scholarly journals Palladium-catalyzed allylic amination: a powerful tool for the enantioselective synthesis of acyclic nucleoside phosphonates

2017 ◽  
Vol 15 (34) ◽  
pp. 7227-7234 ◽  
Author(s):  
Mariam Azzouz ◽  
Sébastien Soriano ◽  
Margarita Escudero-Casao ◽  
M. Isabel Matheu ◽  
Sergio Castillón ◽  
...  
Keyword(s):  
Enantioselective Synthesis ◽  
High Yield ◽  
Allylic Substitution ◽  
Allylic Amination ◽  
Palladium Catalyzed ◽  
Acyclic Nucleoside Phosphonates ◽  
Acyclic Nucleoside ◽  
Acyclic Nucleoside Phosphonate

Acyclic nucleoside phosphonate were prepared in high yield and up to 92% ee using an enantioselective palladium-catalyzed allylic substitution.

Interaction of Phosphates of the Acyclic Nucleoside Phosphonates with Nucleoside Diphosphate Kinase from Yeast and Bovine Liver

2006 ◽  
Vol 71 (1) ◽  
pp. 35-43 ◽  
Author(s):  
Květoslava Horská ◽  
Ivan Votruba ◽  
Antonín Holý
Keyword(s):  
Nucleoside Diphosphate Kinase ◽  
Bovine Liver ◽  
Kinetic Constants ◽  
Aliphatic Chain ◽  
Ndp Kinase ◽  
Hydroxymethyl Group ◽  
Acyclic Nucleoside Phosphonates ◽  
Acyclic Nucleoside ◽  
Acyclic Nucleoside Phosphonate

The ability of monophosphates of selected acyclic nucleoside phosphonates to serve as substrates for the title NDP kinases was studied. Comparison of the kinetic constants (KM, Vmax, kcat and kcat/KM) estimates indicates that the yeast enzyme catalyzes the phosphorylation of purine and pyrimidine acyclic nucleoside phosphate phosphonates of the 9-[2-(phosphonomethoxy)ethyl] and/or 9-[2-(phosphonomethoxy)propyl] series more efficiently than bovine liver NDP kinase. Yeast enzyme preferentially phosphorylates phosphates of the (phosphono- methoxyalkyl)guanines rather than their adenine counterparts; both enzymes phosphorylate R-enantiomers of the 9-[2-(phosphonomethoxy)propyl] series more efficiently than the corresponding S-enantiomers. Substitution of the aliphatic chain at the position 3 with hydroxymethyl group considerably increases the substrate activity of phosphate of acyclic nucleoside phosphonate. The resulting substrate activity (kcat/KM ratio) of all acyclic nucleoside phosphonate phosphates studied is three to five orders of magnitude lower than that for natural NDPs.

Human N6-Methyl-AMP/DAMP Aminohydrolase (Abacavir 5'-Monophosphate Deaminase) is Capable of Metabolizing N6-Substituted Purine Acyclic Nucleoside Phosphonates

2008 ◽  
Vol 73 (2) ◽  
pp. 275-291 ◽  
Author(s):  
Markéta Schinkmanová ◽  
Ivan Votruba ◽  
Riri Shibata ◽  
Bin Han ◽  
Xiaohong Liu ◽  
...  
Keyword(s):  
Biologically Active ◽  
Side Chain ◽  
Moderate Increase ◽  
Intracellular Metabolite ◽  
Nucleotide Analogs ◽  
Substrate Specificities ◽  
Highly Sensitive ◽  
Acyclic Nucleoside Phosphonates ◽  
Acyclic Nucleoside ◽  
Acyclic Nucleoside Phosphonate

Recombinant human abacavir monophosphate deaminase (hABC-MP deaminase) was compared with the recently described ratN6-methyl-AMP (meAMP) aminohydrolase. hABC-MP deaminase, a 42 kDa polypeptide, exists predominantly as a monomer under non-denaturing conditions. Similar to the rat enzyme, hABC-MP deaminase efficiently catalyzes the hydrolytic deamination of natural substrates meAMP (5),N6,N6-dimethyl-AMP (13) and medAMP (6). Acyclic nucleoside phosphonate (ANP)N6-cyclopropyl-2,6-diamino-9-[2-(phosphonomethoxy)ethyl]purine (cPrPMEDAP) (1), an intermediate intracellular metabolite of antileukemic agent GS-9219, was effectively converted to the corresponding active guanine analog by hABC-MP deaminase. In addition to cPrPMEDAP (1), a number of other biologically activeN6-substituted purine ANPs are alternative substrates for hABC-MP deaminase. The efficiency of their deamination depends on the character ofN6-substitution in the adenine and/or 2,6-diaminopurine ring. ANPs withN6-cyclic substituents are deaminated more readily than corresponding compounds with aliphatic substituents of the same length. The deamination of ANPs is also influenced by modifications at the phosphonoalkyl side chain. Among 9-[2-(phosphonomethoxy)propyl] ANPs, (S)-enantiomers are preferred to (R)-enantiomers. Alternatively, the presence of extended 9-[2-(phosphonoethoxy)ethyl] moiety leads to a moderate increase in the reaction velocity compared to cPrPMEDAP (1). Comparison of hABC-MP deaminase and the rat meAMP aminohydrolase across a broad spectrum ofN6-substituted substrates revealed a strong correlation of their substrate specificities. Similar to the rat meAMP aminohydrolase, hABC-MP deaminase was highly sensitive to deoxycoformycin monophosphate, but not to the guanine product of cPrPMEDAP (1) deamination. Together, these data demonstrate that hABC-MP deaminase is human meAMP aminohydrolase involved in the intracellular activation of biologically activeN6-substituted nucleotide analogs.

scholarly journals Novel Acyclic Nucleoside Phosphonate Analogues with Potent Anti-Hepatitis B Virus Activities

2005 ◽  
Vol 49 (3) ◽  
pp. 1177-1180 ◽  
Author(s):  
C. Ying ◽  
A. Holý ◽  
D. Hocková ◽  
Z. Havlas ◽  
E. De Clercq ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Amino Group ◽  
Wild Type ◽  
Pyrimidine Base ◽  
B Virus ◽  
Acyclic Nucleoside Phosphonates ◽  
Acyclic Nucleoside ◽  
Acyclic Nucleoside Phosphonate

ABSTRACT Novel acyclic nucleoside phosphonates with a pyrimidine base preferentially containing an amino group at C-2 and C-4 and a 2-(phosphonomethoxy)ethoxy or (R)-2-(phosphonomethoxy)propoxy group at C-6 selectively inhibit the replication of wild-type and lamivudine-resistant hepatitis B viruses. The activity of the most potent compounds was comparable to that of adefovir.

Palladium-catalyzed asymmetric allylic amination: enantioselective synthesis of chiral α-methylene substituted β-aminophosphonates

2017 ◽  
Vol 4 (2) ◽  
pp. 271-276 ◽  
Author(s):  
Xubin Wang ◽  
Xiaoming Wang ◽  
Zhaobin Han ◽  
Zheng Wang ◽  
Kuiling Ding
Keyword(s):  
Enantioselective Synthesis ◽  
Allylic Amination ◽  
Palladium Catalyzed

Palladium catalyzed asymmetric allylic amination of 2-diethylphosphonate-substituted allylic acetates in the presence of SKP ligands afforded the corresponding chiral β-aminophosphonates in good yields, high regioselectivities, and excellent enantioselectivities.

scholarly journals Xanthine-based acyclic nucleoside phosphonates with potent antiviral activity against varicella-zoster virus and human cytomegalovirus

2018 ◽  
Vol 26 ◽  
pp. 204020661881305 ◽  
Author(s):  
Ondřej Baszczyňski ◽  
Martin Maxmilian Kaiser ◽  
Michal Česnek ◽  
Petra Břehová ◽  
Petr Jansa ◽  
...  
Keyword(s):  
Purine Nucleotide ◽  
Viral Dna ◽  
Single Digit ◽  
Varicella Zoster ◽  
Dna And Rna ◽  
Wide Range ◽  
Acyclic Nucleoside Phosphonates ◽  
Acyclic Nucleoside ◽  
Human Herpesviruses ◽  
Acyclic Nucleoside Phosphonate

While noncanonic xanthine nucleotides XMP/dXMP play an important role in balancing and maintaining intracellular purine nucleotide pool as well as in potential mutagenesis, surprisingly, acyclic nucleoside phosphonates bearing a xanthine nucleobase have not been studied so far for their antiviral properties. Herein, we report the synthesis of a series of xanthine-based acyclic nucleoside phosphonates and evaluation of their activity against a wide range of DNA and RNA viruses. Two acyclic nucleoside phosphonates within the series, namely 9-[2-(phosphonomethoxy)ethyl]xanthine (PMEX) and 9-[3-hydroxy-2-(phosphonomethoxy)propyl]xanthine (HPMPX), were shown to possess activity against several human herpesviruses. The most potent compound was PMEX, a xanthine analogue of adefovir (PMEA). PMEX exhibited a single digit µM activity against VZV (EC50 = 2.6 µM, TK+ Oka strain) and HCMV (EC50 = 8.5 µM, Davis strain), while its hexadecyloxypropyl monoester derivative was active against HSV-1 and HSV-2 (EC50 values between 1.8 and 4.0 µM). In contrast to acyclovir, PMEX remained active against the TK– VZV 07–1 strain with EC50 = 4.58 µM. PMEX was suggested to act as an inhibitor of viral DNA polymerase and represents the first reported xanthine-based acyclic nucleoside phosphonate with potent antiviral properties.

Catalytic enantioselective synthesis of indolizino[8,7-b]indole alkaloid derivatives based on the tandem reaction of tertiary enamides

2021 ◽  
Author(s):  
Xin-Ming Xu ◽  
Ming Xie ◽  
Jiazhu Li ◽  
Mei-Xiang Wang
Keyword(s):  
Indole Alkaloid ◽  
Enantioselective Synthesis ◽  
High Yield ◽  
Tandem Reaction ◽  
Indole Derivatives

An exquisite Pybox/Cu(OTf)2-catalyzed asymmetric tandem reaction of tertiary enamides was developed, which enabled the expeditious synthesis of indolizino[8,7-b]indole derivatives in high yield, excellent enantioselectivity and diastereoselectivity.

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