Nucleoside Scaffolds and Carborane Clusters for Boron Neutron Capture Therapy: Developments and Future Perspective

Area of Science:

• Medicinal Chemistry
• Radiochemistry
• Oncology

Background:

• Carborane nucleosides are crucial boron delivery agents for boron neutron capture therapy (BNCT).
• These compounds are recognized as substrates by human thymidine kinase 1 (hTK1), an enzyme vital for BNCT efficacy.
• Early development focused on the first generation of carboranyl thymidine analogues (3CTAs) with hydrocarbon spacers.

Purpose of the Study:

• To evaluate and improve the performance of carborane nucleosides as boron delivery agents for BNCT.
• To explore structure-activity relationships (SAR) for developing next-generation 3CTAs.
• To enhance tumor cellular uptake, retention, and phosphorylation rates.

Main Methods:

• Synthesis and modification of carboranyl nucleosides, including variations in spacer units and hydrophilic group attachments.
• Evaluation of phosphorylation rates, tumor cellular uptake, and retention of developed compounds.
• Investigation of structure-activity relationships (SAR) to guide further development.

Main Results:

• Development of three generations of 3CTAs, with modifications aimed at improving interactions with hTK1.
• Incorporation of modified spacers (e.g., ethyleneoxide, polyhydroxyl, triazole, tetrazole) and hydrophilic groups enhanced properties.
• Transformation of lipophilic closo-carboranes to hydrophilic nidocarboranes and development of amino acid prodrugs further improved biological and physicochemical characteristics.

Conclusions:

• Systematic modifications of carboranyl nucleosides have led to significant advancements in 3CTA development for BNCT.
• The SAR studies provide a roadmap for designing more effective boron delivery agents.
• Future research can leverage these findings to develop the third generation of 3CTAs with enhanced therapeutic potential.