1,1'-Bis(thymine)ferrocene Nucleoside: Synthesis and Study of Its Stereoselective Formation.

The synthesis of 1,1'-bis(thymine)ferrocene nucleoside is reported. This nucleoside was obtained in a two-step synthetic methodology including a Michael addition reaction of 1,1'-bis(3-chloropropionyl)ferrocene with thymine to afford the bis(thymine) adduct in 44 % yield. In the second step, the two prochiral carbonyl functionalities in the Michael adduct were reduced to hydroxyl groups with sodium borohydride. This apparently straightforward reaction proceeds in a highly stereoselective fashion to yield the title ferrocenyl nucleoside as a racemic mixture that consists of the R,R and the S,S isomers. The absolute configuration of the chiral carbon atoms in the nucleoside was assigned on the basis of single-crystal X-ray diffraction analysis of the methyl derivative. Furthermore, the mechanism of reduction of the bis(thymine) adduct was investigated by using DFT calculations. The two critical minima, pre-reactive complex, and semi-reduced intermediate, as well as two corresponding transition states were located to support the observed stereoselectivity. The redox properties of 1,1'-bis(thymine)ferrocene nucleoside, its precursor, and congeners were investigated using cyclic voltammetry. For the title compound a reversible redox process was found at a low potential of -30 mV versus FcH/FcH+ (FcH=Fe(η5 -C5 H5 )2 ) as the reference redox couple.

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

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.

Can silicon make an excellent drug even better? An in vitro and in vivo head-to-head comparison between loperamide and its silicon analogue sila-loperamide.

Loperamide (1a), an opioid receptor agonist, is in clinical use as an antidiarrheal agent. Carbon/silicon exchange (sila-substitution) at the 4-position of the piperidine ring of 1a (R3 COH→R3 SiOH) leads to sila-loperamide (1b). Sila-loperamide was synthesized in a multistep procedure, starting from triethoxyvinylsilane and taking advantage of the 4-methoxyphenyl (MOP) unit as a protecting group for silicon. The in vitro and in vivo pharmacokinetic (PK) and pharmacodynamic (PD) properties of the C/Si analogues 1a and 1b were determined and compared. Despite significant differences in the in vitro PK properties of loperamide and sila-loperamide regarding clearance, permeability, and efflux, both compounds exhibited nearly identical in vivo PK profiles. The increase in metabolic stability of the silicon compound 1b observed in vitro seems to be counterbalanced by an increase in efflux and diminished permeability compared to the parent carbon compound 1a. Overall, sila-loperamide exhibits high unbound clearance (CLu ), leading to a significant decrease in unbound concentration (Cu ) and unbound area under the curve (AUCu ) after oral exposure, compared to loperamide. In vitro and in vivo metabolic studies showed an altered profile of biotransformation for the silicon compound 1b, leading to the formation of a more polar and quickly cleared metabolite and preventing the formation of the silicon analogue of the neurotoxic metabolite observed for the parent carbon compound 1a. These differences can be correlated with the different chemical properties of the C/Si analogues 1a and 1b. This study provides some of the most detailed insights into the effects of a carbon/silicon switch and how this carbon/silicon exchange affects overall drug properties.