Design, synthesis and anticancer activity of new monastrol analogues bearing 1,3,4-oxadiazole moiety

Fatma A F Ragab; Sahar M Abou-Seri; Salah A Abdel-Aziz; Abdallah M Alfayomy; Mohamed Aboelmagd

doi:10.1016/j.ejmech.2017.06.026

Design, synthesis and anticancer activity of new monastrol analogues bearing 1,3,4-oxadiazole moiety

Eur J Med Chem. 2017 Sep 29:138:140-151. doi: 10.1016/j.ejmech.2017.06.026. Epub 2017 Jun 15.

Authors

Fatma A F Ragab¹, Sahar M Abou-Seri¹, Salah A Abdel-Aziz², Abdallah M Alfayomy³, Mohamed Aboelmagd⁴

Affiliations

¹ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo, P.O. Box, 11562, Egypt.
² Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Al-Azhar University, Assiut, 71524, Egypt.
³ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Al-Azhar University, Assiut, 71524, Egypt. Electronic address: ph_alfayomy@yahoo.com.
⁴ National Center for Natural Products Research, School of Pharmacy, The University of Mississippi, University, MS, 38677, USA; Pharmacognosy Department, National Research Center, Dokki, Giza, 12622, Egypt.

PMID: 28667871
DOI: 10.1016/j.ejmech.2017.06.026

Abstract

A series of dihydropyrimidine (DHPM) derivatives bearing 1,3,4-oxadiazole moiety was designed and synthesized as monastrol analogues. The new compounds were screened for their cytotoxic activity toward 60 cancer cell lines according to NCI (USA) protocol. Seven compounds were further examined against the most sensitive cell lines, leukemia HL-60(TB) and MOLT-4. The most active compounds were 9m against HL-60(TB) (IC₅₀ = 56 nM) and 9n against MOLT-4 (IC₅₀ = 80 nM), more potent than monastrol (IC₅₀ = 147 and 215 nM, respectively). Cell cycle analysis of HL-60(TB) cells treated with 9m and MOLT-4 cells treated with 9n showed cell cycle arrest at G2/M phase and pro-apoptotic activity as indicated by annexin V-FITC staining.

Keywords: 1,3,4-Oxadiazole; Anticancer activity; Apoptosis; Cell cycle arrest; Dihydropyrimidine.

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects
Cell Line, Tumor
Cell Proliferation / drug effects
Cell Survival / drug effects
Dose-Response Relationship, Drug
Drug Design*
Drug Screening Assays, Antitumor
Humans
Molecular Docking Simulation
Molecular Structure
Oxadiazoles / chemistry
Oxadiazoles / pharmacology*
Pyrimidines / chemical synthesis
Pyrimidines / chemistry
Pyrimidines / pharmacology*
Structure-Activity Relationship
Thiones / chemical synthesis
Thiones / chemistry
Thiones / pharmacology*

Substances

Antineoplastic Agents
Oxadiazoles
Pyrimidines
Thiones
1,3,4-oxadiazole
monastrol