Investigations of antiproliferative and antioxidant activity of β-lactam morpholino-1,3,5-triazine hybrids

Somayeh Ranjbari; Maryam Behzadi; Saghi Sepehri; Marzieh Dadkhah Aseman; Aliasghar Jarrahpour; Milad Mohkam; Younes Ghasemi; Amin Reza Akbarizadeh; Sedigheh Kianpour; Zeliha Atioğlu; Namık Özdemir; Mehmet Akkurt; S Masoud Nabavizadeh; Edward Turos

doi:10.1016/j.bmc.2020.115408

Investigations of antiproliferative and antioxidant activity of β-lactam morpholino-1,3,5-triazine hybrids

Bioorg Med Chem. 2020 Apr 15;28(8):115408. doi: 10.1016/j.bmc.2020.115408. Epub 2020 Mar 4.

Affiliations

¹ Department of Chemistry, College of Sciences, Shiraz University, Shiraz 71946-84795, Iran.
² Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
³ Department of Medicinal Chemistry, School of Pharmacy, Ardabil University of Medical Sciences, Ardabil, Iran.
⁴ Faculty of Chemistry, Kharazmi University, Tehran, Iran.
⁵ Department of Chemistry, College of Sciences, Shiraz University, Shiraz 71946-84795, Iran. Electronic address: [email protected].
⁶ Biotechnology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
⁷ Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran; Department of Biotechnology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran.
⁸ Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran.
⁹ Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran; Biotechnology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
¹⁰ İlke Education and Health Foundation, Cappadocia University, Cappadocia Vocational College, The Medical Imaging Techniques Program, 50420 Mustafapaşa, Ürgüp, Nevşehir, Turkey.
¹¹ Department of Physics, Ondokuz Mayıs University, TR-55139 Samsun, Turkey.
¹² Department of Physics, Faculty of Sciences, Erciyes University, 38039 Kayseri, Turkey.
¹³ 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: 32165076
DOI: 10.1016/j.bmc.2020.115408

Abstract

This article reports for the first time the synthesis of some novel β-lactam morpholino-1,3,5-triazine hybrids by a [2+2]-cycloaddition reaction of imines 7a-c, 9a-c and 11 with ketenes derived from substituted acetic acids. The reaction was totally diastereoselective, leading exclusively to the formation of cis-β-lactams 8a-l, 10a-f and 12a-c. The synthesized compounds were tested for activity towards SW1116, MCF-7 and HepG2 cancer cell lines and non-cancerous HEK-293 cell line by MTT assay. None of the compounds exert an observable effect on HepG2, MCF-7 and HEK-293 cells, but compounds 7b, 8f, 8g, 8l, 10c, and 10e exhibited excellent growth inhibitory activity (IC₅₀ < 5 µM) against SW 1116 cells, comparable to that of doxorubicin (IC₅₀ = 6.9 µM). An evaluation of the antioxidant potential of each of the compounds, performed by diphenylpicrylhydrazyl (DPPH) assay, indicated that 7b, 9a, 9b and 9c have strong free radical scavenging activity. UV absorption titration studies reveal that 7b, 8l, 8g and 8f interact strongly with calf-thymus DNA (CT-DNA) in the order of 8l > 7b > 8f > 8g. Collectively, the in vitro capabilities of some of these morpholino-triazine imines and β-lactams suggest possible applications to development of new antioxidants and DNA binding therapeutics.

Keywords: Antioxidants; DNA-binding; Diastereoselective; Morpholino-1,3,5-triazines; Staudinger reaction; β-lactams.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / pharmacology*
Antioxidants / chemical synthesis
Antioxidants / pharmacology*
Cell Line
Drug Design*
Inhibitory Concentration 50
Models, Molecular
Molecular Structure
Structure-Activity Relationship
Triazines / chemistry
Triazines / pharmacology*
beta-Lactams / chemical synthesis
beta-Lactams / pharmacology*

Substances

Antineoplastic Agents
Antioxidants
Triazines
beta-Lactams