Cytopathic effect of HIV

We reported an extensive LIE study of 6 and 11 analogs that included consideration of the alternative amine epimers and protonation states.28 The MC simulations were initiated from the crystal structure for the complex of 8-C1-TIBO and HIV-1 RT.50 Partial charges came from RHF/6-31G CHELPG calculations for each inhibitor. The experimental data are IC50 values for the effective concentration required to achieve 50% protection of MT- 4 cells against the cytopathic effect of HIV-1.51... 

Other interesting hybrids between hydroxyethylene and hydroxyethylamine dipeptide isosteres have been reported. Getman et al (1993) developed a series of hydroxyethylureas that potently inhibited HIV-1 protease. The concept of these urea isosteres, first introduced as renin inhibitors, may be envisioned as a modification of the hydroxyethylene isostere (e.g., compound 22), in which the PV chiral a-car-bon is replaced with a trigonal nitrogen. One example of this class of inhibitors, SC-52151 (26) (Table III), inhibited HIV-1 protease with an IC50 value of 6 nMand blocked the cytopathic effect of HIV-1 in cell cul-... 

Inhibitory concentration against cytopathic effect of HIV-1 in MT-4 cells Eq. 30... 

Unlike other sulfated sterols of marine origin, the AB and carolisterols (42,43) isolated from Styracaster caroli spp. have not shown any protection against the cytopathic effects of HIV-1 in NCI s primary anti-HIV screen (34). 

Astragaloside II, a cycloartane triterpene oligoglycoside from Astragalus spinosus afforded close to 100% protection of T lymphocytes in vitro against cytopathic effects of HIV infection. The EC50of c.a. 2.5. 10 5 molar was difficult to achieve in vivo [148]. 

The pentaol disulphate 243, the tetraol disulphate 248 and the A -steroidal sulphates 245 and 247 have moderate cytotoxic activity (39). In the frame of a project devoted to the evaluation of the anti-HIV activity of sulphated sterols by the National Cancer Institute, Frederik, MD, US A, a selection of sulphated polyhydroxysteroids from ophiuroids (243,244,248,254,258,251,264) has been tested and found to inhibit the cytopathic effects of HIV-1 infections (130). 

Hayasht S, Phadtare S, Zemlica ], Matsukura M. Mitsuya H, Broder S- Adenallene and cytal-lene acyclic nucleoside analogues that inhibit replication and cytopathic effect of HIV in vitro. Proc Natl Acad Sci USA 1988 85 6127-6131. 

Activity Against Human Immunodeficiency Virus (HIV). A sulfate (GE-3-S) prepared by chlorosulfonic acid treatment GE-3, a partially acetylated P(1 - 6)glucan from the lichen Umbilicaria esculenta (Miyoshi) Mink., inhibited the cytopathic effect of HIV in vitro (Hirabayashi et al. 1989). 

Bicyclic adduct 185, derived by the cycloaddition of tosyl cyanide to 5-benzyloxymethyl-cyclopentadiene, was converted into the racemic branched carbocyclic nucleoside 186 ( BCA ), which was found to protect MT-4 cells from the cytopathic effects of HIV-1.216 Resolution of the racemate showed that the bioactivity was due to the (-)-enantiomer.2l7 it was shown that formula... 

ECsot effective concentration required to achieve S0% protection of MT-4 cells against the cytopathic effect of HIV-1. 

Dideoxynebularine (2 ,3 -dideoxypurine nucleoside, ddPN) 1 was one of a number of C-6 modified purine dideoxynucleosides synthesized in our laboratory (Scheme 2). It was designed to be a prodrug of ddl and was synthesized from 5 -protected ddA by reductive deamination using a procedure previously developed by us, followed by deprotection. Compound 1 was found to be inactive against the cytopathic effect of HIV-l and HIV-2 in MT-4 cells. It was not toxic to MT-4 cells at 200 jiM. It was not a substrate for xanthine oxidase. In contrast, C-6 substituted purine dideoxynucleosides that are substrates for mammalian ADA, show anti-HIV activity [e.g., 6-iodo ddPN, 2, synthesized from 5 -protected ddA by radical deamination/halogenation (n-pentyl nitrite, CH,L, CHjCN, A), followed by deprotection]. 

---