833546)
Chirality. 2015 Mar;27(3):228-34. (PMID: 25564994)
Molecules. 2019 Jul 09;24(13):. (PMID: 31323932)
Org Biomol Chem. 2004 Feb 7;2(3):397-401. (PMID: 14747868)
Expert Opin Drug Discov. 2017 Dec;12(12):1253-1269. (PMID: 28971706)
J Chromatogr A. 2011 Aug 12;1218(32):5414-22. (PMID: 21397238)
Molecules. 2020 Dec 19;25(24):. (PMID: 33352660)
Blood. 2008 Mar 15;111(6):2962-72. (PMID: 18332230)
Molecules. 2021 Oct 31;26(21):. (PMID: 34771006)
Br J Hosp Med (Lond). 2017 Feb 2;78(2):C21-C27. (PMID: 28165783)
PLoS One. 2013;8(1):e53263. (PMID: 23308178)
Chirality. 2016 May;28(5):434-40. (PMID: 27095007)
Eur J Med Chem. 2016 Nov 29;124:649-665. (PMID: 27614411)
ACS Med Chem Lett. 2019 Jan 21;10(4):615-620. (PMID: 30996806)
Molecules. 2020 Feb 19;25(4):. (PMID: 32093112)
Chirality. 2013 Nov;25(11):814-22. (PMID: 24038285)
Jpn J Clin Oncol. 2018 Sep 1;48(9):785-793. (PMID: 30102324)
Science. 2016 Aug 5;353(6299):594-8. (PMID: 27493187)
J Pharm Biomed Anal. 2017 Sep 10;144:41-51. (PMID: 28118957)

Keywords: chiral separation; drug discovery; drug resistance; lactam; multiple myeloma; proteasome

EC 3.4.25.1 (Proteasome Endopeptidase Complex)
0 (Proteasome Inhibitors)
0 (Esters)
0 (Antineoplastic Agents)

Date Created: 20221111 Date Completed: 20221114 Latest Revision: 20221117

20240628

PMC9658545

10.3390/ijms232113061

36361848