Identification of novel anti-cancer agents by the synthesis and cellular screening of a noscapine-based library.

Abstract

Noscapine is a natural product first isolated from the opium poppy (Papaver somniferum L.) with anticancer properties. In this work, we report the synthesis and cellular screening of a noscapine-based library. A library of novel noscapine derivatives was synthesized with modifications in the isoquinoline and phthalide scaffolds. The so generated library, consisting of fifty-seven derivatives of the natural product noscapine, was tested against MDA-MB-231 breast cancer cells in a cellular proliferation assay (with a Z' > 0.7). The screening resulted in the identification of two novel noscapine derivatives as inhibitors of MDA cell growth with IC50 values of 5 µM and 1.5 µM, respectively. Both hit molecules have a five-fold and seventeen-fold higher potency, compared with that of lead compound noscapine (IC50 26 µM). The identified active derivatives retain the tubulin-binding ability of noscapine. Further testing of both hit molecules, alongside the natural product against additional cancer cell lines (HepG2, HeLa and PC3 cells) confirmed our initial findings. Both molecules have improved anti-proliferative properties when compared to the initial natural product, noscapine.

• Authors: Faezeh Nemati, Iris Bischoff-Kont, Peyman Salehi, Samad Nejad-Ebrahimi, Maryam Mohebbi, Morteza Bararjanian, Nasim Hadian, Zahra Hassanpour, Yvonne Jung, Sofie Schaerlaekens, Daniel Lucena-Agell, María A Oliva, Robert Fürst, Hamid R Nasiri
• Journal: Bioorganic chemistry (Bioorg Chem) Vol. 115 Pg. 105135 (10 2021) ISSN: 1090-2120 [Electronic] United States
• PMID: 34303039 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 Elsevier Inc. All rights reserved.

Chemical References

• Antineoplastic Agents
• Benzofurans
• Isoquinolines
• Small Molecule Libraries
• Tubulin
• Noscapine
• phthalide
• isoquinoline

Topics

• Antineoplastic Agents (chemical synthesis, metabolism, pharmacology)
• Benzofurans (chemistry)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Drug Design
• Humans
• Isoquinolines (chemistry)
• Noscapine (chemistry)
• Papaver (chemistry, metabolism)
• Protein Binding
• Small Molecule Libraries (chemistry, metabolism, pharmacology)
• Tubulin (chemistry, metabolism)