Synthesis and biological evaluation of phosphoramidate prodrugs of two analogues of 2-deoxy-d-ribose-1-phosphate directed to the discovery of two carbasugars as new potential anti-HIV leads

Abstract

2-Deoxy-α-d-ribose-1-phosphate is of great interest as it is involved in the biosynthesis and/or catabolic degradation of several nucleoside analogues of biological and therapeutic relevance. However due to the lack of a stabilising group at its 2-position, it is difficult to synthesize stable prodrugs of this compound. In order to overcome this lack of stability, the synthesis of carbasugar analogues of 2-deoxyribose-1-phosphate was envisioned. Herein the preparation of a series of prodrugs of two carbocyclic analogues of 2-deoxyribose-1-phosphate using the phosphoramidate ProTide technology, along with their biological evaluation against HIV and cancer cell proliferation, is reported.

Correction of a genetic deficiency in pantothenate kinase 1 using phosphopantothenate replacement therapy

“…The aryl phosphoramidate protection strategy was selected for this feasibility study because of the available background information but this approach is only one of several chemical options that could be employed for the protection and intracellular release of Ppan. These include aryloxy amino acid amidates, cyclic phosphoramidates, phosphorodiamidates, cyclic esters ( cyclo Sal), cyclic disulfides, S-acyl-2-thioethyl phosphotriesters, pivaloyloxymethyl esters (POM), protection by attachment to lipids, and many other options [21–24,26,30–35]. An interesting alternate option may be treatment with phosphopantetheine, which rescues Drosophila cells deficient in CoA by bypassing PanK [36].…”

Current Synthetic Approaches to the Synthesis of Carbasugars from Non-Carbohydrate Sources

“…These results suggest that future experiments may permit generation of the same products even faster and with higher yields. Due to the great diversity in the structures already known, the road is now paved for successful research in chemical and clinical medicine, including HIV and tumor treatment [14,53,54]. Due to the growing population and prevalence of common diseases, the importance of pseudo-sugar synthesis is greater than ever before.…”

Single Diastereomers of the Clinical Anticancer ProTide Agents NUC-1031 and NUC-3373 Preferentially Target Cancer Stem Cells In Vitro

“…1 H NMR (500 MHz, CD 3 OD): δ H 7.74 (d, J = 8.0 Hz, 1H, H-6), 6.27 (dd, J H−F = 9.50, 5.50 Hz, 1H, H-1′), 5.77 (d, J = 7.5 Hz, 1H, H-5), 4.38−4.28 (m, 1H, H-3′), 4.02 (dd, 1H, J = 11.5, 3.5 Hz, H-5′a), 3.92−3.88 (m, 1H, H-4′), 3.80 (dd, 1H, J = 2.0, 11. 5 Hz, H-5′b), 0.93, 0.92 (2s, 18H, C(CH 3 ) 3 ), 0.12, 0.11 (2s, 12H, Si(CH 3 ) 2 ).…”

“…The phosphoramidate (ProTide) approach applied to antiviral and anticancer nucleoside analogues (NAs), and more recently also to non-nucleoside compounds, − continues to be of significant interest in the drug discovery field. This approach is used to overcome the limitations of NAs that are known to restrict their therapeutic potential.…”