Synthesis and biological activities of 5-(hydroxymethyl, azidomethyl, or aminomethyl)-2'-deoxyuridine and related 5'-substituted analogs

Abstract

The synthesis of 5-(azidomethyl)-2'-deoxyuridine (10) has been accomplished by two independent methods. The first involved tosylation of 5-(hydroxymethyl)-2'-deoxyuridine (1) to furnish a mixture of two mono- and a ditosyl nucleosides which were converted into the corresponding 5-(azidomethyl) (10), 5-(azidomethyl)-5'-azido (14), and 5-(hydroxymethyl)-5'-azido (15) derivatives of 2'-deoxyuridine. The second method was more selective and required the formation of the intermediate 5-(bromomethyl)-3',5'-di-O-acetyl-2'-deoxyuridine (8), followed by displacement of the bromo group by lithium azide and deacetylation. Catalytic hydrogenation of the azides 9, 10, 14, and 15 gave the corresponding amines 16, 2, 6, and 7, respectively. Compounds 1, 2, 10, and 16 inhibited the growth of murine Sarcoma 180 and L1210 in culture, and the activity of 2 was prevented by 2'-deoxypyrimidine nucleosides but not by purine nucleosides. The replication of herpes simplex virus type 1 (HSV-1) was strongly inhibited only by 1 and 10. Studies on the binding of the various thymidine analogues to HSV-1 encoded pyrimidine deoxyribonucleoside kinase indicate that 1 and 10 have good affinity for the enzyme.

Activities of 1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)-5-iodocytosine and its metabolites against herpes simplex virus types 1 and 2 in cell culture and in mice infected intracerebrally with herpes simplex virus type 2

“…It is interesting that FHMAU was essentially nontoxic to the host Vero cells (ID50, -300 ,uM), whereas 5-hydroxymethyl-2'-deoxyuridine (which differs structurally from FHMAU only by the absence of a 2'-fluoro group) was cytotoxic to a variety of normal and tumor cell lines (32). The activities of the fluorinated nucleosides were also determined by yield reduction assays.…”

Combinatorial Approaches to the Prevention and Treatment of HIV-1 Infection

“…This enzyme was an obvious target for selective therapeutic intervention because RT is essential for retrovirus replication but is not found within HIV-1-susceptible host cells (77). Drug development efforts over the past 2 to 3 decades have produced nucleoside reverse transcriptase inhibitors (NRTIs) such as zidovudine (AZT) (85), zalcitabine (ddC) (64), and didanosine (ddI) (1) and nonnucleoside reverse transcriptase inhibitors (NNRTIs) such as nevirapine (NVP) (61), delavirdine (DLV) (31), efavirenz (EFV), and etravirine (ETV) (43) ( Table 1). HIV-1 protease, which participates in the assembly of HIV-1 virions, provided another selective target for drug development (60).…”

Syntheses of Two 5-Hydroxymethyl-2′-deoxycytidine Phosphoramidites with TBDMS as the 5-Hydroxymethyl Protecting Group and Their Incorporation into DNA

“…10 Both the 5- and 5′-hydroxyl of 2 are primary alcohols; however, the 5-hydroxyl is more reactive than 5′-hydroxyl since it is in the pseudobenzylic position. 11 Conte et al .…”