Synthesis of New Biscoumarin Derivatives, In Vitro Cholinesterase Inhibition, Molecular Modelling and Antiproliferative Effect in A549 Human Lung Carcinoma Cells.

Mária Kožurková,Rastislav Jendželovský,Peter Fedoročko,Petr Bzonek,Jan Korábečný,Juraj Ševc,Ondrej Soukup,Nikola Novakova,Jana Vargová,Daniel Jun,Lucie Junova,Eva Konkoľová,Kamil Kuča,Jana Janočková,Veronika Ihnatova,Tomáš Kučera,Slávka Hamuľaková,Monika Hudáčová

doi:10.3390/ijms22083830

Abstract

A series of novel C4-C7-tethered biscoumarin derivatives (12a–e) linked through piperazine moiety was designed, synthesized, and evaluated biological/therapeutic potential. Biscoumarin 12d was found to be the most effective inhibitor of both acetylcholinesterase (AChE, IC50 = 6.30 µM) and butyrylcholinesterase (BChE, IC50 = 49 µM). Detailed molecular modelling studies compared the accommodation of ensaculin (well-established coumarin derivative tested in phase I of clinical trials) and 12d in the human recombinant AChE (hAChE) active site. The ability of novel compounds to cross the blood–brain barrier (BBB) was predicted with a positive outcome for compound 12e. The antiproliferative effects of newly synthesized biscoumarin derivatives were tested in vitro on human lung carcinoma cell line (A549) and normal colon fibroblast cell line (CCD-18Co). The effect of derivatives on cell proliferation was evaluated by MTT assay, quantification of cell numbers and viability, colony-forming assay, analysis of cell cycle distribution and mitotic activity. Intracellular localization of used derivatives in A549 cells was confirmed by confocal microscopy. Derivatives 12d and 12e showed significant antiproliferative activity in A549 cancer cells without a significant effect on normal CCD-18Co cells. The inhibition of hAChE/human recombinant BChE (hBChE), the antiproliferative activity on cancer cells, and the ability to cross the BBB suggest the high potential of biscoumarin derivatives. Beside the treatment of cancer, 12e might be applicable against disorders such as schizophrenia, and 12d could serve future development as therapeutic agents in the prevention and/or treatment of Alzheimer’s disease.

Highlights

IntroductionCoumarinsare areeither eithernatural naturalororsynthetic synthetic analogues oxygen-containing heterocyCoumarins analogues of of oxygen-containing heterocycles cles of a typical benzopyrone structure a rich electron count good charge of a typical benzopyrone structure with a with rich electron count and goodand charge transport transport properties [1].The coumarin backbone is used extensively in the synthesis of a properties [1]
The coumarin derivatives were synthesized from resorresorcinol methylation of cinol with with citric citric acid acid in inthe thepresence presenceof ofconcentrated concentratedsulfuric sulfuricacid acid[49]
The results showed that human umbilical vein endothelial cell (HUVEC) cell lines were more resistant to the coumarin derivatives than the tested commercially available drugs [13,55]

Summary

Introduction

The coumarin backbone is used extensively in the synthesis of a properties [1]. The coumarin backbone is used extensively in the synthesis of a wide range wide range ofmolecules functionalfor molecules fordiagnosis biologicaland diagnosis that as probes that of functional biological asand probes display a display variety arange variety range of biological such as anticoagulant, antineurodegenerative, anof biological activities,activities, such as anticoagulant, antineurodegenerative, antioxidant, tioxidant, anti-inflammatory, antidiabetic, antidepression, and antimicrobial anti-inflammatory, antidiabetic, antidepression, anti-cancer, anti-cancer, and antimicrobial effects [2,3,4,5,6]. Biscoumarins can interact with biomacrofeaturethat thatisisextensively extensively pursued in anti-cancer (Figure 1) [11,12,13,14,15].

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