Diverse synthetic approaches towards C1′-branched acyclic nucleoside phosphonates

• Published in: Organic & biomolecular chemistry Vol. 19; no. 32; pp. 6958 - 6963
• Main Authors: Kal ic, Filip, Dra ínský, Martin, Janeba, Zlatko
• Format: Journal Article
• Language: English
• Published: CAMBRIDGE Royal Soc Chemistry 28.08.2021; Royal Society of Chemistry
• Subjects: Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antiviral Agents - chemical synthesis; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Bases (nucleic acids); Biological activity; Chemistry; Chemistry, Organic; Cyclic nucleotides; Intermediates; Molecular Structure; Nucleosides; Nucleosides - chemical synthesis; Nucleosides - chemistry; Nucleosides - pharmacology; Nucleotides; Organophosphonates - chemical synthesis; Organophosphonates - chemistry; Organophosphonates - pharmacology; Phosphonates; Physical Sciences; Science & Technology; MEDICINAL CHEMISTRY; NUCLEOTIDE ANALOGS; REMDESIVIR; VIRUS; PRODRUG; GS-5734; EBOLA; DERIVATIVES; INHIBIT; TENOFOVIR ALAFENAMIDE
• ISSN: 1477-0520; 1477-0539; 1477-0539
• DOI: 10.1039/d1ob00751c

Acyclic nucleoside phosphonates (ANPs) represent a significant class of antiviral, anticancer, and antiprotozoal compounds. It is therefore highly desirable to have diverse synthetic routes leading towards these molecules. In the past, many structural modifications were explored, but surprisingly, the field of C1′-branched ANPs has been neglected with only a handful of articles reporting their synthesis. Herein we describe and compare five convenient approaches leading to key synthetic 6-chloropurine ANPs bearing the 9-phosphonomethoxyethyl (PME) moiety branched at the C1′ position. These intermediates can be further vastly diversified into target C1′-branched ANPs bearing either natural or unnatural nucleobases. The importance of C1′-branched ANPs is emphasized by their analogy with C1′-substituted cyclic nucleotides (such as remdesivir, a broad-spectrum antiviral agent) and evaluation of their biological activity ( e.g. antiviral, antineoplastic, and antiprotozoal) will be a tempting subject of further research. Five diverse synthetic methods leading to 6-chloropurine ANPs branched at C1′ position were developed/optimized. These key intermediates can be used for the synthesis of a library of C1′-branched ANPs for evaluation of their biological properties.