Homo Dinucleoside-α-hydroxyphosphonate Diesters as Prodrugs of the Antiviral Nucleoside Analogues 2',3'-Dideoxythymidine and 3'-Azido-2',3'-dideoxythymidine

Meier, Chris; Habel, Lothar W.; Laux, W; Clercq, Erik De; Balzarini, Jan

doi:10.1080/15257779508012466

Cited by 20 publications

(2 citation statements)

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“…This G-Protein-Coupled-Receptors (GPGCR) family is subdivided into three groups according to their sequence similarity, transduction mechanism and pharmacological profiles. Consequently, a large number of glutamate analogues (41)(42)(43)(44)(45)(46)(47) have been synthesized and assayed in order to identify selective ligands, some of which have proved to be successful and even reached advanced clinical phases [49] (Fig. 8).…”

Section: Selective Agonists Of Metabotropic Glutamate Receptormentioning

confidence: 99%

“…In this perspective, neuraminidase (NA), an essential enzyme cleaving host sialic acid, is used as the drug target. Hydroxyphosphonates and the parent α-hydroxyphosphonic acids were disclosed as antiviral activities [42][43][44][45][46]. In 2013, Khorshin and Pozdeev reported the preparation of α-γ-dihydroxyphosphinates as a new class of protective agent against influenza A subtype H3N2 [47].…”

Section: Influenza a (H3n2) Neuraminidase Inhibitorsmentioning

confidence: 99%

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Synthesis and Biological Applications of Phosphinates and Derivatives

Virieux

Volle

Bakalara

et al. 2014

Topics in Current Chemistry

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This review first outlines general considerations on phosphinic acids and derivatives as bioisosteric groups. The next sections present key aspects of phosphinic acid-based molecules and include a brief description of the biological pathways involved for their activities. The synthetic aspects and the biological activities of such compounds reported in the literature between 2008 and 2013 are also described.

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Section: Selective Agonists Of Metabotropic Glutamate Receptormentioning

confidence: 99%

Section: Influenza a (H3n2) Neuraminidase Inhibitorsmentioning

confidence: 99%

Synthesis and Biological Applications of Phosphinates and Derivatives

Virieux

Volle

Bakalara

et al. 2014

Topics in Current Chemistry

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Nucleotide Delivery fromcycloSaligenyl-3′-azido-3′-deoxythymidine Monophosphates (cycloSal-AZTMP)

Meier¹,

Clercq

Balzarini

1998

Eur. J. Org. Chem.

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The application of our cycloSaligenyl‐ (cycloSal) pronucleotide concept to the approved anti‐HIV dideoxynucleoside 3′‐azido‐3′‐deoxythymidine AZT (1) is reported. This pro‐nucleotide concept has been designed to deliver the corresponding 3′‐azido‐3′‐deoxythymidine monophosphate AZTMP (2) by selective chemical hydrolysis from the lipophilic precursors cycloSal‐AZTMP 4a−h. All derivatives 4a−h were synthesized using differently substituted salicyl alcohols 7a−h as starting materials. In hydrolysis studies, compounds 4 decomposed selectively releasing AZTMP (2) and the salicyl alcohols 7 following the designed tandem reaction. Furthermore, due to the electronic properties introduced by substituents, the half‐lives of the triesters 4 could be ajusted over a wide range. Phosphotriesters 4 exhibited considerable biological activity in HIV‐1 and HIV‐2 infected wild‐type human T‐lymphocyte (CEM/O) cells, whereas, contrary to our expectations, nearly all activity was lost in HIV‐2 infected thymidine‐kinase‐deficient CEM cells.

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2‐Nucleos‐5′‐O‐yl‐4H‐1,3,2‐benzodioxaphosphinin‐2‐oxide—ein neues Konzept für lipophile, potentielle Prodrugs biologisch' aktiver Nucleosidmonophosphate

Meier

1996

Angewandte Chemie

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ZUSCHRIFTEN sein als bei ,,normalen" Ketogruppen. Die anderen Molekiilparameter von A und B, einschliel3lich Bindungs-und Torsionswinkel, entsprechen weitgehend denen anaioger Verbindun-genIg, ' ' 1. Diese Parameter hangen nicht von elektronischen Faktoren ab, sondern werden hauptsachlich durch die intramolekularen sterischen Anforderungen und/oder Gitterkrafte bestimmt.Der Ylid-Charakter von 8 zeigt sich auch in dessen Reaktion mit Acetaldehyd [GI. (b)]. Erhitzt man eine Suspension von 8 in 0 0 2 OPPhj + 8 Nitromethan mit zwei Aquivalenten Acetaldehyd in einer verschlossenen Ampulle auf 60 "C, so lost der Feststoff sich schnell auf. Nach Abdampfen des Losungsmittels erhalt man eine zahe orangefarbene Verbindung. Das 31P{ 'H}-NMR-Spektrum (CDCI,) zeigt ein einziges Signal bei 6 = 27.84, das OPPh, zugeordnet werden kann. Die wichtigsten Signale im 'H-NMR-Spektrum treten bei 6 = 4.40 (q, ,J(HH) = 6.1 Hz) und 1.19 (d, 3J(HH) = 6.1 Hz) im Verhaltnis 1:3 auf. Diese sind auf die Protonen der =CHbzw. -CH,-Gruppen zuriickzufiihren. Im IR-Spektrum ist die Bande bei 1622 cm-', die die Verbindung 8 charakterisiert, verschwunden; dafur weist das Spektrum der orangen Substanz zwei neue intensive Banden bei 1678 und 1553 cm-'. Die spektroskopischen Daten legen nahe, dal3 8 in einer Wittig-Reaktion zu 9 umgesetzt wird. Gegenwartig untersuchen wir die Reaktivitat von 8 gegenuber organischen und metallorganischen Verbindungen. Exper irnen telles 8: Eine 0.044 M Losung von 1 in Toluol(15 mL, 0.66 mmol) wurde bei Raumtemperatur unter Ruhren zu einer Losung von 0.395 g 2 (1.31 mmol) in 25 mL Toluol gegeben. Sofort bildete sich ein gelber Niederschlag. Dieser wurde abfiltriert, mit Aceton gewaschen und im Vakuum getrocknet. So wurden 0.380 g (86%) creme-weiBe Kristalle von 8, Schmp. 245-250 "C (Zers.), erhalten. Die C,H-Analyse lieferte korrekte Werte. IR (Nujol): 1622cm-' (vco). 'H-NMR (200 MHz, CD,Cl,, 25°C): 6 = 7.73-7.55 (m. C,H,). 13C{'H}-NMR (IOOMHz, CD,CI,, 25°C): 91.6 Hz, C=P), 83.10 (m, zentrales C). "P{'H}-NMR (80 MHz, CDCI,, 25°C): 5 = -2.91 (s). FAB-MS in Glycerin: m/z (%): 673 (3) [M+H]+, 672 (2) [MI+'; FAB-MS in m-Nitrobenzylalkohol: 673 (30) [M+H]+, 644 (4) [M-CO]'..

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Homo Dinucleoside-α-hydroxyphosphonate Diesters as Prodrugs of the Antiviral Nucleoside Analogues 2',3'-Dideoxythymidine and 3'-Azido-2',3'-dideoxythymidine

Cited by 20 publications

References 0 publications

Synthesis and Biological Applications of Phosphinates and Derivatives

Synthesis and Biological Applications of Phosphinates and Derivatives

Nucleotide Delivery fromcycloSaligenyl-3′-azido-3′-deoxythymidine Monophosphates (cycloSal-AZTMP)

2‐Nucleos‐5′‐O‐yl‐4H‐1,3,2‐benzodioxaphosphinin‐2‐oxide—ein neues Konzept für lipophile, potentielle Prodrugs biologisch' aktiver Nucleosidmonophosphate

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