Inhibition of human ornithine decarboxylase activity by enantiomers of difluoromethylornithine

Qu, Ning; Ignatenko, Natalia A.; Yamauchi, Phillip; Stringer, David E.; Levenson, Corey; Shannon, P. R. M.; Perrin, Scott R.; Gerner, Eugene W.

doi:10.1042/bj20030382

Cited by 52 publications

(62 citation statements)

References 26 publications

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“…Later research revealed another drawback of oral eflornithine. In rat liver, L-eflornithine (L-difluoromethylornithine) was more effective in irreversibly inhibiting ornithine decarboxylase than D-eflornithine (D-difluoromethylornithine) (128). The mean bioavailability of L-and D-eflornithine in rats was 41% and 62%, respectively, indicating that eflornithine exhibits enantioselective absorption, the more potent L-isomer being less favoured (129).…”

Section: Eflornithinementioning

confidence: 96%

“…A variety of explanations have been put forward to explain the origin of gambiense HAT outbreaks and their tendency to recur (128). Many factors are probably involved; they include sudden modifications to the environment (e.g.…”

Section: Gambiense Human African Trypanosomiasismentioning

confidence: 99%

“…The availability of individual rapid diagnostic tests has been a major step forwards in answering the needs of increased integration of HAT control into the health system. Additional studies on the performance, cost-effectiveness and ease of implementation of these rapid diagnostic tests are being conducted (26,128) to better understand their optimal implementation in different settings. In order to further avoid nonspecific reactions and to standardize and facilitate the test production process, the possibility of replacing the native proteins used as antigens in these tests by recombinant proteins or synthetic peptides is being investigated (24,129).…”

Section: New Developments and Outlookmentioning

confidence: 99%

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6-Arylpyrazine-2-carboxamides: A New Core for Trypanosoma brucei Inhibitors

et al. 2015

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From a whole-organism high throughput screen of approximately 87000 compounds against Trypanosoma brucei brucei, we recently identified eight new unique compounds for the treatment of human African trypanosomiasis. In an effort to understand the structure−activity relationships around these compounds, we report for the first time our results on a new class of trypanocides, the pyrazine carboxamides. Attracted by the low molecular weight (270 g•mol −1 ) of our starting hit (9) and its potency (0.49 μM), the SAR around the core was explored, leading to compounds having an EC 50 as low as 25 nM against T. b. brucei and being more than 1500 times less toxic against mammalian L6 and HEK293 cell lines. The most potent compounds in the series were exquisitely selective for T. brucei over a panel of other protozoan parasites, showing an excellent correlation with the human infective parasite Trypanosoma brucei rhodesiense, the most potent compound (65) having an EC 50 of 24 nM. The compounds are highly drug-like and are able to penetrate the CNS, their only limitation currently being their rate of microsomal metabolism. To that effect, efforts to identify potential metabolites of selected compounds are also reported.

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Section: Eflornithinementioning

confidence: 96%

Section: Gambiense Human African Trypanosomiasismentioning

confidence: 99%

Section: New Developments and Outlookmentioning

confidence: 99%

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6-Arylpyrazine-2-carboxamides: A New Core for Trypanosoma brucei Inhibitors

et al. 2015

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“…For example, in the case of well studied ornithine decarboxylase, only L-Orn is a substrate, whereas the D-isomer is a competitive inhibitor (31). However, in the case of ␣-difluoromethylornithine, which is an enzyme-activated inhibitor of ornithine decarboxylase, both L-and D-isomers are substrates (32), since the inhibitor must be first decarboxylated in order to produce a reactive intermediate, which is responsible for the irreversible inhibition of the enzyme (33). We tested several aldehydes in PAO-dependent oxidation of (R)-and (S)-MeSpd (Table 1 and supplemental Table S1).…”

Section: Tablementioning

confidence: 99%

Guide Molecule-driven Stereospecific Degradation of α-Methylpolyamines by Polyamine Oxidase

Järvinen

Keinänen

Grigorenko

et al. 2006

Journal of Biological Chemistry

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FAD-dependent polyamine oxidase (PAO; EC 1.5.3.11) is one of the key enzymes in the catabolism of polyamines spermidine and spermine. The natural substrates for the enzyme are N 1 -acetylspermidine, N 1 -acetylspermine, and N 1 ,N 12 -diacetylspermine. Here we report that PAO, which normally metabolizes achiral substrates, oxidized (R)-isomer of 1-amino-8-acetamido-5-azanonane and N 1 -acetylspermidine as efficiently while (S)-1-amino-8-acetamido-5-azanonane was a much less preferred substrate. It has been shown that in the presence of certain aldehydes, the substrate specificity of PAO and the kinetics of the reaction are changed to favor spermine and spermidine as substrates. Therefore, we examined the effect of several aldehydes on the ability of PAO to oxidize different enantiomers of ␣-methylated polyamines. PAO supplemented with benzaldehyde predominantly catalyzed the cleavage of (R)-isomer of ␣-methylspermidine, whereas in the presence of pyridoxal the (S)-␣-methylspermidine was preferred. PAO displayed the same stereospecificity with both singly and doubly ␣-methylated spermine derivatives when supplemented with the same aldehydes. Structurally related ketones proved to be ineffective. This is the first time that the stereospecificity of FAD-dependent oxidase has been successfully regulated by changing the supplementary aldehyde. These findings might facilitate the chemical regulation of stereospecificity of the enzymes.Polyamines, spermidine (Spd), 3 and spermine (Spm) and their precursor, putrescine, are present at millimolar concentrations in mammalian cells (1). They are essential for cell growth, participate in the regulation of cellular metabolism and physiology (2, 3). Their cellular levels are strictly controlled at various levels including the synthesis, degradation, uptake, and excretion (4, 5). Furthermore, the polyamine homeostasis is also regulated by a rapid interconversion (6 -8) that in part offers means to supply proper polyamines for each individual process. Spd and Spm appear to be able to substitute for each other to some extent (9, 10). The exact cellular roles of each individual polyamine, however, are not well known (11). One of the approaches to elucidate the impact of each individual polyamine in biological processes is the use of metabolically stable Spd and Spm analogues. Examples of such compounds are MeSpd and bis-␣,␣Ј-methylspermine (Me 2 Spm) that are able to fulfill many of the cellular functions of their native counterparts.Earlier, we have successfully used racemic ␣-methyl analogs of polyamines to study the role of each individual polyamine in vivo. Both MeSpd and Me 2 Spm are capable of preventing acute pancreatitis and restoring early liver regeneration after partial hepatectomy under the condition of severe depletion of the natural polyamines in transgenic rats (12, 13).The interaction of racemic MeSpd with recombinant human PAO (hPAO) in the presence of benzaldehyde (BA), which allows the enzyme to oxidize nonacetylated Spd, led to the formation of putrescine (13)....

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“…Eflornithine elicits its pharmacological effect by irreversible inhibition of ornithine decarboxylase, blocking polyamine biosynthesis in trypanosomes (3,18). It has also been shown that compared to D-eflornithine, the L-enantiomer exhibits Ͼ20 times higher affinity for the target enzyme ornithine decarboxylase in mammalian cells (18).…”

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confidence: 99%

Enantioselective and Nonlinear Intestinal Absorption of Eflornithine in the Rat

Jansson

Malm

Roth

et al. 2008

Antimicrob Agents Chemother

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This study aimed to investigate if the absorption of the human African trypanosomiasis agent eflornithine was stereospecific and dose dependent after oral administration. Male Sprague-Dawley rats were administered single doses of racemic eflornithine hydrochloride as an oral solution (750, 1,500, 2,000, or 3,000 mg/kg of body weight) or intravenously (375 or 1,000 mg/kg of body weight). Sparse blood samples were obtained for determination of eflornithine enantiomers by liquid chromatography with evaporative light-scattering detection (lower limit of quantification [LLOQ], 83 M for 300 l plasma). The full plasma concentration-time profile of racemic eflornithine following frequent sampling was determined for another group of rats, using a high-performance liquid chromatography-UV method (LLOQ, 5 M for 50 l plasma). Pharmacokinetic data were analyzed in NONMEM for the combined racemic and enantiomeric concentrations. Upon intravenous administration, the plasma concentration-time profile of eflornithine was biphasic, with marginal differences in enantiomer kinetics (mean clearances of 14.5 and 12.6 ml/min/kg for L-and D-eflornithine, respectively). The complex absorption kinetics were modeled with a number of transit compartments to account for delayed absorption, transferring the drug into an absorption compartment from which the rate of influx was saturable. The mean bioavailabilities for L-and D-eflornithine were 41% and 62%, respectively, in the dose range of 750 to 2,000 mg/kg of body weight, with suggested increases to 47% and 83%, respectively, after a dose of 3,000 mg/kg of body weight. Eflornithine exhibited enantioselective absorption, with the more potent L-isomer being less favored, a finding which may help to explain why clinical attempts to develop an oral treatment have hitherto failed. The mechanistic explanation for the stereoselective absorption remains unclear.

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Inhibition of human ornithine decarboxylase activity by enantiomers of difluoromethylornithine

Cited by 52 publications

References 26 publications

6-Arylpyrazine-2-carboxamides: A New Core for Trypanosoma brucei Inhibitors

6-Arylpyrazine-2-carboxamides: A New Core for Trypanosoma brucei Inhibitors

Guide Molecule-driven Stereospecific Degradation of α-Methylpolyamines by Polyamine Oxidase

Enantioselective and Nonlinear Intestinal Absorption of Eflornithine in the Rat

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