Syntheses of Base and Side-Chain Modified Pyrimidine 1-[2-(Phosphonomethoxy)propyl] Derivatives as Potent Inhibitors of Thymidine Phosphorylase (PD-ECGF) from SD-Lymphoma

2006 ◽  
Vol 71 (4) ◽  
pp. 595-624 ◽  
Author(s):  
Karel Pomeisl ◽  
Ivan Votruba ◽  
Antonín Holý ◽  
Radek Pohl
Keyword(s):  
Thymidine Phosphorylase ◽  
Cell Lymphoma ◽  
Inhibitory Effect ◽  
Side Chain ◽  
The Novel ◽  
Inhibitory Potency ◽  
Methyl Group ◽  
Acyclic Nucleoside Phosphonates ◽  
Acyclic Nucleoside ◽  
Trifluoromethyl Groups

In this study we synthesized a series of thymine and 5-ethyluracil acyclic nucleoside phosphonates bearing hydroxymethyl, methoxymethyl, azidomethyl, aminomethyl and (trimethylammonio)methyl group in side chain as potent inhibitors of thymidine phosphorylase. In addition, we investigated in particular the novel syntheses of fluorinated derivatives containing fluoromethyl or trifluoromethyl groups in side chain such as 5-ethyl- 1-[(S)-3-fluoro-2-(phosphonomethoxy)propyl]uracil (8) or 5-ethyl-1-[3,3,3-trifluoro-2-(phosphonomethoxy)propyl]uracil and thymine derivatives 27 and 28. Uracil acyclic nucleoside phosphonates 1-{2-[(diisopropoxyphosphoryl)methoxy]ethyl}uracil (12) and 1-{2-[(diisopropoxyphosphoryl)methoxy]-3,3,3-trifluoropropyl}uracil (19) were fluorinated to corresponding 5-fluorouracil derivatives. While the 5-fluorouracil derivatives exhibit a marginal inhibitory effect, thymine and 5-ethyluracil compound with fluorine in side chains possess considerable inhibitory potency toward thymidine phosphorylase from rat spontaneous T-cell lymphoma.

Efficient one-pot synthesis of polysubstituted 6-[(1H-1,2,3-triazol-1-yl)methyl]uracils through the “click” protocol

2011 ◽  
Vol 76 (9) ◽  
pp. 1121-1131 ◽  
Author(s):  
Petr Jansa ◽  
Petr Špaček ◽  
Ivan Votruba ◽  
Petra Břehová ◽  
Martin Dračínský ◽  
...  
Keyword(s):  
Carboxylic Acids ◽  
Inhibitory Activity ◽  
Thymidine Phosphorylase ◽  
Room Temperature ◽  
One Pot ◽  
Decarboxylation Reaction ◽  
Acyclic Nucleoside Phosphonates ◽  
Acyclic Nucleoside ◽  
Potential Inhibitors ◽  
Substituted 1

The preparation of several triazolo acyclic nucleosides and triazolo acyclic nucleoside phosphonates is described. The synthetic methodology has been developed as an efficient one-pot Cu(I)-catalyzed azide alkyne Huisgen “click” cycloaddition. A novel Cu(I)-catalyzed decarboxylation reaction of 1-substituted 1H-1,2,3-triazole-4-carboxylic acids at room temperature was observed and used for the preparation of 1-substituted 1H-1,2,3-triazoles. As congeners of TPI (Taiho pharmaceutical inhibitor), the prepared compounds were screened as potential inhibitors of human thymidine phosphorylase, but no inhibitory activity was observed.

scholarly journals Antiretroviral activities of acyclic nucleoside phosphonates [9-(2-phosphonylmethoxyethyl)adenine, 9-(2-phosphonylmethoxyethyl)guanine, (R)-9-(2-phosphonylmethoxypropyl)adenine, and MDL 74,968] in cell cultures and murine sarcoma virus-infected newborn NMRI mice.

1997 ◽  
Vol 41 (3) ◽  
pp. 611-616 ◽  
Author(s):  
J Balzarini ◽  
T Vahlenkamp ◽  
H Egberink ◽  
K Hartmann ◽  
M Witvrouw ◽  
...  
Keyword(s):  
Cell Cultures ◽  
Inhibitory Effect ◽  
Nmri Mice ◽  
Immunodeficiency Virus ◽  
Murine Sarcoma Virus ◽  
Acyclic Nucleoside Phosphonates ◽  
Sarcoma Virus ◽  
Acyclic Nucleoside ◽  
Murine Sarcoma ◽  
Infected Newborn

From a side-by-side comparative study, the acyclic nucleoside phosphonates (R)-9-(2-phosphonylmethoxypropyl)adenine [(R)-PMPA] and 9-(2-methylidene-3-phosphonomethoxypropyl)guanine (MDL 74,968) proved more selective in their inhibitory effect on human immunodeficiency virus types 1 and 2, feline immunodeficiency virus, and Moloney murine sarcoma virus (MSV) in cell cultures than the 9-(2-phosphonylmethoxyethyl) derivatives of adenine (PMEA) and guanine (PMEG). In particular, PMEG proved quite toxic. PMEA, (R)-PMPA, and MDL 74,968 afforded a marked delay in MSV-induced tumor initiation in MSV-infected newborn NMRI mice and substantially delayed associated animal death at doses as low as 4 to 10 mg/kg of body weight. Treatment of the NMRI mice with PMEA, (R)-PMPA, and MDL 74,968 at 25 or 50 mg/kg resulted in a high percentage of long-term survivors.

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.

Simple Transformation of Thymine 1-[3-Hydroxy-2-(phosphonomethoxy)propyl] Derivatives to Their 1-[3-Fluoro-2-(phosphonomethoxy)propyl] Counterparts

2005 ◽  
Vol 70 (9) ◽  
pp. 1465-1481 ◽  
Author(s):  
Karel Pomeisl ◽  
Radek Pohl ◽  
Antonín Holý ◽  
Ivan Votruba
Keyword(s):  
Hydroxy Group ◽  
Thymidine Phosphorylase ◽  
Simple Transformation ◽  
Acyclic Nucleoside Phosphonates ◽  
Novel Method ◽  
Acyclic Nucleoside ◽  
Sulfonyl Fluoride

A novel method of transformation of HOCH2 group to FCH2 was successfully applied to the preparation of fluorine-containing pyrimidine acyclic nucleoside phosphonates (FPMP compounds) such as (S)- and (R)-1-[3-fluoro-2-(phosphonomethoxy)propyl]thymine (7a, 7b) (FPMPT). The key displacement of hydroxy group with fluorine in 1-{2-[(diisopropoxyphosphoryl)- methoxy]-3-hydroxypropyl}-4-methoxy-5-methylpyrimidin-2(1H)-one (5a, 5b) was performed using perfluorobutane-1-sulfonyl fluoride in the presence of DBU. Novel pyrimidine acyclic nucleoside phosphonates were investigated as inhibitors of thymidine phosphorylase.

Heparin Counteracts the Antiaggregating Effect of Prostacyclin by Potentiating Platelet Aggregation

1983 ◽  
Vol 49 (02) ◽  
pp. 081-083 ◽  
Author(s):  
Vittorio Bertelé ◽  
Maria Carla Roncaglioni ◽  
Maria Benedetta Donati ◽  
Giovanni de Gaetano
Keyword(s):  
Platelet Aggregation ◽  
Human Platelet ◽  
Specific Interaction ◽  
Inhibitory Effect ◽  
Effective Inhibitor ◽  
Inhibitory Potency ◽  
Human Platelet Aggregation

SummaryIt has recently been reported that heparin neutralizes the inhibitory effect of prostacyclin (PGI2) on human platelet aggregation. The mechanism of this interaction has not yet been unequivocally established. We present here evidence that heparin (Liquemin Roche) does not react directly with PGI2 but counteracts its inhibitory effect by potentiating platelet aggregation. In the absence of heparin, PGI2 was a less effective inhibitor of platelet aggregation induced by the combination of ADP and serotonin than by ADP alone. Moreover, the inhibitory effect of PGI2 was similarly reduced when increasing the concentrations of ADP (in the absence of heparin). The lack of a specific interaction between heparin and PGI2 is supported by the observation that, in the presence of heparin, other prostaglandins such as PGD2 and PGE1, and a non-prostanoid compound such as adenosine also appeared to lose their inhibitory potency. It is concluded that heparin opposes platelet aggregation inhibitory effect of PGI2 by enhancement of platelet aggregation.

Comparison of the Potency of 8-L-Arginine, 8-D-Arginine and 8-D-Homoarginine Vasopressin Analogs with Substituted Phenylalanine in Position 2

1994 ◽  
Vol 59 (6) ◽  
pp. 1439-1450 ◽  
Author(s):  
Miroslava Žertová ◽  
Jiřina Slaninová ◽  
Zdenko Procházka
Keyword(s):  
Amino Acid ◽  
Solid Phase Synthesis ◽  
Solid Phase ◽  
Basic Amino Acid ◽  
The Other ◽  
Side Chain ◽  
Inhibitory Potency ◽  
Phase Synthesis ◽  
Other Hand ◽  
Order Of Magnitude

An analysis of the uterotonic potencies of all analogs having substituted L- or D-tyrosine or -phenylalanine in position 2 and L-arginine, D-arginine or D-homoarginine in position 8 was made. The series of analogs already published was completed by the solid phase synthesis of ten new analogs having L- or D-Phe, L- or D-Phe(2-Et), L- or D-Phe(2,4,6-triMe) or D-Tyr(Me) in position 2 and either L- or D-arginine in position 8. All newly synthesized analogs were found to be uterotonic inhibitors. Deamination increases both the agonistic and antagonistic potency. In the case of phenylalanine analogs the change of configuration from L to D in position 2 enhances the uterotonic inhibition for more than 1 order of magnitude. The L to D change in position 8 enhances the inhibitory potency negligibly. Prolongation of the side chain of the D-basic amino acid in position 8 seems to decrease slightly the inhibitory potency if there is L-substituted amino acid in position 2. On the other hand there is a tendency to the increase of the inhibitory potency if there is D-substituted amino acid in position 2.

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