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.

Bifunctional Acyclic Nucleoside Phosphonates. 1. Symmetrical 1,3-Bis[(phosphonomethoxy)propan-2-yl] Derivatives of Purines and Pyrimidines

2006 ◽  
Vol 71 (4) ◽  
pp. 543-566 ◽  
Author(s):  
Silvie Vrbovská ◽  
Antonín Holý ◽  
Radek Pohl ◽  
Milena Masojídková
Keyword(s):  
Biological Activity ◽  
Cytostatic Activity ◽  
Secondary Alcohols ◽  
Phosphonic Acids ◽  
Acyclic Nucleoside Phosphonates ◽  
Pyrimidine Bases ◽  
Acyclic Nucleoside ◽  
Derivatives Of ◽  
Purines And Pyrimidines ◽  
General Method

We report here a general method for the synthesis of new symmetrical bis-phosphonates of acyclic nucleosides. 1,3-Bis[(diisopropoxyphosphoryl)methoxy] derivatives of purine and pyrimidine bases were prepared by their reaction with 1,3-bis[(diisopropoxyphosphoryl)-methoxy]propan-2-yl tosylate. Cytosine, uracil and thymine provided regiospecificallyN1-isomers. This alkylation regiospecificity applies to several other tosylates of primary and secondary alcohols as well. 6-Chloropurine and 2-amino-6-chloropurine were alkylated in N9position. Resulting bis-phosphonates were converted to the respective free phosphonic acids and tested for antiviral and cytostatic activity. Despite the fact that no biological activity was found so far, the outcome of this work can serve as a useful tool in synthesis of novel groups of acyclic nucleoside phosphonates (ANPs).

Novel and Efficient Synthesis of gem -Difluorinated Derivatives of Acyclic Nucleoside Phosphonates (ANPs)

2016 ◽  
Vol 1 (10) ◽  
pp. 2102-2106 ◽  
Author(s):  
Karel Pomeisl ◽  
Petr Beier ◽  
Radek Pohl ◽  
Marcela Krečmerová
Keyword(s):  
Efficient Synthesis ◽  
Acyclic Nucleoside Phosphonates ◽  
Acyclic Nucleoside ◽  
Derivatives Of

scholarly journals Dipyridamole Potentiates the Activity of Various Acyclic Nucleoside Phosphonates against Varicella-Zoster Virus, Herpes Simplex Virus and Human Cytomegalovirus

1994 ◽  
Vol 5 (5) ◽  
pp. 312-321 ◽  
Author(s):  
R. Snoeck ◽  
G. Andrei ◽  
J. Balzarini ◽  
D. Reymen ◽  
E. De Clercq
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Varicella Zoster Virus ◽  
Human Cytomegalovirus ◽  
Varicella Zoster ◽  
Antiviral Effects ◽  
Acyclic Nucleoside Phosphonates ◽  
Acyclic Nucleoside ◽  
Simplex Virus ◽  
Derivatives Of

Dypiridamole (DPM) is widely used in the treatment of cardiovascular diseases as a coronary vasodilator and inhibitor of platelet aggregation. Phosphonylmethoxyethyl (PME) and 3-hydroxy-2-phosphonylmethoxypropyl (HPMP) derivatives of purines and pyrimidines are potent and selective inhibitors of varicella-zoster virus (VZV), herpes simplex virus (HSV) and human cytomegalovirus (HCMV). We have found that DPM markedly potentiates the antiviral effects of the PME derivatives of adenine (PMEA) and 2,6-diaminopurine (PMEDAP), and of the HPMP derivatives of adenine (HPMPA), 3-deazaadenine (HPMPc3A) and cyclic HPMPA (cHPMPA). This was reflected by a significant decrease in the 50% inhibitory concentration of the acyclic nucleoside phosphonates for VZV-, HSV- and HCMV-induced cytopathic effect or plaque formation. DPM did not enhance the activity of vidarabine, acyclovir or ganciclovir. These results were confirmed by virus yield assays (for HSV and HCMV) and flow cytometry (for VZV).

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.

New 2-Alkynyl Derivatives of the Acyclic Nucleoside 9-(2,3-Dihydroxypropyl)adenine and Their 6-Guanidinopurine Counterparts as Potential Effectors of Adenosine Receptors

2003 ◽  
Vol 68 (11) ◽  
pp. 2201-2218 ◽  
Author(s):  
Michal Česnek ◽  
Antonín Holý ◽  
Milena Masojídková
Keyword(s):  
Adenosine Receptors ◽  
Sonogashira Coupling ◽  
Acyclic Nucleoside ◽  
Derivatives Of

A series of the new 2-alkynyl derivatives of the acyclic nucleoside 9-(2,3-dihydroxypropyl)- adenine and their 6-guanidinopurine analogues were prepared by the Sonogashira coupling. The effect of the prepared compounds on A1 and A2A receptors was examined.

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