Synthesis of Boron-Containing Nucleoside Analogs

Abstract

Over the last century, nucleoside-based therapeutics have demonstrated remarkable effectiveness in the treatment of a wide variety of diseases from cancer to HIV. In addition, boron-containing drugs have recently emerged as an exciting and fruitful avenue for medicinal therapies. However, borononucleosides have largely been unexplored in the context of medicinal applications. Herein, we report the synthesis, isolation, and characterization of two novel boron-containing nucleoside compound libraries which may find utility as therapeutic agents. Our synthetic strategy employs efficient one-step substitution reactions between a diverse variety of nucleoside scaffolds and an assortment of n-alkyl potassium trifluoroborate-containing electrophiles. We demonstrated that these alkylation reactions are compatible with cyclic and acyclic nucleoside substrates, as well as increasing alkyl chain lengths. Furthermore, regioselective control of product formation can be readily achieved through manipulation of base identity and reaction temperature conditions.

Figure 1

Conversion of boronic acid from a neutral, trigonal planar species to an anionic, tetrahedral species.

Figure 2

Current FDA-approved boron-containing drugs.

Figure 3

(i) Example of FDA-approved nucleoside analogs; anti-HIV and Hepatitis B drugs, including cyclic azidothymidine (AZT) and acyclic adefovir, respectively. (ii) Two acyclic borononucleoside analogs previously reported to exhibit anti-HIV properties (1 and 2). Thymidine borononucleoside analogue 3 behaves as a weak substrate toward human TMP kinase.

Scheme 1. Synthesis of Boronic Acid-Adefovir Analogs(naNuc)

Compound identification key: n = alkyl chain length, a = boronic acid, Nuc (nucleobase) = CP (6-Chloropurine); DCP (2,6-Dichloropurine); ACP (2-Amino-6-chloropurine); or A (Adenine). Compound 7d (2-(6-aminopurin-9-yl)ethanol) is commercially available.

Figure 4

Final compound library of adefovir-boronic acid nucleoside analogs (naNuc). Isolated yields reported. All compound purity values ≥95% by quantitative NMR (qNMR). Compound Identification Key: n = alkyl chain length, a = boronic acid, Nuc (nucleobase) = CP (6-Chloropurine); DCP (2,6-Dichloropurine); ACP (2-Amino-6-chloropurine); or A (Adenine).

Scheme 2. Formation of Boron-Containing Nucleoside Analogs Utilizing Base and Temperature-Dependent Regioselective Control

Compound identification key: N = nucleobase-substituted, n = alkyl chain length, a = boronic acid, c = pinacolborane, and Nuc (nucleoside) = T (Thymidine).

Figure 5

First generation library of boron-containing nucleoside analogs. Isolated yields reported. All compound purity values >95% by quantitative NMR (qNMR). Compound identification key: N = nucleobase-substituted, n = alkyl chain length, a = boronic acid, c = pinacolborane, Nuc (nucleoside) = T (Thymidine); U (Uridine); S (Stavudine); L (Lamivudine); or E (Emtricitabine).