Cymantrene, cyrhetrene and ferrocene nucleobase conjugates: Synthesis, structure, computational study, electrochemistry and antitrypanosomal activity

A series of cymantrene- and cyrhetrene-nucleobase derivatives together with the ferrocene-adenine conjugates have been prepared and characterized. The key step in synthesis of all compounds involved an N1-regioselective Michael addition of the respective nucleobase nucleophile to an in situ generated organometallic acryloyl electrophile reagent. The mechanism of this reaction was examined by DFT calculations. A single crystal X-ray diffraction study of cymantrene-adenine (5) were carried out and revealed that the plane of the adenine and the cyclopentadienyl group are almost perpendicular to each other. The cyclic voltammetry measurements on the cymantrenyl-nucleobases showed irreversible behavior for all compounds which can be explain by a ligand exchange of carbonyls with the donor functionality of the nucleobases. Cymantrene and cyrhetrene ketone nucleobases displayed significant in vitro activity against Trypanosoma brucei a causative parasite of sleeping sickness. They showed no cytotoxicity against human HL-60 cancer cells.