Reverse transcriptase applications

Harringtonine and homoharringtonine were both found to be inactive as inhibitors of HIV-1 (168) and HIV-2 (169) reverse transcriptase. Applications of homoharringtonine in ophthalmology have also been investigated (170-174). 

Other applications include bioequivalent measurements of bromazepam, an anticonvulsant, in human plasma. The lower limit of quantitation (LLOQ) was 1 ng/mL (Gongalves et al. 2005). Kuhlenbeck et al. (2005) studied antitussive agents (dextromethorphan, dextrophan, and guaifenesin) in human plasma LLOQ values were 0.05, 0.05, and 5 ng/mL, respectively. Other compounds studied were nucleoside reverse transcriptase inhibitors, zidovudine (AZT) and lamivudine (3TC) (de Cassia et al. 2004) and stavudine (Raices et al. 2003) in human plasma, and paclitaxel, an anticancer agent, in human serum (Schellen et al. 2000). 

Gussio, R., Pattabieaman, N., Kellogg, G.E., Zahaeevitz, D.W. Use of 3D QSAR methodology for data mining the National Cancer Institute Repository of Small Molecules application to HlV-1 reverse transcriptase inhibition. Methods 1998, 14, 255-263. 

Efavirenz is a nonnucleoside reverse transcriptase inhibitor specific for HIV-1. After binding to a site distant from the active site on the HIV-1 reverse transcriptase, it disrupts catalytic activity of the enzyme by causing a conformational change and does not compete with deoxynucleoside triphosphates. Efavirenz does not inhibit HIV-2 reverse transcriptase and human DNA polymerases a, (3, 7 and 8. The resistance to the drug develops rapidly from site-directed mutagenesis specifically at codon 103, and also at codons 100, 106, 108, 181, 190 and 225 of viral reverse transcriptase. This resistance will be applicable for all nonnucleoside transcriptase inhibitors. 

AIDS Reverse Transcriptase and HIV Protease Inhibitors 389 13.3 Pharmaceutical Applications of Biocatalysis 393... 

Downstream application [PCR (polymerase chain reaction), cloning, labeling, blotting, RT (reverse transcriptase)-PCR, cDNA synthesis, RNAse protection assays, gene therapy, etc.]... 

R-(R, S )]-p-Methyl-a-phenyl-1-pyrrolidineethanol is an important chiral mediator for the enantioselective addition of an acetylide to a prochiral ketone.2 3 This reaction has been successfully applied to the synthesis of the reverse transcriptase inhibitor efavirenz (DMP-266) (Scheme 1).3.4 Preparation of the enantiomer, (1S,2R)-N-pyrrolidinylnorephedrine, has been reported.2 The method used potassium carbonate (K2CO3) as base, but the yield of the product was only 33%. The submitters have extensively studied the formation of the pyrrolidinyl ring under various conditions as summarized in Table I. Eventually they found that the reaction was extremely efficient when it was run in toluene using sodium bicarbonate (NaHCC>3) as base (entry 8, Table I),5 which gave [R-(R, S )]-p-methyl-a-phenyl-1-pyrrolidineethanol quantitatively. Enantioselective (up to 99% ee) addition of cyclopropylacetylene to the ketoaniline 1 is achieved when the solution of [R-(R, S )]-p-methyl-a-phenyl-1-pyrrolidineethanol is used as a chiral additive.3 In addition, this method is also applicable to the preparation of a variety of alkylated norephedrines and other amino alcohols in excellent yields as Illustrated in Table II. These amino alcohols are potentially useful in asymmetric syntheses. 

Benzodiazepines and 3//-1,5-benzodiazepines are important classes of compounds because of their interesting pharmacological properties. They show anticonvulsant, antianxiety, analgesic, sedative, antidepressive, hypnotic, antiinflammatory activity and also potent inhibitor of HIV-1 reverse transcriptase. Besides their biological relevance, benzodiazepines have also found application as dyes for acrylic fibers [163]. 

The use of the Pathfinder descriptor for QSAR is exemplified here through application to two datasets taken from the literature (i) 31 steroids utilized in the original CoMFA study [3], since considered a benchmark for evaluating QSAR methods [4] (ii) 55 inhibitors of HIV-1 reverse transcriptase proposed by Chan and coworkers [5], interestingly this series could only be successfully correlated by means of a structure-based approach [6]. 

Application as a Synthetic Building Block in Pharmaceutical Compounds. The best-known application of the (lS,2/ )-enantiomer of cw-aminoindanol is as a component of Indinavir (4), the primary component of a Crixivan combination therapy (with other reverse transcriptase inhibitors) for AIDS7 An excellent account of the synthetic approach to Indinavir, as well as the use of 1 in other drugs, can be found in a recent review. ... 

There have been relatively few applications of compounds of this type. The l,2-dioxolan-3-ones 132 have been tested as anti-malarials but have weak activity <2005TL2757>. The 4-amino-l,2-oxathiole 2,2-dioxides 119 have been examined as potential reverse transcriptase inhibitors for treatment of HlV-1 but are essentially inactive <1997T17795, 1998TL4123> and the nitrates 96 and 97 have been patented for the treatment of neurological conditions <1997W046521>. 

Lamivudine This is a cytosine(cytidine)-nucleoside analogue. Its effect is based on the inhibition of reverse transcriptase in HIV and of DNA polymerase in HBV The daily oral dosage is 1 (-3) x 100 mg/day. After discontinuation of lamivudine, the previous findings recur here, too, efficacy only exists with continued therapy. A combination with famciclovir seems promising. Its clinical application is mainly in combination with IFN. Long-term monotherapy over several years may be necessary. (48,54) (s. p. 704)... 

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