In Vitro Anti-Human Immunodeficiency Virus Activities of Z - and E -Methylenecyclopropane Nucleoside Analogues and Their Phosphoro- l -Alaninate Diesters

Abstract

Nucleoside analogues with a Z-or an E-methylenecyclopropane moiety were synthesized and examined for activity against human immunodeficiency virus type 1 (HIV-1) in vitro. The addition of a methyl phenyl phosphoro-L-alaninate moiety to modestly active analogues resulted in potentiation of their anti-HIV-1 activity. Two such compounds, designated QYL-685 (with 2,6-diaminopurine) and QYL-609 (with adenine), were most potent against HIV-1 in vitro, with 50% inhibitory concentrations of 0.034 and 0.0026 M, respectively, in MT-2 cell-based assays. Both compounds were active against zidovudine-resistant, didanosine-resistant, and multidideoxynucleoside-resistant infectious clones in vitro. Further development of these analogues as potential therapies for HIV-1 infection is warranted.

A review of recent advances in mass spectrometric methods for gas-phase chiral analysis of pharmaceutical and biological compounds

“…An increasing number of unnatural L-nucleoside analogs are being investigated as potent chemotherapeutic agents against human immunodeficiency virus (HIV) [142] and hepatitis B virus (HBV) [143]. Clevudine (L-FMAU, 2 -fluoro-5-methyl-␤-l-arabinofuranosyluracil), for instance, was investigated as a potent anti-HBV agent [144].…”

Synthesis and antiherpetic activity of (Z)- and (E)-9-(3-phosphonomethoxyprop-1-en-yl)adenines

“…The residue was dissolved in 93 : 7 chloroform-methanol and chromatographed on a silica gel column (1 × 15.5 cm). Fractions absorbing in UV light were concentrated and dried in a vacuum to give 34 mg (76%) of (VI); UV (CH 3 N 6 -Dimethylaminomethylidene-9-(3-hydroxyprop-1-en-1-yl)adenine (XVI) A solution of (E)-9-(3hydroxyprop-1-en-1-yl)adenine (VIII) (25 mg, 0.13 mmol) and dimethylformamide diethylacetal (400 µl, 2.33 mmol) in DMF (10 ml) was kept for 18 h at room temperature and evaporated in a vacuum. The residue was coevaporated with water (2 × 10 ml), dis-solved in chloroform (1 ml), and chromatographed on a silica gel column (1 × 15.5 cm) eluted with CHCl 3 and then with 95 : 5 CHCl 3 -EtOH.…”

“…Both a variety of structures and a wide range of antiviral activities are characteristic of them. 2 For example, synadenol ( I ) and relative compounds inhibit the reproduction of HSV, HIV, and hepatitis B viruses [1][2][3]. Compounds containing the phosphonomethoxy fragment, e.g., PMEA ( II ) and ( S )-9-(3 -hydroxy)-2-phosphonomethoxypropyl)adenine ( III ), which inhibit both the HIV and HSV replication, belong to another group of analogues [4].…”

“…The residue was coevaporated with toluene (2 × 25 ml) and dissolved in 50% aqueous methanol. The solution was washed with chloroform (2 × 15 ml) and evaporated in a vacuum; yield of (VIII) 98 mg (83%); UV (CH3 OH): λ max 261 nm; mp 224-227°C; 1 H NMR (D 2 O): 8.33 (1 H, s, H8), 8.26 (1 H, s, H2), 7.18 (1 H, dt, 3 J 1', 2' 14.3, 4 J 1', 3' 1.2, H1'), 6.54 (1 H, dt, 3 J 2', 3' 5.9, H2'), 4.40 (2 H, dd, H3').…”

Novel compounds in preclinical/early clinical development for the treatment of HIV infections

“…In addition to 3TC and (-)FTC, the structurally related 2k-deoxy-3k-oxa-4k-thiocytidine (dOTC) [89], the dioxolanyl purine nucleoside analogues [90], and the methylenecyclopropane nucleoside analogues (and their phosphoro-L-alaninate diesters) [91,92] have recently been described as new anti-HIV agents. All these compounds may ultimately, upon their intracellular metabolism, act as chain terminators, akin to AZT (Figure 9).…”