Mgr. Kamil Paruch, Ph.D.

Project: NUCLANGS - Nucleoside analogs with targeted biological activity

Person in Charge: doc. RNDr. Ctibor Mazal, CSc.

Host institution: Chemistry Department, Faculty of Science, Masaryk University

Country of Origin: Czech Republic

Country of scientific activity: USA

Project duration: 36 months

Scientific panel: Chemistry

Abstract:

The project includes organic synthesis and biological evaluation of carbocyclic nucleoside analogs that are envisioned to selectively modulate the activity of specific components of DNA-processing molecular machinery (namely DNA polymerase alpha and ribonucleotide reductase). Combined with e.g. the selective CHK1 inhibitor we developed recently, they might induce the synthetic lethal phenotype in cancer cells. Also proposed is the synthesis of aza- and carbocyclic analogs of the DNA polymerase alpha inhibitor – dehydroaltenusine. The overarching concept of the proposed research is finding novel agents that would be useful in the treatment of cancer. The proposed research efforts will be part of a compact medicinal chemistry program that will include several research groups located mainly in the newly built campus of Masaryk University in Brno.

The ongoing project summary:

The goals of the first year of the proceject were the following:
Establishing of fully functional laboratory; molecular modelling; docking of target molecules into the
protein (models); initiation of chemical syntheses; preparation of key intermediates.
We have managed to establish a functional organic synthesis laboratory and equip it with small
instruments, laboratory equipment and some indispensable chemicals. More expensive
instrumentation wil be purchased via the ICRC project, in which the PI (KP) is involved.

One of the key aspects is the personnel of the research team. In general, students are not very
attracted to natural sciences, especially to (organic) chemistry, which can present a significant
limiting factor. Nevertheless, the PI managed to build an independent research team; currently
consisting of: leader (KP), 2 doctoral, 1 MSc, and 4 BSc. students. The manpower is at thsi point
therefore sufficient for successful realization of the project. In the following year, further expansion
of the team is planned, namely with 1-2 docotral students and one postdoctoral researcher.

We have initiated some syntheses, namely the targets within series 2 and 3. We have prepared not
only the key intermediates, but also the final target compound 23 (series 3) and its monocrystal so
that its structure could be unequivocally confirmed by X-ray crystallography. Its synthesis consists of
a multistep sequence that contains hiherto unknown non-trivial intermediates (e.g. compounds 27
and other).

Within series 2, we have successfully prepared gram quantities of suitably substituted advanced
intermediate (structurally related to compound 17). Subsequent cyclizations and final deprotections
are expected to yield (racemic) target structures 7b and 8.

Publication of the results in quality peer-reviewed periodicals is planned in the following year.