Quantum chemical design, synthesis and biological properties of organometallic nucleobase derivatives – OrDeN

Project Head: Valerije Vrček, Faculty of Pharmacy and Biochemistry, University of Zagreb

Duration: 1 Mar 2017 – 28 Feb 2021

Funding: HRK 937,000.00

Abstract

Organometallic nucleobase derivatives (OrDeNs) correspond to a new generation of conjugates in which metallocenes are linked to the basic structural elements of heredity. Due to their electrophoric and bioactive properties, OrDeNs are of use in (bio)analytical and medicinal chemistry. The preparation of OrDeNs is based on the copulation reaction between the organometallic part with a heterocyclic base, by using different linkers. The choice of fragments usually follows the target of the ever-growing diversity of structural motifs. In this project all modifications of OrDeNs structures will be directed toward derivatives with marked electrochemical and biological properties. An extensive quantum chemical study will precede the experimental part of the research. By using the density functional theory methods (DFT methods) the chemical properties of OrDeNs, such as stability/reactivity, reduction potential, substituent and solvation effects, can be predicted. These parameters can assist in designing OrDeNs with enhanced bioactivity. A benchmark study in evaluating DFT methods will be performed. DFT methods which are superior in the description of biorganometallic models (for which experimental data are known) will be used to study OrDeNs. New structural elements in OrDeNs include the functional linker, a series of homoannular substituents, selected metallocene-nucleobase pairs, and bis-adducts. A new linker type, which connects the two constitutional parts in OrDeNs, is a carbonyl group and its reduced forms, hydroxyl and methylene groups. The electron communication between metallocene and nucleobase depends, therefore, on the oxidation state and hybridization of the functional linker, and can be tuned by using selected substituents at the cyclopentadienyl ring. The interplay between quantum chemical estimates and electrochemical/biological profiles for model compounds will advance the (re)design of new metallocenes-nucleobase pairs and bis-adducts of OrDeNs.