Group of Nucleic Acid Chemistry

Systematic SAR activity study in this field further implicates the effect of various structural alterations at the purine heterocyclic base of the pharmacophore. For example, N-substitution of the exocyclic amino groups at purine bases exposed enhanced antiviral effects against cytomegaloviruses and herpes zoster viruses. This direction requires further attention. Partial ring opening of purine in all types of ANP also led to novel type of antivirals which are to be further investigated in detail. One of the present tasks is improvement of their synthetic accessibility.

Polar character of ANP causes their limited transport to the target cells. It is aimed to develop general synthons which would enable to routinely synthesize novel types of prodrugs and to follow the changes in their cellular transport.

5-Substituted pyrimidine ANPs and related compounds will be synthesized with the aim to find novel thymidine phosphorylase inhibitors as potential anti-angiogenic agents for cancer chemotherapy.

Another project deals with the synthesis of guanidino analogues of 2- or 6-amino group in purine nucleosides, acyclic nucleosides and ANP. It is aimed at the comparison with their counterparts in biological screening systems.

The investigation of antiviral activities is performed in collaboration with the Rega Institute, Katholic University Leuven (Belgium) and with Gilead Sciences (USA). It focuses on identification of novel types of antivirals, in particular compounds active against the mutants resis­tant against commonly used drugs. Further studies are directed to the investi­gation of antitumor activity of selected purine acyclic nucleotide analogs PMEA and PMEDAP and their derivatives, and the mechanism of this activity.

The immunomodula­tory activity of acyclic nucleotide analogues which was discovered earlier, is the subject of a study focused on the effect of ANP modification on cytokine formation. It is performed in collaboration with the Institute of Experimental Medicine, Academy of Sciences, Prague.

The metal coordination studies of selected acyclic phosphonates, their comparison with the behavior of natural nucleotides and the possible biological implications are subject of a joint project with the University of Basel sponsored by COST programme of the European Union.

Synthesis of racemic 2-hydroxy-4- and 2-hydroxy-5-(hydroxymethyl)cyclohexane and 2-hydroxy-4,4- and 2-hydroxy-5,5-bis(hydroxymethyl)cyclohexane nucleoside analogues. Inexpensive cyclohexane epoxides are used as starting material.

Synthesis of carbocyclic analogues of 4-C-(hydroxymethyl)hexopyranosyl nucleosides. The multistep synthesis starts from 3-O-benzyl-1,2-O-isopropylidene-α-D-glucofuranose-5,6-O-sulfate.

We cordially invite talented and hard-working organic chemistry students interested in medicinal chemistry to join our group and to participate in our projects.