Discovery of the Biginelli hybrids as novel caspase-9 activators in apoptotic machines: Lipophilicity, molecular docking study, influence on angiogenesis gene and miR-21 expression levels

Nenad Janković; Jovana Trifunović Ristovski; Milan Vraneš; Aleksandar Tot; Jelena Petronijević; Nenad Joksimović; Tatjana Stanojković; Marija Đorđić Crnogorac; Nina Petrović; Ivana Boljević; Ivana Z Matić; Goran A Bogdanović; Momir Mikov; Zorica Bugarčić

doi:10.1016/j.bioorg.2019.02.026

Discovery of the Biginelli hybrids as novel caspase-9 activators in apoptotic machines: Lipophilicity, molecular docking study, influence on angiogenesis gene and miR-21 expression levels

Bioorg Chem. 2019 May:86:569-582. doi: 10.1016/j.bioorg.2019.02.026. Epub 2019 Feb 12.

Authors

Affiliations

¹ Department of Chemistry, Faculty of Science, University of Kragujevac, Radoja Domanovića 12, 34000 Kragujevac, Serbia. Electronic address: nenad.jankovic@kg.ac.rs.
² Department of Pharmacology, Toxicology and Clinical Pharmacology, Faculty of Medicine, University of Novi Sad, Hajduk Veljkova 3, 21000 Novi Sad, Serbia.
³ Department of Chemistry, Biochemistry and Environmental Protection, University of Novi Sad, Trg Dositeja Obradovića 3, 21000 Novi Sad, Serbia.
⁴ Department of Chemistry, Faculty of Science, University of Kragujevac, Radoja Domanovića 12, 34000 Kragujevac, Serbia.
⁵ Institute for Oncology and Radiology of Serbia, Pasterova 14, 11000 Belgrade, Serbia.
⁶ Institute for Oncology and Radiology of Serbia, Pasterova 14, 11000 Belgrade, Serbia; Vinča Institute of Nuclear Science, University of Belgrade, P.O. Box 522, 11001 Belgrade, Serbia.
⁷ Vinča Institute of Nuclear Science, University of Belgrade, P.O. Box 522, 11001 Belgrade, Serbia.

PMID: 30782575
DOI: 10.1016/j.bioorg.2019.02.026

Abstract

In order to investigate potential therapeutically agents, novel products of Biginelli reaction (4a-l) were synthesized and exposed to cytotoxic and caspase activities, angiogenesis, cell cycle distribution, gene and microRNA expression levels, lipophilicity assessment and docking study. Among the twelve novel compounds (4a-l) evaluated for the cytotoxic activity, five of them (4c, 4d, 4f, 4k and 4l) that showed excellent activity on the tested cell lines (HeLa, LS174 and A549) were selected for further evaluation. Interestingly, compound 4f has up to three times higher selectivity index (SI) towards cancer cells than cisplatin (on HeLa, LS174 and A549 SI = 18.2, 13.5 and 11.2, respectively). The obtained results from cell cycle distribution and caspase activity indicate that tested compounds (4c, 4d, 4f, 4k and 4l) promoted caspase-9 activation, implicated in the intrinsic pathway of apoptosis. Lipophilicity of 4a-l was determinate by using reversed-phase high-performance liquid chromatography.

Keywords: Apoptosis; Biginelli scaffold; Caspase-9; Lipophilicity; Selectivity index.

Publication types

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

MeSH terms

A549 Cells
Aldehydes / chemical synthesis
Aldehydes / chemistry
Aldehydes / pharmacology
Antineoplastic Agents, Phytogenic / chemical synthesis
Antineoplastic Agents, Phytogenic / chemistry
Antineoplastic Agents, Phytogenic / pharmacology*
Apoptosis / drug effects*
Caspase 9 / metabolism*
Cell Proliferation / drug effects
Cells, Cultured
Cisplatin / chemistry
Cisplatin / pharmacology
Dose-Response Relationship, Drug
Drug Discovery*
Drug Screening Assays, Antitumor
HeLa Cells
Humans
Hydrophobic and Hydrophilic Interactions
MicroRNAs / antagonists & inhibitors*
MicroRNAs / genetics
Molecular Docking Simulation*
Molecular Structure
Neovascularization, Pathologic / drug therapy*
Neovascularization, Pathologic / genetics
Neovascularization, Pathologic / pathology
Oxazocines / chemical synthesis
Oxazocines / chemistry
Oxazocines / pharmacology
Pyrimidinones / chemical synthesis
Pyrimidinones / chemistry
Pyrimidinones / pharmacology
Structure-Activity Relationship

Substances

Aldehydes
Antineoplastic Agents, Phytogenic
MIRN21 microRNA, human
MicroRNAs
Oxazocines
Pyrimidinones
Caspase 9
Cisplatin