Of a series of nucleoside analogues synthesised, 9-(2-hydroxyethoxymethyl) guanine was found to have marked antiviral activity in animal models of herpes virus infections, associated with very low toxicity.

A guanine derivative with an acyclic side chain, 2-hydroxyethoxymethyl, at position 9 has potent antiviral activity [dose for 50% inhibition (ED50) = 0.1 ,uM] against herpes simplex virus type 1. This acyclic nucleoside analog, termed acycloguanosine, is converted to a monophosphate by a virusspecified pyrimidine deoxynucleoside (thymidine) kinase and is subsequently converted to acycloguanosine di-and triphosphates. In the uninfected host cell (Vero) these phosphorylations of acycloguanosine occur to a very limited extent. Acycloguanosine triphosphate inhibits herpes simplex virus DNA polymerase (DNA nucleotidyltransferase) 10-30 times more effectively than cellular (HeLa S3) DNA polymerase. These factors contribute to the drug's selectivity; inhibition of growth of the host cell requires a 3000-fold greater concentration of drug than does the inhibition of viral multiplication. There is, moreover, the strong possibility of chain termination of the viral DNA by incorporation of acycloguanosine.The identity of the kinase that phosphorylates acycloguanosine was determined after separation of the cellular and virus-specified thymidine kinase activities by affinity chromatography, by reversal studies with thymidine, and by the lack of monophosphate formation in a temperature-sensitive, thymidine kinase-deficient mutant of the KOS strain of herpes simplex virus type 1 (tsAl).

Nachhaltigkeit ist zugleich historisches Kulturgut und moderne Antwort auf die aktuelle globale Krisensituation im Kontext des Klimawandels. Insbesondere im Bauwesen ist der strategische Ansatz der Nachhaltigkeit in den letzten Jahren durch die Entwicklung und Implementierung von Nachhaltigkeitszertifizierungssystemen fest verankert worden. Derzeit weist die Bau‐ und Immobilienwirtschaft vor allem in den Bereichen der Diversifikation entwickelter Bewertungs‐ und Optimierungswerkzeuge und der Ausbildung eines praxistauglichen rechtlichen Rahmens für die beteiligten Akteure eine wesentliche Dynamik auf. Beyond Platin – Sustainability trends in the construction and real estate industry. Sustainability is both a cultural asset and a modern answer to the current global crisis of climate change. In the past few years, sustainability has become especially important in the construction industry, anchored by the development and implementation of a number of sustainability certification systems. Today, the construction and real estate industry shows an essential dynamism in areas of diversifying of the developed assessment and optimization tools as well as establishing of a suitable legal framework for the involved players.

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Acyclovir {9-[(2-hydroxyethoxy)methyllguanine} is an acyclic guanine nucleoside analogue that is widely used clinically as an antiherpetic agent. Its limited absorption in humans after oral administration prompted the search for prodrugs. A congener, referred to as 6-deoxyacyclovir {2-amino-9-[(2-hydroxyethoxy)methyl]-9H-purine}, was synthesized and found to be 18 times more water soluble than was acyclovir. Surprisingly, this congener was readily oxidized to acyclovir by xanthine oxidase (EC 1.2.3.2). It was also oxidized by aldehyde oxidase (EC 1.2.3.1) largely to 8-hydroxy-6-deoxyacyclovir {2-amino-8-hydroxy-9-[(2-hydroxyethoxy)methyl]-9H-purine} and then to 8-hydroxyacyclovir {2-amino-6,8-dihydroxy-9[(2-hydroxyethoxy)methylj-9H-purine}. 6-Deoxyacyclovir and the major products of its oxidation by aldehyde oxidase lacked appreciable activity against herpes simplex type I in vitro. On the basis of these results, it was apparent that the success of 6-deoxyacyclovir as a prodrug in vivo would depend upon how well its desired activation by xanthine oxidase competed with the nonactivating oxidations by aldehyde oxidase.In rats dosed orally with 6-deoxyacyclovir, absorption was extensive and the major urinary metabolite was acyclovir. In two human volunteers, urinary excretions of acyclovir were 5-6 times greater than those typically observed after administration of equivalent doses of acyclovir itself. The areas under the plasma concentration-time curves for acyclovir were also 5-6 times greater. Plasma levels of acyclovir peaked soon after ingestion of the prodrug, indicating rapid absorption and metabolic conversion. These results suggested that 6-deoxyacyclovir might have clinical usefulness as a prodrug of acyclovir suitable for oral administration.Acyclovir {9-[(2-hydroxyethoxy)methylJguanine; Zovirax} is a clinically useful antiherpetic agent (1, 2). Intravenous (3, 4), oral (5), or topical (6, 7) administration provides-effective therapy. Only 15-20% of the dose is typically absorbed in humans after oral administration (8). This degree of absorption is adequate for efficacy against herpes simplex infections (5). However, greater absorption might be important in therapy against less sensitive viruses such as varicella-zoster virus (9). The clinical experience to date clearly indicates that although acyclovir represents a major therapeutic advance in the treatment of herpetic infections, a means of enhancing gastrointestinal absorption would significantly extend its usefulness.Considerable effort has been expended in attempts to find a prodrug that is well absorbed after oral administration and then converted to acyclovir. Esterification of the hydroxyl group of the (2-hydroxyethoxy)methyl moiety of acyclovir has been an approach taken by two separate laboratories (10,11). Unfortunately, those esters that have been tested showed no significant improvement in absorption after oral dosing (unpublished results).The 6-deoxy-6-amino congener of acyclovir {2,6-diamino-9-[(2-hydroxyethoxy)methyl]-9H-purine} (...

The syntheses of some erythro-and threo-9-(2-hydroxy-3-alkyl)adenines from 5-amino-4,6-dichloropyrimidine and the appropriate amino alcohols are described. Based on earlier studies, it was predicted and substantiated that the erythro diastereoisomers would be more potent inhibitors of adenosine deaminase than their corresponding threo diastereoisomers. These data support the concept that on adenosine deaminase there is a single binding site for the adenine moiety of the inhibitors and that there is a close spatial relationship of the methyl binding site, the hydroxyl binding site, and the large hydrophobic region utilized by the 9 substituent of the inhibitors.Earlier studies have shown that calf intestinal mucosal adenosine deaminase possesses several regions which are important for binding the 9 substituent of various 9-substituted adenines.1"3 These binding areas for the 9 substituent are a large hydrophobic region,1 a hydroxyl binding site,2 and a specific methyl binding region.3 Furthermore, it has been demonstrated that when the 9 substituent of some 9-substituted adenines contains a chiral center, there is a stereoselectivity in the formation of the enzyme-inhibitor complex.3•4 For example, with some 9-( 1hydroxy-2-alkyl)adenines, the preferred chiral center for El complex formation has the R configuration4 whereas with 9-(2-hydroxypropyl)adenine, the chiral center with the S' configuration is bound more tightly to the enzyme than the compound with R configuration.3 With this insight into the types of binding regions and the stereoselectivity of inhibition of adenosine deaminase at two different chiral centers of some 9-substituted adenines, it should be possible to design potent inhibitors of this enzyme. This paper describes the syntheses of some 9-(2hydroxy-3-alkyl)adenines and their evaluation as inhibitors of adenosine deaminase.

The syntheses of six 6-substituted-9-,B-~-ribofuranosplpurines from 6-chloro-9-P-~-ribofuranosylpurine have been accomplished.i o 0