6038-56-8Relevant academic research and scientific papers
[d4U]-Spacer-[HI-236] double-drug inhibitors of HIV-1 reverse-transcriptase
Younis, Yassir,Hunter, Roger,Muhanji, Clare I.,Hale, Ian,Singh, Rajinder,Bailey, Christopher M.,Sullivan, Todd J.,Anderson, Karen S.
scheme or table, p. 4661 - 4673 (2010/08/19)
Four double-drug HIV NRTI/NNRTI inhibitors 15a-d of the type [d4U]-spacer-[HI-236] in which the spacer is varied as 1-butynyl (15a), propargyl-1-PEG (15b), propargyl-2-PEG (15c) and propargyl-4-PEG (15d) have been synthesized and biologically evaluated as RT inhibitors against HIV-1. The key step in their synthesis involved a Sonogashira coupling of 5-iodo d4U's benzoate with an alkynylated tethered HI-236 precursor followed by introduction of the HI-236 thiourea functionality. Biological evaluation in both cell-culture (MT-2 cells) as well as using an in vitro RT assay revealed 15a-c to be all more active than d4T. However, overall the results indicate the derivatives are acting as chain-extended NNRTIs in which for 15b-d the nucleoside component is likely situated outside of the pocket but with no evidence for any synergistic double binding between the NRTI and NNRTI sites. This is attributed, in part, to the lack of phosphorylation of the nucleoside component of the double-drug as a result of kinase recognition failure, which is not improved upon with the phosphoramidate of 15d incorporating a 4-PEG spacer.
New telluride-mediated elimination for novel synthesis of 2′,3′-didehydro-2′,3′-dideoxynucleosides
Sheng, Jia,Hassan, Abdalla E. A.,Huang, Zhen
, p. 3725 - 3729 (2008/09/20)
(Chemical Equation Presented) Several 2′,3′-dideoxynucleosides (ddNs) and 2′,3′-didehydro-2′,3′-dideoxynucleosides (d4Ns) are FDA-approved anti-HIV drugs. Via conveniently synthesized 2,2′-anhydronucleosides, we have developed a novel synthesis of d4Ns by discovering and applying a new telluride-mediated elimination reaction. Our experiment results show that after substitution of 2,2′-anhydronucleosides with a telluride monoanion, a telluride intermediate is formed, and its elimination leads to formation of the olefin products (d4Ns). Our mechanistic study indicates that this telluride-assisted reaction consists of two steps: substitution (or addition) and elimination. By using dimethyl ditelluride (0.1 equiv) as the reagent, d4Ns can be synthesized with yields up to 90% via this telluride-mediated elimination. Our novel strategy has great potential to simplify synthesis of these drugs and to further reduce cost of AIDS treatment and will also facilitate development of novel d4N and ddN analogues.
Highly efficient synthesis of 2′,3′-didehydro-2′, 3′-dideoxy-β-nucleosides through a sulfur-mediated reductive 2′,3′-trans-elimination. From iodomethylcyclopropanes to thiirane analogs
De Cienfuegos, Luis álvarez,Mota, Antonio J.,Rodríguez, Concepción,Robles, Rafael
, p. 469 - 473 (2007/10/03)
A very simple methodology to achieve 2′,3′-didehydro-2′, 3′-dideoxy nucleoside derivatives was performed by means of the treatment of 2′-deoxy-2′-iodo-β-nucleosides with NaHS. The same procedure leads to thiiranes from iodomethylcyclopropane derivatives. Taking into account the thiophilic properties of iodine, a very simple methodology to achieve 2′,3′-didehydro-2′,3′-dideoxy-β-nucleosides in high yield was performed, using mild, and inexpensive conditions, by means of the treatment of 2′-deoxy-3′,5′-dibenzoyl-2′-iodo-β- nucleoside derivatives with NaHS. The process has shown to be highly dependent of the relative geometry between the iodine atom and the adjacent leaving group. In this way, different essays carried out with pyranose derivatives have concluded in no reaction when the vicinal groups to eliminate do not adopt a trans-diaxial disposition. In addition, the treatment of 2-iodomethyl- cyclopropane-1,1-dicarboxylic acid diethyl ester under the same conditions softly and readily leads to the obtention of a mixture of the expected 2-allyl-malonic acid diethyl ester (as the minor product) and the thiirane derivative 2-thiiranylmethyl-malonic acid diethyl ester (as the major product). In this case, the responsible of the reaction progress are the nucleophilic properties of the sulfur atom rather than the thiophilic character of the iodine atom.
SYNTHESIS OF 2',3'-DIDEHYDRO-2',3'-DIDEOXYNUCLEOSIDES UTILIZING COUPLING REACTIONS BETWEEN NUCLEIC BASES AND PHENYLTHIOSUBSTITUTED 2,3-DIDEOXYRIBOSE
Kawakami, Hiroshi,Ebata, Takashi,Koseki, Koshi,Matsumoto, Katsuya,Matsushita, Hajime,et al.
, p. 2451 - 2470 (2007/10/02)
Stereoselectivities in coupling reactions between silylated pyrimidine bases and 3- or 2-α-phenylthio-2,3-dideoxyribose were examined.In the former case, no stereoselectivies were observed when the coupling reactions were performed either with 1-chlorosugar in an SN2 mode or in the presence of Lewis acids as catalyst in an SN1 mode.Coupling reaction with 2-α-phenylthio-2,3-dideoxyribose in the presence of Lewis acids, especially SnCl4, proceeded with good stereoselectivity to give anomeric mixtures of α : β = 1 : 9.All these nucleosides were converted to 2',3'-didehydro-2',3'-dideoxynucleosides by oxidation to sulfoxides followed by thermal elimination of sulfenic acid.
Synthesis and in vitro evaluation of some modified 4-thiopyrimidine nucleosides for prevention or reversal of AIDS-associated neurological disorders
Palomino,Meltsner,Kessel,Horwitz
, p. 258 - 263 (2007/10/02)
Oxygen-sulfur exchange at the C-4 carbonyl of several modified pyrimidine, including 3'-azido-3'-deoxythymidine (AZT), is described in an effort to enhance the lipophilicity and, thereby, the delivery to the central nervous system of the sulfur analogues without compromising the anti-HIV activities of the parental structures. Preparation of 3'-azido-3'-deoxy-4-thiothymidine (3) proceeded from 4-thiothymidine (1) and utilized the same methodology developed for the initial synthesis of AZT. Thiation of 2',3'-didehydro-3'-deoxythymidine (4a) and 2',3'-didehydro-2',3'-dideoxyuridine (4c) was carried out with Lawesson's reagent on the corresponding 5'-O-benzoate esters, 4b and 4d, to give 5 a and 5c, respectively. The latter, on alkaline hydrolysis, gave 2',3'-didehydro-3'-deoxy-4-thiothymidine (5b) and 2',3'-didehydro-2',3'-dideoxyuridine (5d), respectively. The same series of reactions were applied to the 5'-O-benzoate esters of 2',3'-dideoxyuridine (6a) and 3'-deoxythymidine (6b) to give 2',3'-dideoxy-4-thiouridine (7d) and 3'-deoxy-4-thiothymidine (7b), respectively. Characterization of the saturated and unsaturated thionucleosides included mass spectrometric studies. Under electron impact conditions, the thiated analogues gave more intensive parent ions than the corresponding oxygen precursors. The lipophilicity of thymidine and the 3'-deoxythymidine derivatives are enhanced significantly, as indicated, by increases in corresponding P values (1-octanol-0.1 M sodium phosphate) upon replacement of the 4-carbonyl oxygens by sulfur. Compounds 5b, 5d, 7b, and 7d were evaluated for their effects on HIV-induced cytopathogenicity of MT-2 and CEM cells. Only 5b and 7b were moderately active in protecting both cell lines against the cytolytic effect of HIV. The inhibitory effects of analogous 5b, 5d, 7b, and 7d on thymidine phosphorylation by rabbit thymus thymidine kinase were evaluated. Only 3 showed moderate affinity (K(i) = 54 μM) for the enzyme. The generally weak anti-HIV activities of the remaining thio analogues are consistent with correspondingly low susceptibilities to thymidine kinase phosphorylation as estimated from the respective K(i) values of the synthetic nucleosides. However, the phosphorylation of the 5'-monophosphate derivatives to their respective 5'-triphosphates must also be considered in connection with the weak in vitro anti-HIV effects of these thiated compounds.
DERIVES CHLORES DE L'URIDINE: NOUVELLES VOIES D'ACCES COMMODE AU 1-(2,3-DIDESOXY-β-D-glycero-PENT-2-ENOFURANOSYL)URACILE ("URIDINENE")
David, Serge,Sennyey, Gerard de
, p. 45 - 50 (2007/10/02)
Treatment of 1-(2,3-anhydro-5-O-benzoyl-β-D-lyxofuranosyl)uracil with hydrogen chloride gave the 3-chloro-D-arabino analog, which was converted into the 2,3-dichloro-D-ribo analog (3) with the tetrachloromethane-triethyl phosphate-triethylphosphine reagen
