Pyrazole-based lamellarin O analogues: synthesis, biological evaluation and structure-activity relationships

Karolina Dzedulionytė; Nina Fuxreiter; Ekaterina Schreiber-Brynzak; Asta Žukauskaitė; Algirdas Šačkus; Verena Pichler; Eglė Arbačiauskienė

doi:10.1039/d3ra00972f

Pyrazole-based lamellarin O analogues: synthesis, biological evaluation and structure-activity relationships

RSC Adv. 2023 Mar 10;13(12):7897-7912. doi: 10.1039/d3ra00972f. eCollection 2023 Mar 8.

Authors

Karolina Dzedulionytė¹, Nina Fuxreiter², Ekaterina Schreiber-Brynzak², Asta Žukauskaitė³, Algirdas Šačkus^{1

4}, Verena Pichler², Eglė Arbačiauskienė¹

Affiliations

¹ Department of Organic Chemistry, Faculty of Chemical Technology, Kaunas University of Technology Radvilėnų pl. 19 LT-50254 Kaunas Lithuania egle.arbaciauskiene@ktu.lt.
² Department of Pharmaceutical Sciences, Division of Pharmaceutical Chemistry, Faculty of Life Sciences, University of Vienna Althanstraße 14 1090 Vienna Austria verena.pichler@univie.ac.at.
³ Department of Chemical Biology, Faculty of Science, Palacký University Šlechtitelů 27 CZ-78371 Olomouc Czech Republic.
⁴ Institute of Synthetic Chemistry, Faculty of Chemical Technology, Kaunas University of Technology K. Baršausko g. 59 LT-51423 Kaunas Lithuania.

Abstract

A library of pyrazole-based lamellarin O analogues was synthesized from easily accessible 3(5)-aryl-1H-pyrazole-5(3)-carboxylates which were subsequently modified by bromination, N-alkylation and Pd-catalysed Suzuki cross-coupling reactions. Synthesized ethyl and methyl 3,4-diaryl-1-(2-aryl-2-oxoethyl)-1H-pyrazole-5-carboxylates were evaluated for their physicochemical property profiles and in vitro cytotoxicity against three human colorectal cancer cell lines HCT116, HT29, and SW480. The most active compounds inhibited cell proliferation in a low micromolar range. Selected ethyl 3,4-diaryl-1-(2-aryl-2-oxoethyl)-1H-pyrazole-5-carboxylates were further investigated for their mode of action. Results of combined viability staining via Calcein AM/Hoechst/PI and fluorescence-activated cell sorting data indicated that cell death was triggered in a non-necrotic manner mediated by mainly G2/M-phase arrest.