Publications

Abstract For Abstract see ChemInform Abstract in Full Text.

Palladium-catalyzed cross-coupling of 8-bromo-2'-deoxyadenosine with terminal alkynes in the presence of copper(I) iodide in dimethylformamide resulted in a series of 8-(1-alkyn-1-yl)-2'-deoxyadenosines. Hydrogenation of alkynyl derivatives over 10% Pd/C under atmospheric pressure gave 8-n-alkyl analogues in nearly quantitative yields. On partial saturation of heptynyl, pentynyl, and propynyl derivatives over Lindlar catalyst, the corresponding cis-olefins were obtained along with minor amounts of trans isomers. Of the analogues tested, the following showed some activity, i.e. they were found to be active at concentrations that were at least 3-fold lower than the cytotoxic concentrations: the 8-heptynyl derivative against vaccinia virus (VV), vesicular stomatitis virus (VSV), cytomegalovirus (CMV), and respiratory syncytial virus (RSV); the 8-propyl derivative against varicella-zoster virus (VZV) and CMV; the 8-pentyl derivative against CMV; the 8-heptyl derivative against VV, CMV, RSV, and influenza A; and the 8-heptenyl derivative against VV, RSV, and influenza A. The unsubstituted 2'-deoxyadenosine did not show any antiviral effect, except against RSV. Except for 8-propyl-dA, the antivirally active dA analogues were rather inhibitory to the growth of human embryonic lung cells. The most cytotoxic was the 8-ethynyl derivative.

Tick-borne encephalitis virus (TBEV) is a pathogen that causes severe human neuroinfections in Europe and Asia for which there is currently no specific therapy. The adenosine analogue galidesivir (BCX4430), a broad-spectrum RNA virus inhibitor, has entered a phase 1 clinical safety and pharmacokinetics study in healthy subjects and is under clinical development for treatment of Ebola and yellow fever virus infections. Moreover, galidesivir also inhibits the reproduction of TBEV and numerous other medically important flaviviruses. Until now, studies of this antiviral agent have not yielded resistant viruses. In our study, we performed serial in vitro passaging of TBEV in the presence of increasing concentrations of galidesivir (up to 50 μM), which resulted in the generation of two drug-resistant TBEV mutants. The first TBEV mutant was characterized by a single amino acid change, E460D. The other carried two amino acid changes, E460D and Y453H. Both mutations mapped to the active site of the viral RNA-dependent RNA polymerase (RdRp). Galidesivir-resistant TBEV exhibited no cross-resistance to structurally different antiviral nucleoside analogues, such as 7-deaza-2′-C-methyladenosine, 2′-C-methyladenosine, and 4′-azido-aracytidine. Although the E460D substitution led to only a subtle decrease in viral fitness in cell culture, galidesivir-resistant TBEV was highly attenuated in vivo, with a 100% survival rate and no clinical signs observed in infected mice. Furthermore, no virus was detected in the sera, spleen, or brain of mice inoculated with the galidesivir-resistant TBEV. By contrast, infection with wild-type virus resulted in fatal infections for all animals. Our results contribute to understanding the molecular basis of galidesivir antiviral activity, flavivirus resistance to nucleoside inhibitors, and the potential contribution of viral RdRp to flavivirus neurovirulence.

Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

As a key structural protein, HIV capsid (CA) protein plays multiple roles in the HIV life cycle, and is considered a promising target for anti-HIV treatment. Based on the structural information of CA modulator PF-74 bound to HIV-1 CA hexamer, 18 novel phenylalanine derivatives were synthesized via the Ugi four-component reaction. In vitro anti-HIV activity assays showed that most compounds exhibited low-micromolar-inhibitory potency against HIV. Among them, compound I-19 exhibited the best anti-HIV-1 activity (EC50 = 2.53 ± 0.84 μM, CC50 = 107.61 ± 27.43 μM). In addition, I-14 displayed excellent HIV-2 inhibitory activity (EC50 = 2.30 ± 0.11 μM, CC50 > 189.32 μM) with relatively low cytotoxicity, being more potent than that of the approved drug nevirapine (EC50 > 15.02 μM, CC50 > 15.2 μM). Additionally, surface plasmon resonance (SPR) binding assays demonstrated direct binding to the HIV CA protein. Moreover, molecular docking and molecular dynamics simulations provided additional information on the binding mode of I-19 to HIV-1 CA. In summary, we further explored the structure—activity relationships (SARs) and selectivity of anti-HIV-1/HIV-2 of PF-74 derivatives, which is conducive to discovering efficient anti-HIV drugs.

Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Abstract 5-Alkynyl 2′-deoxyuridines were prepared in low to modest yields by the palladium and nickel-catalyzed reaction of alkynylzinc reagents with 0–3′, 5′-bis (trimethylsilyl) deoxyuridine in THF. 1H-NMR and 13C-NMR studies showed that, in DMSO-d6, these synthesized nucleosides have the anti conformation as for the glycosidic bond and that the S conformation of the 2-deoxyribose ring is preponderant. 5-(5-Chloro-1-pentynyl) dUrd (6c) exhibited a potent antiviral activity, reminiscent of that reported before for 5-ethynyl-dUrd and 5-propynyl-dUrd. However, none of these 5-ethynyl-dUrd analogues proved selective in its antiviral action.

Traditionally, process planning and scheduling have been rather separate activities within a company. Nowadays, the need for more flexible production and shorter production lead times urges for a close collaboration between these activities as a first step towards simultaneous engineering. This article describes the results of the ongoing ESPRIT Project COMPLAN, which aims at the implementation of an integrated automatic process planning and scheduling system based on the concept of non-linear process plans. Additionally to the use of NLPP for flexible load balancing and re-active rescheduling, a new collaborative approach is presented that is based on production constraints as a means to realise a feedback from scheduling to process planning. A process planning kernel is described that integrates this concept of production constraints.