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

The synthesis of four cymantrene-5-fluorouracil derivatives (-) and two cymantrene-adenine derivatives ( and ) is reported. All of the compounds were characterized by spectroscopic methods and the crystal structure of two derivatives ( and ), together with the previously described cymantrene-adenine compound was determined by X-ray crystallography. While the compounds and crystallized in the triclinic P-1 space group, compound crystallized in the monoclinic 2₁/ space group. The newly synthesized compounds - were tested together with the two previously described cymantrene derivatives and 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 (methicillin-sensitive, methicillin-resistant and vancomycin-intermediate strains), , and , including clinical isolates of and , as well as against the protozoan parasite . The most cytotoxic compounds were derivatives and for A549 and SKOV-3 cancer cell lines, respectively, with 50% growth inhibition (IC) 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 (, and ) displayed promising antitrypanosomal activity, with GI values in the low micromolar range (3-4 µM). The introduction of the 5-fluorouracil moiety in enhanced the trypanocidal activity when compared to the activity previously reported for the corresponding uracil derivative. The antibacterial activity of cymantrene compounds and was within the range of 8-64 µg/mL and seemed to be the result of induced cell shrinking.