Selective Index

As 1,2,5-thiadiazole analogues, potent HlV-1 reverse transcriptase inhibitors, some simple 1,2,5-oxadiazoles, compounds 4-6 (Fig. 9), have been synthesized using the traditional Wieland procedure as key for the heterocycle formation [121]. Such as thiadiazole parent compounds, derivative with chlorine atoms on the phenyl ring, i.e., 5, showed the best anti-viral activity. Selectivity index (ratio of cytotoxic concentration to effective concentration) ranked in the order of 5 > 6 > 4. The activity of Fz derivative 6 proved the N-oxide lack of relevance in the studied bioactivity. These products have been claimed in an invention patent [122]. On the other hand, compound 7 (Fig. 9) was evaluated for its nitric oxide (NO)-releasing property (see below) as modulator of the catalytic activity of HlV-1 reverse transcriptase. It was found that NO inhibited dose-dependently the enzyme activity, which is hkely due to oxidation of Cys residues [123]. 

Level 3 of the screen is designed to determine the cytotoxic selectivity of samples for tumor cells vs. normal cells. Where possible, the same patient s tissues are used. As in Level 2, six serial dilutions (of four- to five-fold each) are assayed in triplicate for each sample. The diluted samples are then added to the tumor cell and normal cell cultures, and the IC50 is determined. A "selectivity index" (SI) is determined based on the IC50 for normal cells/IC5Q for tumor cells. Samples with an SI of three or more are advanced to Level 4 of the screen. Additionally, only purified and well-characterized compounds are promoted for further testing. 

These oxidations suffer from the fact that the high selectivities are only observed at low conversions (<7%). At higher conversions, the carboxylic acid products leach the transition metals out of the zeolite framework into solution where the selectivity index is much lower [63]. As these reactions proceed, the 3 -I- oxidation states of the metal ions return to their 2 -I- states, accompanied by their characteristic color change. In the case of MnAlPO-18, the spent catalyst (Mn ) was washed with methanol and reactivated in dry air at 550°C and successfully recycled (Mn Mn ) twice without appreciable loss of activity [64]. 

Results from testing against a variety of polymerase enzymes show that efavirenz is inactive up to 300 p,M for a 50% inhibition (Young et al., 1995). The polymerase enzymes studied were Moloney murine leukemia virus RT, human DNA polymerases a, 3, and 7, Escherichia coli RNA polymerase, and the Klenow fragment. Cytotoxicity studies in their primary cells and in a T-cell line reveal that efavirenz has a selectivity index of 80,000. 

Breeding includes the choice of suitable performance parameters (breeding goals/traits), ways to combine performance information (e.g. selection index), selection of animals to reach breeding goals and the respective breeding techniques (e.g. natural mating, artificial insemination [AI]). 

Table 5. Anti-HSV-1 Activity, Cytotoxicity and Selectivity Index...

Betulinic acid and platanic acid are triterpenoids isolated from Syzygium claviflorum. They exhibit inhibitory activity against HIV-1 replication in H9 lymphocyte cells at an IC50 of 1.4 and 6.5 pM, respectively (selectivity index 9.3 and 14, respectively). Hydrogenation of betulinic acid... 

Bellenamine, (R)-3,6-diamino-V-(aminomethyl)hexanamide is a (very) small-molecular-weight (MW 174) antibiotic produced by Streptomyces nashvillensis. It has only weak antibacterial activity but inhibits HIV-1 infection at an IC50 of 0.62 pg/ml (3.6 iM). With a CC50 of > 2 mg/ml (11.5 mM), the selectivity index of bellenamine can be estimated at well above 2000. Similarl to the well-established glycosylation inhibitors castanospermine and 1-deoxynojirimycin, bellenamine inhibits the secondary spread of HIV, although, unlike the glycosylation inhibitors, bellenamine had no apparent inhibitory effect on the glycosylation process. Therefore, its antiviral mechanism remains to be elucidated. 

A global electrophilicity index of common benzylating and acylating agents has been established from MO calculations and it shows a quantitative linear correlation with the experimental substrate selectivity index from a series of benzylation and acylation reactions.21 The values of relative rate coefficients predicted from the index may be accurate to within 10%. The reaction of /-butyl chloride with anisole catalysed by /Moluenesulfonic acid in supercritical difluoromethane has been subject to kinetic analysis.22 The proportions of substitution at the ortho -position and disubstitution increase at lower pressures, attributed to the decrease in the hydrogen-bonding ability of the solvent. 

Tencer J, Torffvit O, Thysell H et al. (1998) Proteinuria selectivity index based on a2-macroglobulin or IgM is superior to the IgG based index in differentiating glomerular diseases. Kidney Int 54 2098-2105... 

Tencer J, Bakoush O, Torffvit O (2000) Diagnostic and prognostic significance of proteinuria selectivity index in glomerular diseases. Clin Chim Acta 297 73-83 Thongboonkerd V, Klein JB, McLeish KR (2002) Proteomic identification of biomarkers of glomerular diseases. J Am Soc Nephrol 13 120A... 

As emphasized in Section IV of this chapter, the lithiotropy is of much consequence in the reactivity of enolates, the O and C sites competing toward electrophiles. This problem has been examined recently by Meneses and coworkers202, who described a local hardness parameter that can be used as a selectivity index, in particular for a set of ketone lithium enolates. 

The correlation between the carbcnc selectivity and its substitution has been disclosed In Moss s classical work (ll- He defined a selectivity index mexY of a carbene as the slope of the linear correlations obtained by plotting [log(fc/Ao)] c fK versus [log(/fMo)lcc/2 corresponds to the cyclo-... 

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