Among the most prominent realizations of Morris J. Robins in the antiviral nucleoside chemistry are <i>(i)</i> the synthesis of 8-substituted (methyl-, amino-, bromo-, iodo) derivatives of acyclovir, <i>(ii)</i> xylotubercidin as an inhibitor of herpes simplex virus (HSV) infections, <i>(iii)</i> the anti-HIV activity of the 2',3'-dideoxyriboside of 2,6-diaminopurine (ddDAPR) and the 3'-azido- and 3'-fluoro derivatives thereof (AzddDAPR and FddDAPR, respectively), <i>(iv)</i> the potentiating effect of ribavirin on the anti-HIV activity of 2',3'-dideoxyinosine (ddI) and ddDAPR, <i>(v)</i> S-adenosylhomocysteine hydrolase (SAH) inhibitors principally active against vaccinia virus (VV) and vesicular stomatitis virus (VSV), and <i>(vi)</i> furo[2,3-d]pyrimidinone derivatives active against varicella-zoster virus (VZV).
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Summary Die and mold manufacturing represents a significant area of production technology since it influences the feasibility and economics of producing a very large number of discrete components. Modern die manufacturing includes just about all aspects of manufacturing: part design, geometry handling and transfer, die design, process modeling, prototype production, control of dimensional and surface quality as well as advanced mechanical, electrical, and electrochemical machining methods. This paper, prepared with input from various CIRP colleagues, attempts to review the latest advances and practical applications in the field.
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Human CMV (HCMV) is an opportunistic pathogen associated with significant morbidity and mortality among immunocompromised patients (in particular immunosuppressed patients with stem cell or solid organ transplantation, AIDS or cancer). Additionally, congenital HCMV infections are a leading cause of birth defects and infections in children, occurring in 1 to 2% of all live births. Drugs currently available for the treatment of HCMV diseases in the immunocompromised individual include ganciclovir, its oral prodrug valganciclovir, cidofovir, foscavir and fomivirsen. Although these drugs have proved successful in the management of HCMV disease in immunocompromised patients, their use is limited because of toxicity, poor oral bioavailability, modest efficacy and the development of drug resistance. Furthermore, no drug has been licensed for use in the treatment of congenital HCMV. Therefore, there is a need to develop new compounds against HCMV diseases. The search for novel inhibitors of HCMV replication has led to the identification of new molecular targets such as the viral protein kinase UL97, and the viral proteins involved in genome replication or in DNA maturation and egress. Moreover, a new strategy based on the identification of specific cellular targets required for viral replication has been developed. This review focuses on non-nucleoside compounds that inhibit specific viral processes and on cell-based approaches that result in the selective inhibition of virus replication.
Facile synthesis of C-4 aryl pyrimidinone nucleoside analogues from an easily prepared O4-arylsulfonate derivative of thymidine is reported. Two O4-arylsulfonylthymidine precursors, (4-methylphenyl)sulfonyl and (2,4,6-trimethylphenyl)sulfonyl, were prepared and analyzed for their stabilities. Of the two, the latter possessed suitable stability as well as reactivity for Pd-catalyzed C-C bond-forming reactions with a variety of arylboronic acids. These reactions at the C-4 position are nontrivial in comparison with similar reactions at the C-5 position of pyrimidine nucleosides, with hydrolysis of the arylsulfonate precursor being a competing reaction in some cases. There are pronounced solvent influences in these reactions, but successful reactions can be attained by careful control of conditions. Many reactions proceeded efficiently at room temperature, and electron-deficient arylboronic acids can also be cross-coupled under suitable conditions. Desilylation of these products was also nontrivial, and various conditions were tested. Finally, antiviral screening was performed with the C-4 aryl pyrimidinone nucleoside analogues, but none possessed any interesting activity. The study represents the first successful synthesis of C-4 aryl pyrimidinone nucleoside analogues by cross-coupling of arylboronic acids with an arylsulfonate derived from a pyrimidine nucleoside, as well as antiviral testing of this new class of compounds.
