Late-Stage Carboranylation of Nucleos(t)ides Enabled by Minisci and Pd-Catalyzed B-N Cross-Coupling Reactions: Toward the Synthesis of Carboranyl-Modified Oligonucleotides.

Authors

Yutong Zhou, Raghunath Bag, Dazhi Zhou, Yujie Jiang, Yingchuan Que, Ruoqian Xie, Ruowen Wang, Yangyan Li, Zhiming Li, Gang Chen

Published in

Journal of the American Chemical Society. Jun 22, 2026. Epub Jun 22, 2026.

Abstract

Carboranyl-modified nucleosides are promising boron-10 (¹⁰B) delivery agents for boron neutron capture therapy (BNCT), yet methods for directly forming B-C/B-N bonds at unprotected nucleosides are scarce. We report herein two operationally simple, orthogonal strategies for the late-stage installation of carboranyl units at heteroaromatic C(sp²) centers and exocyclic amino groups of native nucleosides, nucleotides, and analogues. The first method uses a visible-light-mediated Minisci-type radical reaction, where 9-meta-carboranyltrifluoroborate serves as a nucleophilic B(9)-vertex radical precursor to selectively forge C(sp²)-B bonds at the C⁸-position of guanine, C²-position of adenine, and C⁵-position of uracil. Theoretical calculations revealed that the selectivity for adenosine and uridine is substrate-dependent: in adenosine, C²-selectivity arises from steric repulsion that disfavors C⁸-addition, whereas in uridine, C⁵-selectivity is dictated by stabilizing interactions. The second strategy employs Pd-catalyzed Buchwald-Hartwig-type amination to form B-N bonds at the N⁶-position of adenosine, the N²-position of guanosine, and the N⁴-position of cytidine. Furthermore, carboranyl groups were successfully incorporated into DNA oligonucleotides at various positions via solid-phase synthesis. To assess their suitability for BNCT applications, ¹⁰B-enriched carboranyl-modified oligonucleotides, carboranyl-modified DNA aptamers (Sgc8c) targeting protein tyrosine kinase 7 (PTK7), along with ¹⁰B-enriched carboranyl-modified aptamers, were prepared. Cellular uptake studies showed that the aptamer-carborane conjugates effectively recognize and internalize into PTK7-overexpressing HCT116 cells, thereby providing a basis for future exploration of BNCT applications. These methods expand the chemical space of boron-rich nucleos(t)ides and represent a step toward the development of next-generation BNCT agents.

PMID:
42329658
Bibliographic data and abstract were imported from PubMed on 22 Jun 2026.

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