Inhibition of cAMP-dependent protein kinase by adenosine cyclic 3‘-, 5‘-phosphorodithioate, a second cAMP antagonist.

Botelho, L; Webster, Leland C.; Rothermel, J. D.; Baraniak, Janina; Stec, Wojciech J.

doi:10.1016/s0021-9258(18)60715-x

Cited by 33 publications

(1 citation statement)

References 12 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…6 Other examples of members among the nucleoside phosphorodithioate family are the cyclic analogue of 2',3'-cUMP described in 1970 by Eckstein8 and that of 3',5'-cAMP prepared by Baraniak and Stec.9 The latter compound was found to have unique properties as a cAMP antagonist, being a competitive inhibitor of cAMP-dependent protein kinase. 10 Recently a considerable synthetic effort is being observed in several laboratories to develop efficient methods of preparation of oligonucleotide phosphorodithioates as potential "antisense" modulators of gene expression.11 -13 In this paper, we present our approach to the synthesis of nucleoside 5'-0-( 1,1-dithiotriphosphates)…”

Section: Introductionmentioning

confidence: 99%

The Synthesis of Nucleoside 5'-O-(1,1-Dithiotriphosphates)

Okruszek¹,

Olesiak²,

Balzarini³

1994

J. Med. Chem.

View full text Add to dashboard Cite

Appropriately protected nucleoside 5'-O-(2-thio-1,3,2-dithiaphospholanes) react with inorganic pyrophosphate in the presence of a strong base catalyst (DBU) to give nucleoside 5'-O-(1,1-dithiotriphosphates) 1a-g. The latter compounds, including an AZT analogue, show modest antivirial activity against HIV-1 and HIV-2 replication in CEM cells. The AZT and deoxyadenosine derivatives were found to be inhibitors of HIV reverse transcriptase.

show abstract

Section: Introductionmentioning

confidence: 99%

The Synthesis of Nucleoside 5'-O-(1,1-Dithiotriphosphates)

Okruszek¹,

Olesiak²,

Balzarini³

1994

J. Med. Chem.

View full text Add to dashboard Cite

show abstract

Stereokontrollierte Synthese von Oligonucleosidphosphorothioaten

Stec

Wilk

1994

Angewandte Chemie

View full text Add to dashboard Cite

Bei der Modulation der Genexpression durch Antisense‐Oligonucleotide oder deren Analoga wurden Ergebnisse erzielt, die auf eine neue Generation von Therapeutica gegen virale Infektionen, Krebs und andere Krankheiten hoffen lassen. Oligonucleosidphosphorothioate (Oligo‐S) sind die wirksamsten Analoga bei der Unterdrückung der Biosynthese „ungewollter”︁ Proteine. Erste klinische Untersuchungen von Oligo‐S als Antisense‐Präparate gegen Warzen im Genitalbereich und akute myeloische Leukämie werden zur Zeit durchgeführt; auch gegen Aids sollen Oligo‐S getestet werden. Details des Wirkungsmechanismus, der Aufnahme in die Zelle, des Zelltransports, der subzellulären Lokalisierung und der Wechselwirkung mit zellulären Proteinen sind noch nicht bekannt. A priori wird bei der Applikation angenommen, daß eine rasche und effiziente molekulare Erkennung der Ziel‐RNA durch Oligo‐S erfolgt. Der Einfluß der Chiralität als Eigenschaft des Oligo‐S‐Gesamtmoleküls konnte bislang nicht geklärt werden, da diese Verbindungen nicht stereokontrolliert herstellbar sind. Aufgrund fehlender analytischer Methoden wurde die Diastereomerenzusammensetzung nie bestimmt. Da jedes Diastereomer eine eindeutig definierte stereochemische Einheit ist, stellt sich die Frage, welche Diastereomere die beobachtete biologische Antwort, die positive (heilende) Wirkung und die mögliche negative (toxische) Nebenwirkung, bewirken. Das Ziel dieser Übersicht ist, eine (zum Teil auch spekulative) Abschätzung der Probleme, die mit einer stereokontrollierten Synthese von Oligo‐S verbunden sind, zu liefern sowie den Forschungsstand zu referieren, wobei auch auf Strategien eingegangen werden soll, die zu Oligo‐S mit vorbestimmter Chiralität führen könnten. Dieser Ansatz soll keinesfalls Wissenschaftler von Untersuchungen mit Oligo‐S‐Diastereomerengemischen als Pharmaca abhalten, denn in der medizinischen Chemie wurden viele nützliche Medikamente ohne die genaue Kenntnis der Struktur entwickelt und angewandt. So ist z.B. heute noch die Struktur von Impfstoffen, die Pasteur entdeckte, nicht geklärt.

show abstract

Stereocontrolled Synthesis of Oligo(nucleoside phosphorothioate)s

Stec

Wilk

1994

Angew. Chem. Int. Ed. Engl.

113

View full text Add to dashboard Cite

Encouraging results obtained for modulation of gene expression by antisense oligonucleotides and their analogues have kindled hopes for a new generation of therapeutics against viral infections, cancer, and many other diseases. Among such analogues, oligo(nuc1eoside phosphorothioate)s (Oligo-S) have generally shown the highest efficacy in inhibiting the biosynthesis of "unwanted" proteins. The first clinical trials of antisense agents are now in progress using Oligo-S against genital warts and acute myeloid leukemia, and tests of Oligo-S against AIDS should follow soon. Nevertheless. their mechanism of action, internalization, cellular trafficking, subcellular localization, and interaction with cellular proteins is still poorly understood. It is assumed a priori that application involves rapid and efficient molecular recognition of target RNA by Oligo-S; however, the effects of the chirality of Oligo-S have so far been unappreciated, because Oligo-S has not yet been synthesized with stereocontrol. Indeed. the diastereomeric composition of Oligo-S has never been determined, primarily because of the lack of appropriate analytical methods. Since each of the diastereomers is a stereochemically unique chemical entity, questions arise as to which diastereomer is responsible for an observed biological response, including positive (curative) or possibly negative (toxic) side effects.In this review we intend provide a perhaps somewhat speculative assessment of the problems associated with the stereocontrolled synthesis of Oligo-S and to discuss the state-of-the-art in this field including strategies that may lead to Oligo-S of predetermined chirality. This article is not intended to discourage researchers from further studies of diasteromeric mixtures of Oligo-S as potential pharmaceuticals. Throughout the history of medicinal chemistry numerous useful medicines were discovered, developed, and employed without the detailed knowledge of their structure. Indeed, the composition of the vaccines discovered by Pasteur is a subject of vigorous study still today.

show abstract

Inhibition of cAMP-dependent protein kinase by adenosine cyclic 3‘-, 5‘-phosphorodithioate, a second cAMP antagonist.

Cited by 33 publications

References 12 publications

The Synthesis of Nucleoside 5'-O-(1,1-Dithiotriphosphates)

The Synthesis of Nucleoside 5'-O-(1,1-Dithiotriphosphates)

Stereokontrollierte Synthese von Oligonucleosidphosphorothioaten

Stereocontrolled Synthesis of Oligo(nucleoside phosphorothioate)s

Contact Info

Product

Resources

About