Cymantrenyl-Nucleobases: Synthesis, Anticancer, Antitrypanosomal and Antimicrobial Activity Studies
Artur Jabłoński,
Karolina Matczak,
Aneta Koceva-Chyła,
Kamil Durka,
Dietmar Steverding,
Katarzyna Jakubiec-Krześniak,
Jolanta Solecka,
Damian Trzybiński,
Krzysztof Woźniak,
Vanesa Andreu,
Gracia Mendoza,
Manuel Arruebo,
Krzysztof Kochel,
Barbara Krawczyk,
Dominik Szczukocki,
Konrad Kowalski
Affiliations
Artur Jabłoński
Department of Organic Chemistry, Faculty of Chemistry, University of Łódź, Tamka 12, 91-403 Łódź, Poland
Karolina Matczak
Department of Medical Biophysics, Faculty of Biology and Environmental Protection, University of Łódź, Pomorska 141/143, 90-236 Łódź, Poland
Aneta Koceva-Chyła
Department of Medical Biophysics, Faculty of Biology and Environmental Protection, University of Łódź, Pomorska 141/143, 90-236 Łódź, Poland
Kamil Durka
Department of Medical Biophysics, Faculty of Biology and Environmental Protection, University of Łódź, Pomorska 141/143, 90-236 Łódź, Poland
Dietmar Steverding
Bob Champion Research & Education Building, Norwich Medical School, University of East Anglia, Norwich Research Park, Norwich NR4 7UQ, UK
Katarzyna Jakubiec-Krześniak
National Institute of Public Health-National Institute of Hygiene, Chocimska 24, 00-791 Warszawa, Poland
Jolanta Solecka
National Institute of Public Health-National Institute of Hygiene, Chocimska 24, 00-791 Warszawa, Poland
Damian Trzybiński
Biological and Chemical Research Centre, Department of Chemistry, University of Warsaw, Żwirki and Wigury 101, 02-089 Warszawa, Poland
Krzysztof Woźniak
Biological and Chemical Research Centre, Department of Chemistry, University of Warsaw, Żwirki and Wigury 101, 02-089 Warszawa, Poland
Vanesa Andreu
Department of Chemical Engineering. Aragon Institute of Nanoscience (INA), University of Zaragoza, Campus Río Ebro-Edificio I+D, C/ Poeta Mariano Esquillor S/N, 50018 Zaragoza, Spain
Gracia Mendoza
Department of Chemical Engineering. Aragon Institute of Nanoscience (INA), University of Zaragoza, Campus Río Ebro-Edificio I+D, C/ Poeta Mariano Esquillor S/N, 50018 Zaragoza, Spain
Manuel Arruebo
Department of Chemical Engineering. Aragon Institute of Nanoscience (INA), University of Zaragoza, Campus Río Ebro-Edificio I+D, C/ Poeta Mariano Esquillor S/N, 50018 Zaragoza, Spain
Krzysztof Kochel
Department of Medical Biophysics, Faculty of Biology and Environmental Protection, University of Łódź, Pomorska 141/143, 90-236 Łódź, Poland
Barbara Krawczyk
Faculty of Chemistry, Department of Inorganic and Analytical Chemistry, University of Łódź, Tamka 12, 91-403 Łódź, Poland
Dominik Szczukocki
Faculty of Chemistry, Department of Inorganic and Analytical Chemistry, University of Łódź, Tamka 12, 91-403 Łódź, Poland
Konrad Kowalski
Department of Organic Chemistry, Faculty of Chemistry, University of Łódź, Tamka 12, 91-403 Łódź, Poland
The synthesis of four cymantrene-5-fluorouracil derivatives (1–4) and two cymantrene-adenine derivatives (5 and 6) is reported. All of the compounds were characterized by spectroscopic methods and the crystal structure of two derivatives (1 and 6), together with the previously described cymantrene-adenine compound C was determined by X-ray crystallography. While the compounds 1 and 6 crystallized in the triclinic P-1 space group, compound C crystallized in the monoclinic P21/m space group. The newly synthesized compounds 1–6 were tested together with the two previously described cymantrene derivatives B and C for their in vitro antiproliferative activity against seven cancer cell lines (MCF-7, MCF-7/DX, MDA-MB-231, SKOV-3, A549, HepG2m and U-87-MG), five bacterial strains Staphylococcus aureus (methicillin-sensitive, methicillin-resistant and vancomycin-intermediate strains), Staphylococcus epidermidis, and Escherichia coli, including clinical isolates of S. aureus and S. epidermidis, as well as against the protozoan parasite Trypanosoma brucei. The most cytotoxic compounds were derivatives 2 and C for A549 and SKOV-3 cancer cell lines, respectively, with 50% growth inhibition (IC50) values of about 7 µM. The anticancer activity of the cymantrene compounds was determined to be due to their ability to induce oxidative stress and to trigger apoptosis and autophagy in cancer cells. Three derivatives (1, 4 and 5) displayed promising antitrypanosomal activity, with GI50 values in the low micromolar range (3–4 µM). The introduction of the 5-fluorouracil moiety in 1 enhanced the trypanocidal activity when compared to the activity previously reported for the corresponding uracil derivative. The antibacterial activity of cymantrene compounds 1 and C was within the range of 8–64 µg/mL and seemed to be the result of induced cell shrinking.
