The transformation using the soft NO⊕-species

Jørgensen, Karl Anker; Ghattas, A.-B. A. G.; Lawesson, S.‐O.

doi:10.1016/0040-4020(82)85099-0

Cited by 83 publications

(13 citation statements)

References 39 publications

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“…Our efforts in the direct thiation of 1 a with Lawesson's reagent [23] were unsuccessful. Therefore, we decided to tritylate 4-thio-2'-deoxyuridine 27 to 4-thio-5'-O-trityl-2'-deoxyuridine [24] 9.…”

Section: Modified Base Analoguesmentioning

confidence: 99%

Modified 5′‐Trityl Nucleosides as Inhibitors of Plasmodium falciparum dUTPase

et al. 2011

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2'-Deoxyuridine triphosphate nucleotidohydrolase (dUTPase) is a potential drug target for the treatment of malaria. We previously reported the discovery of 5'-tritylated analogues of deoxyuridine as selective inhibitors of this Plasmodium falciparum enzyme. Herein we report further structure-activity studies; in particular, variations of the 5'-trityl group, the introduction of various substituents at the 3'-position of deoxyuridine, and modifications of the base. Compounds were tested against both the enzyme and the parasite. Variations of the 5'-trityl group and of the 3'-substituent were well tolerated and yielded active compounds. However, there is a clear requirement for the uracil base for activity, because modifications of the uracil ring result in loss of enzyme inhibition and significant decreases in antiplasmodial action.

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Section: Modified Base Analoguesmentioning

confidence: 99%

Modified 5′‐Trityl Nucleosides as Inhibitors of Plasmodium falciparum dUTPase

et al. 2011

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“…2). Although the sulfuration of carbamates has been reported (16), this is the first example of sulfuration of benzoxazin-2-ones with this reagent. The reaction yield is poor; however, after several recyclings of the unreacted product, the thio-substituted derivative can be obtained with a yield of Ͼ95%.…”

Section: Synthesismentioning

confidence: 99%

“…The thio-substituted analog sefavirenz was obtained by direct sulfuration (16) of efavirenz with Lawesson's reagent (Fig. 2).…”

Section: Synthesismentioning

confidence: 99%

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Selective Interaction of the Human Immunodeficiency Virus Type 1 Reverse Transcriptase Nonnucleoside Inhibitor Efavirenz and Its Thio-Substituted Analog with Different Enzyme-Substrate Complexes

Maga

Ubiali

Salvetti

et al. 2000

Antimicrob Agents Chemother

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Accumulating data have brought the nonnucleoside reverse transcriptase (RT) inhibitors (NNRTIs) into the forefront of antiretroviral therapy. Among the emerging compounds in this class, a particularly attractive one is efavirenz (Sustiva), recently approved for clinical use by the U.S. Food and Drug Administration. In the present study, the equilibrium dissociation constants for efavirenz binding to the different catalytic forms of human immunodeficiency virus type 1 RT as well as the association and dissociation rates have been determined using a steady-state kinetic approach. In addition, the same enzymological analysis has been extended to the thio-substituted analog, sefavirenz, which showed comparable activity in vitro against RT. Both compounds have been found to act as purely uncompetitive inhibitors at low drug concentrations (5 to 50 nM) and as mixed noncompetitive inhibitors at higher doses (50 to 500 nM). This behavior can be interpreted in terms of the relative affinities for the different catalytic forms of the enzyme. Both efavirenz and sefavirenz showed increasing affinities for the different forms of RT in the following order: free enzyme < (i.e., bound with lower affinity) binary RT-template-primer (TP) complex < ternary RT-TP-deoxynucleoside triphosphate (dNTP) complex. The rate of binding of the two inhibitors to the different enzyme-substrate complexes was well below the diffusion limit (on the order of 10 4 M ؊1 s ؊1 ); however, both inhibitors, when bound to the ternary RT-TP-dNTP complex, showed very low dissociation rates, on the order of 10 ؊4 s ؊1 for both compounds, typical of tightly binding inhibitors. Thus, efavirenz and its thio-substituted derivative sefavirenz appear to be peculiar in their mechanism of action, being selective tightly binding inhibitors of the ternary RT-TP-dNTP complex. Efavirenz is the first clinically approved NNRTI to show this property.

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“…[1 -4] Generally, ureas can be prepared readily by the reaction of alkyl chloride or acyl chloride with cyanate salts and arylamines catalyzed by metal halide. [5] Substituted ureas can also be prepared by the transformation of C5 5S into C5 5O using many oxidants, such as benzeneselenic anhydride, [6] soft NO þ species, [7] cuprous chloride -sodium hydroxide, [8] and trifluoroacetic anhydride. [9] Recently, oxides of iodine were used as a reagents for the transformation of C5 5S of substituted thioureas into C5 5O, readily affording ureas.…”

Section: Introductionmentioning

confidence: 99%