Alternative synthesis of 9-{3-[(diisopropoxyphosphoryl)methoxy]-2-hydroxypropyl}adenine and its free phosphonates substituted at the C-8 position of purine base

2010 ◽  
Vol 75 (3) ◽  
pp. 371-381 ◽  
Author(s):  
Zlatko Janeba ◽  
Milena Masojídková ◽  
Antonín Holý
Keyword(s):  
Antiviral Activity ◽  
Allyl Alcohol ◽  
Alkylating Agent ◽  
Bromine Atom ◽  
General Interest ◽  
Nucleophilic Substitutions ◽  
Purine Base ◽  
Alternative Synthesis ◽  
Acyclic Nucleoside Phosphonates ◽  
Acyclic Nucleoside

For its high therapeutic effect, (S)-9-[3-hydroxy-2-(phosphonomethoxy)propyl]adenine (HPMPA) is an important member of a class of acyclic nucleoside phosphonates (ANPs). Although its constitutional isomer, 9-[2-hydroxy-3-(phosphonomethoxy)propyl]adenine (iso-HPMPA), exhibits no antiviral activity, our general interest in C-8 substituted adenine ANPs led us to prepare certain iso-HPMPA derivatives modified at the C-8 position of adenine. Novel alkylating agent, diisopropyl {[2-(tetrahydro-2-pyranyl)oxy-3-tosyloxypropoxy]methyl}phosphonate (9), was prepared by procedure starting from allyl alcohol (4). 9-{3-[(Diisopropoxyphosphoryl)methoxy]-2-hydroxypropyl}adenine (12) was prepared by alkylation of adenine with the alkylating agent 9 followed by acid hydrolysis, although elimination by-product 9-{3-[(diisopropoxyphosphoryl)methoxy]prop-1-enyl}adenine (11) predominated in the reaction mixture. Bromination of the compound 12 gave 8-bromoadenine derivative 13 quantitatively. Nucleophilic substitutions of the bromine atom of compound 13 with N- and O-nucleophiles, followed by phosphonate deprotection, afforded the free phoshonic acids 15–18.

Versatile synthesis of oxime-containing acyclic nucleoside phosphonates – synthetic solutions and antiviral activity

2015 ◽  
Vol 13 (44) ◽  
pp. 10946-10956
Author(s):  
Pavel N. Solyev ◽  
Maxim V. Jasko ◽  
Alla A. Kleymenova ◽  
Marina K. Kukhanova ◽  
Sergey N. Kochetkov
Keyword(s):  
Antiviral Activity ◽  
Wide Spectrum ◽  
Different Types ◽  
Acyclic Nucleoside Phosphonates ◽  
Spectrum Activity ◽  
Acyclic Nucleoside

New oxime-containing acyclic nucleoside phosphonates 9-{2-[(phosphonomethyl)oximino]ethyl}adenine (1), -guanine (2) and 9-{2-[(phosphonomethyl)oximino]propyl}adenine (3) with wide spectrum activity against different types of viruses were synthesized.

Bifunctional Acyclic Nucleoside Phosphonates: 2. Symmetrical 2-{[Bis(phosphono)methoxy]methyl}ethyl Derivatives of Purines and Pyrimidines

2007 ◽  
Vol 72 (7) ◽  
pp. 965-983 ◽  
Author(s):  
Silvie Vrbková ◽  
Martin Dračínský ◽  
Antonín Holý
Keyword(s):  
Building Block ◽  
Alkylating Agent ◽  
Cytostatic Activity ◽  
Arbuzov Reaction ◽  
Methyl Ethyl ◽  
Acyclic Nucleoside Phosphonates ◽  
Bisphosphonic Acids ◽  
Acyclic Nucleoside ◽  
Derivatives Of ◽  
Purines And Pyrimidines

Novel bisphosphonate alkylating agent, tetraisopropyl {2-[(mesyloxy)methyl]propane-1,3-diyl}bis(oxymethylene)bisphosphonate 19, was synthesized from diethyl 2,2-bis(hydroxymethyl)malonate. Decarbethoxylation of the diethyl 2,2-dimethyl-1,3-dioxane-5,5-dicarboxylate was followed by chloromethylation of 2-[(benzyloxy)methyl]propane-1,3-diol and Arbuzov reaction with triisopropyl phosphite. Bisphosphonate building block 19 was used in the alkylation of various nucleobases (2-amino-6-chloropurine, adenine, 2-amino-6-(cyclopropyl)aminopurine, cytosine, uracil and 4-methoxy-5-methylpyrimidin-2(1H)-one). N9-Substituted purines and N1-substituted pyrimidines were converted to appropriate free bisphosphonic acids. No antiviral or cytostatic activity was detected.

scholarly journals New prodrugs of two pyrimidine acyclic nucleoside phosphonates: Synthesis and antiviral activity

2017 ◽  
Vol 25 (17) ◽  
pp. 4637-4648 ◽  
Author(s):  
Marcela Krečmerová ◽  
Martin Dračínský ◽  
Robert Snoeck ◽  
Jan Balzarini ◽  
Karel Pomeisl ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Acyclic Nucleoside Phosphonates ◽  
Acyclic Nucleoside

New in vitro method for evaluating antiviral activity of acyclic nucleoside phosphonates against plant viruses

2010 ◽  
Vol 88 (3) ◽  
pp. 296-303 ◽  
Author(s):  
J. Špak ◽  
A. Holý ◽  
D. Pavingerová ◽  
I. Votruba ◽  
V. Špaková ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Plant Viruses ◽  
In Vitro Method ◽  
Acyclic Nucleoside Phosphonates ◽  
Acyclic Nucleoside

scholarly journals Inhibition of Herpesvirus Replication by Hexadecyloxypropyl Esters of Purine- and Pyrimidine-Based Phosphonomethoxyethyl Nucleoside Phosphonates

2008 ◽  
Vol 52 (12) ◽  
pp. 4326-4330 ◽  
Author(s):  
Mark N. Prichard ◽  
Caroll B. Hartline ◽  
Emma A. Harden ◽  
Shannon L. Daily ◽  
James R. Beadle ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Epstein Barr Virus ◽  
Hiv Infections ◽  
Barr Virus ◽  
Immunodeficiency Virus ◽  
Acyclic Nucleoside Phosphonates ◽  
Acyclic Nucleoside ◽  
Epstein Barr ◽  
Simplex Virus ◽  
Ester Prodrugs

ABSTRACT Patients infected with human immunodeficiency virus (HIV) often suffer from herpesvirus infections as a result of immunosuppression. These infections can occur while patients are receiving antiretroviral therapy, and additional drugs required to treat their infection can adversely affect compliance. It would be useful to have antivirals with a broader spectrum of activity that included both HIV and the herpesviruses. We reported previously that alkoxyalkyl ester prodrugs of cidofovir are up to 3 orders of magnitude more active against herpesvirus replication and may be less toxic than the unmodified drug. To determine if this strategy would be effective for certain phosphonomethoxyethyl nucleoside phosphonates which are also active against HIV infections, the hexadecyloxypropyl (HDP) esters of 1-(phosphonomethoxyethyl)-cytosine, 1-(phosphonomethoxyethyl)-5-bromo-cytosine (PME-5BrC), 1-(phosphonomethoxyethyl)-5-fluoro-cytosine, 9-(phosphonomethoxyethyl)-2,6-diaminopurine (PME-DAP), and 9-(phosphonomethoxyethyl)-2-amino-6-cyclopropylaminopurine (PME-cPrDAP) were evaluated for activity against herpesvirus replication. The HDP esters were substantially more active than the unmodified acyclic nucleoside phosphonates, indicating that esterification with alkoxyalkyl groups increases the antiviral activity of many acyclic nucleoside phosphonates. The most interesting compounds included HDP-PME-cPrDAP and HDP-PME-DAP, which were 12- to 43-fold more active than the parent nucleoside phosphonates against herpes simplex virus and cytomegalovirus, and HDP-PME-cPrDAP and HDP-PME-5BrC which were especially active against Epstein-Barr virus. The results presented here indicate that HDP-esterified acyclic nucleoside phosphonates with antiviral activity against HIV also inhibit the replication of some herpesviruses and can extend the spectrum of activity for these compounds.

scholarly journals Antiviral Activities of Novel 5-Phosphono-Pent-2-en-1-yl Nucleosides and Their Alkoxyalkyl Phosphonoesters

2006 ◽  
Vol 51 (2) ◽  
pp. 611-615 ◽  
Author(s):  
Hyunah Choo ◽  
James R. Beadle ◽  
Earl R. Kern ◽  
Mark N. Prichard ◽  
Kathy A. Keith ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Antiviral Activity ◽  
Oral Bioavailability ◽  
Dna Viruses ◽  
B Virus ◽  
Acyclic Nucleoside Phosphonates ◽  
Antiviral Activities ◽  
Acyclic Nucleoside

ABSTRACT Three acyclic nucleoside phosphonates are currently approved for clinical use against infections caused by cytomegalovirus (Vistide), hepatitis B virus (Hepsera), and human immunodeficiency virus type 1 (Viread). This important antiviral class inhibits viral polymerases after cellular uptake and conversion to their diphosphates, bypassing the first phosphorylation, which is required for conventional nucleoside antivirals. Small chemical alterations in the acyclic side chain lead to marked differences in antiviral activity and the spectrum of activity of acyclic nucleoside phosphonates against various classes of viral agents. We synthesized a new class of acyclic nucleoside phosphonates based on a 5-phosphono-pent-2-en-1-yl base motif in which the oxygen heteroatom usually present in acyclic nucleoside phosphonates has been replaced with a double bond. Since the intrinsic phosphonate moiety leads to low oral bioavailability and impaired cellular penetration, we also prepared the hexadecyloxypropyl esters of the 5-phosphono-pent-2-en-1-yl nucleosides. Our earlier work showed that this markedly increases antiviral activity and oral bioavailability. Although the 5-phosphono-pent-2-en-1-yl nucleosides themselves were not active, the hexadecyloxypropyl esters were active against DNA viruses and hepatitis B virus, in vitro. Notably, the hexadecyloxypropyl ester of 9-(5-phosphono-pent-2-en-1-yl)-adenine was active against hepatitis B virus mutants resistant to lamivudine, emtricitabine, and adefovir.

scholarly journals Acyclic nucleoside phosphonates with a branched 2-(2-phosphonoethoxy)ethyl chain: Efficient synthesis and antiviral activity

2011 ◽  
Vol 19 (15) ◽  
pp. 4445-4453 ◽  
Author(s):  
Dana Hocková ◽  
Antonín Holý ◽  
Graciela Andrei ◽  
Robert Snoeck ◽  
Jan Balzarini
Keyword(s):  
Antiviral Activity ◽  
Efficient Synthesis ◽  
Acyclic Nucleoside Phosphonates ◽  
Acyclic Nucleoside

Antiviral Activity of Acyclic Nucleoside Phosphonates with Branched 2-(2-Phosphonoethoxy)ethyl Chain

2010 ◽  
Vol 86 (1) ◽  
pp. A56
Author(s):  
Dana Hocková ◽  
Antonín Holý ◽  
Graciela Andrei ◽  
Robert Snoeck ◽  
Jan Balzarini
Keyword(s):  
Antiviral Activity ◽  
Acyclic Nucleoside Phosphonates ◽  
Acyclic Nucleoside
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