Cymantrene, Cyrhetrene and Ferrocene Nucleobase Conjugates: Synthesis, Structure, Computational Study, Electrochemistry and Antitrypanosomal Activity

Abstract

A series of 11 cymantrene and cyrhetrene nucleobase conjugates, together with the hitherto unreported N7 isomer of a ferrocene-adenine conjugate were synthesised and characterised. The synthetic approach involved a Michael addition reaction of in-situ-generated acryloylcymantrene, acryloylcyrhetrene and acryloylferrocene with the canonical nucleobases thymine, uracil and adenine. The mechanism of these reactions was investigated by means of density functional theory calculations. The products were characterised by spectroscopic and electrochemical methods. The molecular structure of one cymantrene-adenine conjugate in the solid state was determined by single-crystal X-ray structure analysis, confirming the N9-substitution of the adenine moiety. It was found that the molecule adopts a bent conformation with the adenine and cyclopentadienyl planes in almost perpendicular orientation. The cymantrenyl nucleobases showed an irreversible redox behaviour, which is associated with ligand-exchange reactions of the radical cationic species. The newly synthesised compounds were also tested for their activity against the protozoan parasite Trypanosoma brucei and human myeloid leukaemia HL-60 cells. Some compounds showed promising antitrypanosomal activity, and most of them were non-toxic to HL-60 cells. It was also found that cymantrene and cyrhetrene ketone nucleobases were more active than their alcohol congeners. These findings indicate the potential of cymantrenyl and cyrhetrenyl nucleobase conjugates as possible lead compounds for future antitrypanosomal drug development.