PhD Student: Procedure no. DSMBBC/2026/08: Design and Synthesis of Novel Nucleoside Analogues with Biological Importance

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PhD Student: Procedure no. DSMBBC/2026/08: Design and Synthesis of Novel Nucleoside Analogues with Biological Importance Sintesi in italiano (traduzione automatica): Il progetto di ricerca dottorale si concentra sulla progettazione, sintesi e valutazione biologica di nuovi analoghi di nucleosidi con potenziale attività anticancro e antivirale. Il candidato lavorerà presso un'organizzazione internazionale e si occuperà di modifiche strutturali degli analoghi di adenosina, seguite da valutazioni biologiche per stabilire relazioni struttura-attività. È richiesta una laurea in Chimica o un campo correlato. Le principali mansioni includono la sintesi di nuovi derivati, studi di citotossicità su linee cellulari umane e la valutazione dell'attività antivirale contro virus clinicamente rilevanti. Il progetto prevede anche collaborazioni con laboratori di screening per la valutazione dell'attività antivirale dei composti sintetizzati. This doctoral research project focuses on the design, synthesis and biological evaluation of novel nucleoside analogues with potential anticancer and antiviral activity. In our preliminary studies, we synthesized a series of adenosine analogues exhibiting promising anticancer and antiviral activity (manuscript submitted to Bioorganic Chemistry). The most active compounds, bearing bulky hydrophobic substituents at the N6 and C8 positions of the purine ring, showed potent and selective cytotoxicity independent of p53 protein activity. In contrast, the activity of reference anticancer agents, including cisplatin and the antileukemic nucleoside analogues fludarabine and cladribine, were strongly influenced by p53 status. These findings suggest that these novel compounds may represent promising candidates for overcoming p53-related mechanisms of cancer drug resistance. In addition, a separate group of less cytotoxic adenosine analogues, modified in the N6 position of the purine ring, exhibited selective antiviral activity against human parainfluenza virus type 3 (HPIV-3) and human adenovirus type 5 (AdV5), both of which are important causative agents of respiratory tract infections. Building on these findings, one of the primary objectives of this doctoral project will be the design and synthesis of new adenosine derivatives, followed by comprehensive biological evaluation to establish structure–activity relationships (SAR). The planned structural modifications of adenosine will include: Replacement of the ribose moiety with 2'-deoxyribose or arabinose, as well as additional modifications of the sugar component, such as halogen substitution; • synthesis of homologous series containing different aliphatic chain lengths and other hydrophobic groups at the N6 and C8 positions and/or a chlorine atom at position 2; • further modifications of the heterocyclic moiety, e.g., introduction of hydrophobic sulfide groups by exchange reaction of halogenated derivatives with appropriate long-chain thiols. In the second stage of the project, the doctoral student will focus on design and synthesis of novel derivatives of tubercidin (7-deazadenosine), a naturally occurring nucleoside antibiotic isolated from Streptomyces species. Tubercidin and structurally related natural antibiotics, including toyocamycin and sangivamycin, exhibit pronounced cytotoxic activity in numerous cellular models and represent attractive scaffolds for anticancer drug development. 7-Deazadenosine is synthesized in a coupling reaction between an appropriate heterocyclic base and a sugar derivative. Such an approach led to the two isomeric derivatives: the typical N7-substituted product and the less common/more unusual N1-substituted product. Preliminary studies demonstrated selective and promising cytotoxic activity, warranting further investigation within this doctoral project. Alternatively, additional classes of nucleoside derivatives may also be designed, synthesized, and biologically evaluated during the course of the PhD project. Biological evaluation will include cytotoxicity studies using normal human fibroblasts (BJ and MRC-5), cancer cell lines (A-431, A-549, NCI-H1299, and HCT116), and the p53-deficient HCT116 p53-/- cell line to assess potency, selectivity, and the influence of p53 status. Antiviral studies will be conducted through an established collaboration with the Screening Laboratory at the Institute of Medical Biology, PAS. The antiviral activity of the synthesized compounds will be evaluated against a panel of clinically relevant DNA and RNA viruses, including herpes simplex virus type 1 (HSV-1), HPIV-3, encephalomyocarditis virus (EMCV), human cytomegalovirus (HCMV), and AdV5. Annuncio in inglese. Fonte: Euraxess (Commissione europea).