Three-component synthesis of chromeno β-lactam hybrids for inflammation and cancer screening

Nassim Borazjani; Saghi Sepehri; Maryam Behzadi; Aliasghar Jarrahpour; Javad Ameri Rad; Maryam Sasanipour; Milad Mohkam; Younes Ghasemi; Amin Reza Akbarizadeh; Carole Digiorgio; Jean Michel Brunel; Mohammad Mehdi Ghanbari; Gyula Batta; Edward Turos

doi:10.1016/j.ejmech.2019.06.036

Three-component synthesis of chromeno β-lactam hybrids for inflammation and cancer screening

Eur J Med Chem. 2019 Oct 1:179:389-403. doi: 10.1016/j.ejmech.2019.06.036. Epub 2019 Jun 17.

Affiliations

¹ Department of Chemistry, College of Sciences, Shiraz University, Shiraz, 71946-84795, Iran.
² Department of Medicinal Chemistry, School of Pharmacy, Ardabil University of Medical Sciences, Ardabil, Iran.
³ Pharmaceutical Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
⁴ Department of Chemistry, College of Sciences, Shiraz University, Shiraz, 71946-84795, Iran. Electronic address: jarahpor@shirazu.ac.ir.
⁵ Biotechnology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
⁶ Pharmaceutical Research Center, Shiraz University of Medical Sciences, Shiraz, Iran; Department of Biotechnology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran.
⁷ Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran.
⁸ Centre de Recherche en Cancérologie de Marseille (CRCM), CNRS, UMR7258, Institut Paoli Calmettes, Ai X-Marseille Université, UM 105, Inserm, U1068, Faculté de Pharmacie, Bd Jean Moulin, F-13385, Marseille, France.
⁹ Department of Chemistry, Sarvestan Branch, Islamic Azad University, Sarvestan, Iran.
¹⁰ Department of Chemistry, University of Debrecen, Debrecen, Egyetem Tér 1, 4032, Debrecen, Hungary.
¹¹ Center for Molecular Diversity in Drug Design, Discovery, and Delivery, Department of Chemistry, CHE 205, 4202 East Fowler Avenue, University of South Florida, Tampa, FL, 33620, USA.

PMID: 31260892
DOI: 10.1016/j.ejmech.2019.06.036

Abstract

Highly diastereoselective synthesis of chromeno β-lactam hybrids was achieved by an efficient one-pot three-component reaction. With this procedure, the desired β-lactam products were obtained in good yields and with exclusive cis stereoselection, by combining a variety of benzaldehydes, malononitrile, and either 5,5-dimethylcyclohexane-1,3-dione or 4-hydroxycoumarin in the presence of 1,4-diazabicyclo [2.2.2]octane under reflux conditions. These adducts were structurally characterized on the basis of IR, 1D and 2D NMR spectra, X-ray analysis, H-H COSY and H-C HSQC two-dimensional NMR experiments, and elemental analysis. Each of the synthesized compounds was screened for anti-inflammatory and anticancer activities. β-Lactams 5b and 8b showed a 53.4 and 19.8 anti-inflammatory ratio, respectively, and 5b appeared more active than the well-known dexamethasone corticosteroid used for the treatment of rheumatoid and skin inflammation. β-Lactams 5a, 5b, 5e, 5f, 5g, 8c, 8j and 8p also showed good antitumor activity against the SW1116 (colon cancer) cell line without notable cytotoxicity towards the HepG2 control cell line.

Keywords: Anti-inflammatory; Anticancer; Colon cancer; Cytotoxicity; DABCO; β-Lactams.

MeSH terms

Animals
Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis
Anti-Inflammatory Agents, Non-Steroidal / chemistry
Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Benzopyrans / chemistry
Benzopyrans / pharmacology*
Cell Proliferation / drug effects
Cell Survival / drug effects
Dose-Response Relationship, Drug
Drug Evaluation, Preclinical
Drug Screening Assays, Antitumor
Hep G2 Cells
Humans
Inflammation / drug therapy*
Mice
Molecular Structure
Neoplasms / drug therapy*
RAW 264.7 Cells
Structure-Activity Relationship
Tumor Cells, Cultured
beta-Lactams / chemistry
beta-Lactams / pharmacology*

Substances

Anti-Inflammatory Agents, Non-Steroidal
Antineoplastic Agents
Benzopyrans
beta-Lactams