4,552 publications from this institution
An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.
Tanovea® (first named GS-9219, then VDC-1101, generic name: rabacfosadine) is a pro-prodrug or "double" prodrug of PMEG [9-(2-phosphonylmethoxyethyl)guanine], which has been conditionally approved by the US FDA (Food and Drug Administration) for the treatment of lymphoma in dogs. Tanovea has been demonstrated to be effective against non-Hodgkin's lymphoma (NHL) in dogs, as well as canine cutaneous T-cell lymphoma, spontaneous canine multiple myeloma, naïve canine multicentric lymphoma and relapsed canine B-cell lymphoma. As a double prodrug of PMEG, GS-9219 is first converted intracellularly by hydrolysis to cPr-PMEDAP, then deaminated to PMEG, which is then phosphorylated twice to its active metabolite PMEGpp, acting at the level of the cellular DNA polymerases.
Abstract The development of new HIV nonnucleoside reverse transcriptase inhibitors (NNRTIs) offers the possibility of generating structures of increased potency. On this basis, a series of 5‐alkylsulfanyl and 5‐(4′‐arylsulfonyl)piperazine derivatives of 1‐phenyl‐2‐alkyl‐4‐nitroimidazoles 5–21 was synthesized with the aim to develop new NNRTIs. The new synthesized compounds were assayed against HIV‐1 and HIV‐2 in MT‐4 cells. Compounds 9 and 13 , with an alkylsulfanyl group at C‐5 of the 4‐nitroimidazole backbone, showed inhibition of HIV‐1 with EC 50 4.04 μg/mL and 2.37 μg/mL, and therapeutic indexes (SI) of 17 and 13, respectively. © 2007 Wiley Periodicals, Inc. Heteroatom Chem 18:333–340, 2007; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/hc.20301
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Ceramic materials have become important for various industrial applications. Many types have these materials have been developed. However, research and development of ceramic materials, especially suited for electrical discharge machining (EDM), is still limited. This paper presents a detailed investigation of the material removal mechanisms of some commercially available electrical conductive ceramic materials through analysis of the debris and the surface/sub-surface quality. ZrO2-based, Si3N4-based and Al2O3-based ceramic materials, with additions of electrical conductive phases like TiN and TiCN, have been studied. This paper points out that besides the typical EDM material removal mechanisms, such as melting/evaporation and spalling, other mechanisms can occur such as oxidation and dissolution of the base material.
This review article that complements the previous review article on "The discovery of antiviral agents: ten different compounds, ten different stories" presents ten more compounds and ten more stories in which I have been closely involved at one or another point of my scientific career: (i) interferon (IFN) (in particular, IFN-beta); (ii) poly(I).poly(C); (iii) suramin; (iv) novel acyclic nucleoside phosphonates; (v) the double prodrug of [9-(2-phosphonomethoxyethyl)guanine]; (vi) cyclic nucleoside phosphonates; (vii) picornavirus inhibitors; (viii) human immunodeficiency virus (HIV) co-receptor inhibitors; (ix) nonimmunosuppressive cyclosporin A analogues; and (x) bicyclic (furanopyrimidine) nucleoside analogues. With the exception of the HIV co-receptor CCR5 inhibitor none of the compounds described here have already been marketed (for the indication they were initially developed). Successful antiviral drug development depends on the interplay of three disciplines, chemistry, biology/medicine, and industry, crucial factors being open mindedness for the unexpected, preparedness to explore serendipitous observations, and perseverance (in trying) to overcome the hurdles or setbacks inevitably compounding any drug development.
Nucleoside and nucleotide analogues have proven to be an effective approach toward the development of antiviral compounds. This approach has so far yielded a number of clinically useful antiviral drugs, such as BVDU (brivudin), (val)aciclovir, cidofovir, adefovir dipivoxil, and tenofovir disoproxil fumarate, and current perspectives justify the further development of other nucleoside analogues, such as FV-100, and that of the DAPy-based nucleotide analogues, the 5-aza analogue of cidofovir, and prodrug derivatives thereof.
Substitution of particular residues postulated to have a role in active site architecture can alter the overall fidelity of DNA polymerization by HIV-1. The effects of this kind of substitution were determined in a lacZ-based assay using HIV-1 reverse transcriptase with specifically mutated residues. We found that the reported higher fidelity of nucleotide incorporation by the Met184-->Val and Glu89-->Gly mutant reverse transcriptases (RTs) was not reflected in a substantial increase in the overall fidelity for these RT mutants. For the 3TC-resistant Met184-->Val RT mutant an almost wild-type level of overall mutation frequency was observed, while the foscarnet-resistant RTs harbouring the Glu89-->Gly mutation showed only a twofold decrease in mutation frequency. The Tyr183-->Phe mutant RT displayed a slightly lower fidelity than wild-type RT. Conversely, the ddI-resistant RT mutant containing the Leu74-->Val mutation showed a 3.5-fold higher fidelity compared to the wild-type enzyme. Finally, the Tyr115-->Ala substitution rendered the enzyme substantially more error-prone for DNA polymerization. These results correlate with three-dimensional structural studies of the polymerase active site and confirm the postulated impact of the Leu74, Tyr183 and Tyr115 RT residues on the overall fidelity of DNA polymerization by HIV-1 RT.
