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From Nature to Synthetic Compounds: Novel 1(N),2,3 Trisubstituted-5-oxopyrrolidines Targeting Multiple Myeloma Cells.
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- معلومة اضافية
- المصدر:
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
- بيانات النشر:
Original Publication: Basel, Switzerland : MDPI, [2000-
- الموضوع:
- نبذة مختصرة :
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.
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- Contributed Indexing:
Keywords: chiral separation; drug discovery; drug resistance; lactam; multiple myeloma; proteasome
- الرقم المعرف:
EC 3.4.25.1 (Proteasome Endopeptidase Complex)
0 (Proteasome Inhibitors)
0 (Esters)
0 (Antineoplastic Agents)
- الموضوع:
Date Created: 20221111 Date Completed: 20221114 Latest Revision: 20221117
- الموضوع:
20240628
- الرقم المعرف:
PMC9658545
- الرقم المعرف:
10.3390/ijms232113061
- الرقم المعرف:
36361848
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