Cymantrenyl-Nucleobases: Synthesis, Anticancer, Antitrypanosomal and Antimicrobial Activity Studies

The synthesis of four cymantrene-5-fluorouracil derivatives (1–4) and two cymantrene-adeninederivatives (5and6) is reported. All of the compounds were characterized by spectroscopic methodsand the crystal structure of two derivatives (1and6), together with the previously describedcymantrene-adenine compoundCwas determined by X-ray crystallography. While the compounds1and6crystallized in the triclinic P-1 space group, compoundCcrystallized in the monoclinicP21/mspace group. The newly synthesized compounds1–6were tested together with the twopreviously described cymantrene derivativesBandCfor theirin vitroantiproliferative activityagainst seven cancer cell lines (MCF-7, MCF-7/DX, MDA-MB-231, SKOV-3, A549, HepG2m andU-87-MG), five bacterial strainsStaphylococcus aureus(methicillin-sensitive, methicillin-resistant andvancomycin-intermediate strains),Staphylococcus epidermidis, andEscherichia coli, including clinicalisolates ofS. aureusandS. epidermidis, as well as against the protozoan parasiteTrypanosoma brucei.The most cytotoxic compounds were derivatives2andCfor A549 and SKOV-3 cancer cell lines,respectively, with 50% growth inhibition (IC50) values of about 7μM. The anticancer activity of thecymantrene compounds was determined to be due to their ability to induce oxidative stress and totrigger apoptosis and autophagy in cancer cells. Three derivatives (1,4and5) displayed promisingantitrypanosomal activity, with GI50values in the low micromolar range (3–4μM). The introductionof the 5-fluorouracil moiety in1enhanced the trypanocidal activity when compared to the activitypreviously reported for the corresponding uracil derivative. The antibacterial activity of cymantrenecompounds1andCwas within the range of 8–64μg/mL and seemed to be the result of inducedcell shrinking.