Biomedical subjects

W R Weimar

Publications and source records attributed to W R Weimar.

At least 19 recordsLinked to original sources

PubMed2001

Synthesis and evaluation of hydroxylated polyamine analogues as antiproliferatives.

A new means of accessing N(1)-cyclopropylmethyl-N(11)-ethylnorspermine (CPMENSPM) and the first synthesis of (2R,10S)-N(1)-cyclopropylmethyl-2,10-dihydroxy-N(11)-ethylnorspermine [(2R,10S)-(HO)(2)CPMENSPM] are described. Both of these polyamine analogues are shown to be more active against L1210 murine leukemia cell growth than either N(1),N(11)-diethylnorspermine (DENSPM) or (2R,10R)-N(1),N(11)-diethyl-2,10-dihydroxynorspermine [(2R,10R)-(HO)(2)DENSPM] after 96 h of treatment; the activity was comparable to that of (2S,10S)-N(1),N(11)-diethyl-2,10-dihydroxynorspermine [(2S,10S)-(HO)(2)DENSPM] at 96 h. Both cyclopropyl compounds reduced putrescine and spermidine pools, but less effectively than did DENSPM and its derivatives. Only CPMENSPM, and not (2R,10S)-(HO)(2)CPMENSPM, lowered spermine pools. As with DENSPM and (2R,10R)-(HO)(2)DENSPM, both cyclopropyl analogues diminished ornithine decarboxylase and S-adenosylmethionine decarboxylase activity. Unlike the hydroxylated DENSPM compounds, both cyclopropyl norspermines substantially upregulated spermidine/spermine N(1)-acetyltransferase. The most interesting effect of hydroxylating CPMENSPM is the profound reduction in toxicity compared with that of the parent drug. The same phenomenon had been observed for the DENSPM/(2R,10R)-(HO)(2)DENSPM pair. Thus, hydroxylation of norspermine analogues appears to be a way to maintain the compounds' antiproliferative activity while reducing their toxicity.

Acetyltransferases↗

PubMed2001

Significance of asymmetric sites in choosing siderophores as deferration agents.

The syntheses of the microbial iron chelators L-fluviabactin, its unnatural enantiomer, D-fluviabactin, L-homofluviabactin, and L-agrobactin, are described. The key steps involve the selective bis-acylation of the terminal nitrogens of norspermidine, spermidine, or homospermidine with 2,3-bis(benzyloxy)benzoic acid in the presence of 1,1-carbonyldiimidazole, followed by coupling of the N-hydroxysuccinimide ester of CBZ-protected L- or D-threonine with the central nitrogen. The effectiveness of each of these ligands in supporting the growth of Paracoccus denitrificans in a low-iron environment and the ability of these compounds to promote iron uptake are evaluated. The stereochemical configuration of the oxazoline ring is shown to be the major structural factor controlling both microbial growth stimulation and iron uptake. L-Fluviabactin, L-homofluviabactin, and L-agrobactin all promoted growth and iron uptake; D-fluviabactin was only marginally active. As with the microorganism's native siderophore, L-parabactin, all three ligands in the L-configuration investigated exhibited biphasic, i.e., both high-affinity and low-affinity, kinetics. The high-affinity system (iron concentration < 1 microM) yielded K(m) values between 0.11 and 0.23 microM and V(max) values from 157 to 129 pg-atoms Fe min(-1) (mg of protein)(-1), whereas the low-affinity scheme (iron concentration > 1 microM) gave K(m) values from 0.53 to 3.5 microM and V(max) values between 96 and 413 pg-atoms Fe min(-1) (mg of protein)(-1). Both L- and D-fluviabactin are very effective at clearing iron from the bile duct-cannulated rodent; when given subcutaneously at a dose of 150 micromol/kg, both ligands had iron clearing efficiencies of >13%, which is much greater than that of desferrioxamine in this model. Thus, by altering the stereochemistry of certain microbial siderophores, it is possible to generate deferration agents that are still effective at clearing iron from animals, yet do not promote microbial growth.

Animals↗

PubMed2001

Polyamine analogue antidiarrheals: a structure-activity study.

The syntheses of a group of spermine polyamine analogues and their evaluation as antidiarrheals are described. Each compound was assessed in a rodent castor oil-induced diarrhea model for its ability to reduce stool output and weight loss in a dose-dependent manner. The spermine pharmacophore is shown to be an excellent platform from which to construct antidiarrheals. The activity of the compounds is very dependent on both the nature of the terminal alkyl groups and the geometry of the methylene spacers separating the nitrogens. The toxicity profile is also quite dependent on these same structural features. On the basis of subcutaneous dose-response data and toxicity profiles, two compounds, N(1),N(12)-diisopropylspermine and N(1),N(12)-diethylspermine, were taken forward into more complete evaluation. These measurements included formal acute and chronic toxicity trials, drug and metabolic tissue distribution studies, and assessment of the impact of these analogues on tissue polyamine pools. Finally, the remarkable activity of N,N'-bis[3-(ethylamino)propyl]-trans-1,4-cyclohexanediamine underscores the need to further explore this framework as a pharmacophore for the construction of other antidiarrheal agents.

Administration, Oral↗

PubMed2000

Metabolism and pharmacokinetics of N1,N11-diethylnorspermine in a Cebus apella primate model.

The tissue distribution, metabolic profile, and pharmacokinetic parameters of i.v.-administered N1,N11-diethylnorspermine (DENSPM) are evaluated in Cebus apella primates, and the results are compared with data gathered from canine and human studies. Although the metabolic processing of DENSPM (i.e., deethylation and deaminopropylation) in dogs and primates is very similar, there are some significant differences in tissue distribution of the parent drug. In dogs, the organ concentration of DENSPM follows the order kidney >> liver approximately = lung > spleen. In the primate, the order is liver >> kidney approximately = spleen > lung. The difference in pharmacokinetic parameters between the species is profound with (area under the time-concentration curve)primate << (area under the time-concentration curve)dog; (terminal elimination half-life)primate << (terminal elimination half-life)dog; and (mean residence time)primate << (mean residence time)dog. The most notable difference between dogs and primates is seen in the fraction of parent drug excreted unchanged in the urine, 50% in the dog and < 1% in the primate. However, the pharmacokinetic parameters and urinary drug clearance in C. apella primates are remarkably similar to those in humans. Thus, C. apella is established as an excellent model for assessing the metabolism, tissue distribution, and pharmacokinetic properties of polyamine analogues.

Animals↗

PubMed2000

Synthesis and evaluation of hydroxylated polyamine analogues as antiproliferatives.

The synthesis of four hydroxylated polyamine analogues, (2R, 10R)-N(1),N(11)-diethyl-2,10-dihydroxynorspermine, (2S,10S)-N(1), N(11)-diethyl-2,10-dihydroxynorspermine, (3S,12S)-N(1), N(14)-diethyl-3,12-dihydroxyhomospermine, and (3R,12R)-N(1), N(14)-diethyl-3,12-dihydroxyhomospermine, is described along with their impact on the growth and polyamine metabolism of L1210 murine leukemia cells. Four different synthetic approaches are set forth, two each for the hydroxylated norspermines and for the hydroxylated homospermines. The key step in the assembly of the norspermines was the coupling of either N-[(2R)-2,3-epoxypropyl]-N-ethyl p-toluenesulfonamide or N-[(2S)-2,3-epoxypropyl]-N-ethyl trifluoromethanesulfonamide to N,N'-dibenzyl-1,3-diaminopropane. The key step with homospermines employed alkylation of putrescine with (3S)-N-(benzyloxycarbonyl)-N-ethyl-3,4-epoxybutylamine or of N, N'-bis(mesitylenesulfonyl)-1,4-butanediamine with (2R)-2-benzyloxy-4-[N-(mesitylenesulfonyl)ethylamino]-O-tosyl-1-++ +butan ol. All of the hydroxylated analogues were active against L1210 cells with 96-h IC(50) values of </=2 microM, and they also effectively reduced putrescine and spermidine, although the effect on spermine pools ranged from moderate to insignificant. Interestingly, the impact of the hydroxylated analogues on ornithine decarboxylase (ODC) was significantly less than that of unhydroxylated parent drug (e.g., N(1),N(11)-diethylnorspermine [DENSPM]) at 1 microM; however, S-adenosylmethionine decarboxylase (AdoMetDC) depletion was nearly identical to what was observed in cells treated with parent drug. The most notable difference between the parent and hydroxylated analogues was seen with spermidine/spermine N(1)-acetyltransferase (SSAT) upregulation in the DENSPM series. The hydroxylated analogues, especially (R, R)-(HO)(2)DENSPM, were much less effective at upregulation than the parent DENSPM. Finally, a comparison of the toxicity of (R, R)-(HO)(2)DENSPM with that of DENSPM at subchronic doses revealed that the neurological effects seen with DENSPM were now absent.

Animals↗

PubMed1999

Effects of C-4 stereochemistry and C-4' hydroxylation on the iron clearing efficiency and toxicity of desferrithiocin analogues.

Additional structure-activity studies of desferrithiocin analogues are carried out. The effects of stereochemistry at C-4 on the ligands' iron clearing efficiency are reviewed and assessed using the enantiomers 4,5-dihydro-2-(2, 4-dihydroxyphenyl)thiazole-4(R)-carboxylic acid and 4,5-dihydro-2-(2, 4-dihydroxyphenyl)thiazole-4(S)-carboxylic acid. The utility of 4'-hydroxylation as a method of reducing the toxicity of desazadesferrithiocin analogues is also examined further with the synthesis and in vivo comparison of 4, 5-dihydro-2-(2-hydroxyphenyl)-4-methylthiazole-4(S)-carboxylic acid, which is the natural product 4-methylaeruginoic acid, and 4, 5-dihydro-2-(2,4-dihydroxyphenyl)-4-methylthiazole-4(S)-carboxylic acid. The stereochemistry at C-4 is shown to have a substantial effect on the iron clearing efficiency of desferrithiocin analogues, as does C-4'-hydroxylation on the toxicity profile. All of the compounds are evaluated in a bile-duct-cannulated rodent model to determine iron clearance efficiency and are carried forward to the iron-overloaded primate for iron clearing measurements. On the basis of the results of the present work, although 4,5-dihydro-2-(2, 4-dihydroxyphenyl)thiazole-4(S)-carboxylic acid is still the most promising candidate for clinical evaluation, 4,5-dihydro-2-(2, 4-dihydroxyphenyl)-4-methylthiazole-4(S)-carboxylic acid (4'-hydroxydesazadesferrithiocin) also merits further preclinical assessment.

Animals↗

PubMed1999

Desazadesmethyldesferrithiocin analogues as orally effective iron chelators.

Further structure-activity studies of desferrithiocin analogues are carried out. (S)-Desazadesmethyldesferrithiocin, 2-(2-hydroxyphenyl)-Delta2-thiazoline-4(S)-carboxylic acid, serves as the principal framework in the current paper. Desazadesmethyldesferrithiocin can be structurally altered with facility, and data are already available on its iron-clearing properties and toxicity parameters. Four different kinds of structural modifications of this framework are undertaken: introduction of hydroxy, carboxy, or methoxy groups on the aromatic ring; alteration of the thiazoline ring; increasing the distance between the ligand donor atoms; and benz-fusion of the aromatic rings. The structural modifications described are shown to have a tremendous impact on both the iron clearance and toxicity profiles of the desazadesmethyldesferrithiocin molecule. All of the compounds are assessed in a bile-duct-cannulated rodent model to determine iron clearance efficiency. Ligands which demonstrate an efficiency of greater than 2% are carried forward to the iron-overloaded primate for iron-clearing measurements. Ligands with efficiencies greater than 3% in the primate are then evaluated in a formal toxicity study in rodents. On the basis of the results of the present work, 2-(2, 4-dihydroxyphenyl)-Delta2-thiazoline-4(S)-carboxylic acid is a promising candidate for clinical evaluation.

Administration, Oral↗

PubMed1999

Pharmacokinetics of orally administered desferrithiocin analogs in cebus apella primates.

The pharmacokinetic behavior of three iron chelators based on the desferrithiocin (DFT) pharmacophore, (S)-4, 5-dihydro-2-(2-hydroxyphenyl)-4-thiazolecarboxylic acid (desmethyldesferrithiocin, DMDFT, 2); (S)-4,5-dihydro-2-(2, 4-dihydroxyphenyl)-4-thiazolecarboxylic acid [4-(S)-hydroxydesazaDMDFT, 3); and (R)-2-(2-hydroxyphenyl)-4-oxazolinecarboxylic acid, the oxazoline analog of desazaDMDFT, 4, is described. Although 2 and 3 are comparably effective in inducing iron excretion upon oral administration, they exhibit markedly different plasma pharmacokinetics. Ligand 2 achieves a substantially higher plasma concentration than does 3, yet the renal clearance of these compounds is similar. The oxazoline analog 4 shows poor iron clearance when administered orally, although it remains in the plasma for extended periods. Chelator 4 demonstrates a marked capacity to bind to human serum albumin compared with the thiazoline derivatives. The possible implications for designing ligands for the treatment of transfusional iron overload are discussed.

Administration, Oral↗

PubMed1998

Synthesis of reagents for the construction of hypusine and deoxyhypusine peptides and their application as peptidic antigens.

Two new synthetic methods which allow access to (2S)-deoxyhypusine, natural (2S,9R)-hypusine, (2S,9S)-hypusine, and deoxyhypusine- and hypusine-containing peptides are described. The methods involve both the construction of a deoxyhypusine reagent in which the alpha-nitrogen protecting group is orthogonal to the N-7 and N-12 protecting groups and an alternate synthesis of our previous hypusine reagent, a synthesis which provides for better stereochemical control at C-9. Synthetic hypusine and deoxyhypusine can be generated from these reagents. The hypusine-containing hexapeptide (Cys-Thr-Gly-Hpu-His-Gly) is conjugated to ovalbumin (OVA), keyhole limpet hemocyanin (KLH), and a bis-maleimide; KLH conjugates are also made with the deoxyhypusine- and lysine-containing hexapeptides. Monoclonal antibodies are generated to the hypusine-containing hexapeptide-OVA conjugate in mice. These are isolated and screened against the hypusine-containing hexapeptide-KLH and hypusine-containing hexapeptide-bis-maleimide conjugates, as well as against the deoxyhypusine-containing and lysine-containing hexapeptide-KLH conjugates. These antibodies may be useful in localizing intracellular hypusine-containing peptides as well as peptides containing hypusine analogues.

Animals↗

PubMed1998

Effect of polyamine analogues on hypusine content in JURKAT T-cells.

The availability of synthetic hypusine and deoxyhypusine has made it possible to develop analytical methods which allow for the measurement of these compounds in various tissues. The methods involve dansylation of extracts from the pellet remaining after perchloric acid precipitation of cell or tissue homogenates, followed by high-performance liquid chromatography. To demonstrate the utility of this approach, the impact of four polyamine analogues, N1,N11-diethylnorspermine (DENSPM), N1,N14-diethylhomospermine (DEHSPM), 1,6,12-triazadodecane [(4,5) triamine], and 1,7, 13-triazatridecane [(5,5) triamine], on hypusine levels in a human T-cell line (JURKAT) is evaluated. All four analogues are active in controlling cell growth and compete well with spermidine for the polyamine transport apparatus. After 144 h of exposure to JURKAT cells, DENSPM reduces putrescine to below detectable limits and spermidine to 10% of the level in control cells. The other three analogues diminish both putrescine and spermidine to below detectable limits. The effectiveness with which the compounds lower spermine levels is DENSPM > DEHSPM > (4,5) triamine > (5,5) triamine. The analogues decrease the activities of ornithine decarboxylase and S-adenosylmethionine decarboxylase in a similar fashion. Of the four polyamines, DENSPM and DEHSPM are potent at lowering intracellular hypusine levels after 144 h: 59 +/- 9% and 73 +/- 12% of control levels, respectively. The other two analogues have marginal effects.

Adenosylmethionine Decarboxylase↗

PubMed1998

The origin of the differences in (R)- and (S)-desmethyldesferrithiocin. Iron-clearing properties.

The iron clearance properties, toxicity, and pharmacokinetics of (R)- and (S)-desmethyldesferrithiocin (DMDFT) are described. The studies were performed in rodent and primate models. While both enantiomers were found to be effective iron chelators with minimal toxicity in the rodents, only (S)-DMDFT was able to induce the clearance of any iron in the primates. In addition, two out of nine of the monkeys given (R)-DMDFT died within 24 h of drug administration. The reason for the differences in iron clearance properties and the apparent toxicity of the (R)-enantiomer in the primates is likely related to the disparities in the pharmacokinetics of the two analogues. The pharmacokinetic data suggest enantioselectivity in renal clearance of the desferrithiocins and their iron complexes with (S)-DMDFT clearance 3.5 times greater than that of (R)-DMDFT, and FeIII [(S)-DMDFT]2 clearance 6.8 times greater than that of FeIII [R-DMDFT]2. In all primates studied FeIII [(R)-DMDFT]2 in the plasma exceeded 25 mg/L (50 microM) for several hours and remained above 10 mg/L (20 microM) at 8 h while levels of FeIII [(S)-DMDFT]2 never exceeded 50 microM and were at or below the limits of detection 8 h post-injection.

Animals↗

PubMed1998

Polyamine analogue antiarrhythmics.

A group of polyamine analogues was assessed for their ability to prevent isoproterenol-induced ventricular fibrillation and death in a desoxycorticosterone acetate (DOCA)/saline rodent model. The compounds tested included polyamine antimetabolites and putrescine mimics. A structure-activity analysis revealed that tetraamines that are dicationic at physiological pH with their terminal nitrogens incorporated into pyridine rings are the most active analogues. It is clear from this study that there was no correlation between the compounds' ability to diminish polyamine metabolism and their effects on the electrical properties of the heart. In fact, the most potent polyamine antimetabolites were among the least effective antiarrhythmics. The most active of the compounds investigated, N1, N3-bis(4-pyridyl)-1,3-diaminopropane, PYR(3,3,3), was shown to both prevent isoproterenol-induced arrhythmias in DOCA/saline-treated rodents and reverse the progression of arrhythmic events that would otherwise culminate in ventricular fibrillation and death. Electrocardiographic tracings demonstrated that PYR(3,3,3) and propranolol both protect from and reverse the progression of arrhythmic events to ventricular fibrillation. In addition, cardiac pathologies from rats treated with both drugs are similar, but are substantially different from the control (isoproterenol)-treated animals. (c) 1998 The Italian Pharmacological Society.

Animals↗

PubMed1997

A comparison of structure-activity relationships between spermidine and spermine analogue antineoplastics.

A systematic investigation of the impact of spermidine analogues both in vitro and in vivo is described. The study characterizes the effects of these analogues on L1210 cell growth, polyamine pools, ornithine decarboxylase, S-adenosyl-L-methionine decarboxylase, spermidine/spermine N1-acetyltransferase, the maintenance of cellular charge, i.e., cationic equivalence associated with the polyamines and their analogues, and compares their ability to compete with spermidine for transport. The findings clearly demonstrate that the activity of the linear polyamine analogues is highly dependent on the length of the triamines and the size of the N(alpha),N(omega)-substituents. It appears that there is an optimum chain length for various activities and that the larger the N(alpha),N(omega)-alkyls, the less active the compound. Metabolic transformation including N-dealkylation of these compounds is also evaluated. While there is no monotonic relationship between chain length and the ability of the analogue to be metabolized, the dipropyl triamines are clearly more actively catabolized than the corresponding methyl and ethyl systems. A comparison of the triamines with the corresponding tetraamines is made throughout the text regarding both in vitro activity against L1210 cells and in vivo toxicity measurements, suggesting that several triamine analogues may offer therapeutic advantages over the corresponding tetraamines.

Acetyltransferases↗

PubMed1997

The influence of molecular conformation upon the self-assembly of cyclohexane diamide diacids.

BACKGROUND: Information regarding the self-association of small peptide motifs can be used in the design of peptide microstructures. Previous work in our laboratories illustrated the self-association of certain diamide diacids into microcapsules. In this report a series of cyclohexane diamide diacids are investigated. The cyclohexylene (R-C6H10-R) system (with its axial and equatorial requirements) provided an opportunity to study the influence of molecular conformation upon the self-aggregation process. RESULTS: Condensation of the respective cis- and trans-1,2-, 1,3-, and 1,4- cyclohexane dicarboxylic acid platforms with two equivalents of a L-Phe ester followed by deprotection gave the desired diamide diacids. Basic solutions of cis-1,2-, trans-1,3-, and cis-1,4-diamide diacids generated solid microspheres when acidified to pH 2.4. Molecular modeling revealed that 1,3-diaxial interactions favor a helical turn within these diamides. CONCLUSIONS: Access to 'complementary' molecular geometries is needed to self-associate into microscopic architectures.

Amides↗

PubMed1996

Polyamine analogue regulation of NMDA MK-801 binding: a structure-activity study.

A series of analogues and homologues of spermine were synthesized, and their impact on MK-801 binding to the N-methyl-D-aspartate (NMDA) receptor was evaluated. These tetraamines encompass both linear and cyclic compounds. The linear molecules include norspermine, N1, N11-diethylnorspermine, N1,N12-bis(2,2,2-trifluoroethyl)spermine, homospermine, and N1,N14-diethylhomospermine. The cyclic tetraamines consist of the piperidine analogues N1,N3-bis(4-piperidinyl)-1,3-diaminopropane, N1,N4-bis(4-piperidinyl)-1,4-diaminobutane, N1,N4-bis(4-piperidinylmethyl)-1,4-diaminobutane, and N1,N4-bis[2-(4-piperidinyl)ethyl]-1,4-diaminobutane and the pyridine analogues N1,N3-bis(4-pyridyl)-1,3-diaminopropane, N1,N4-bis(4-pyridyl)-1,4-diaminobutane, N1,N4-bis(4-pyridylmethyl)-1,4-diaminobutane, and N1,N4-bis[2-(4-pyridyl)-ethyl]-1,4-diaminobutane. This structure-activity set makes it possible to establish the importance of charge, intercharge distance, and terminal nitrogen substitution on polyamine-regulated MK-801 binding in the NMDA channel. Four families of tetraamines are included in this set: norspermines, spermines, homospermines, and tetraazaoctadecanes. Calculations employing a SYBYL modeling program revealed that the distance between terminal nitrogens ranges between 12.62 and 19.61 A. The tetraamines are constructed such that within families cyclics and acyclics have similar lengths but different nitrogen pKa's and thus different protonation, or charge, states at physiological pH. The pKa values for all nitrogens of each molecule and its protonation state at physiological pH are described. The modifications at the terminal nitrogens include introduction of ethyl and beta,beta,beta-trifluoroethyl groups and incorporation into piperidinyl or pyridyl systems. The studies clearly indicate that polyamine length, charge, and terminal nitrogen substitution have a significant effect on how the tetraamine regulates MK-801 binding to the NMDA receptor. Thus a structure-activity basis set on which future design of MK-801 agonists and antagonists can be based is now available.

Animals↗

PubMed1996

Metabolically programmed polyamine analogue antidiarrheals.

The design, synthesis, and testing of a novel class of antidiarrheal drugs based on a tetraamine pharmacophore are reported. While N1,N14-diethylhomospermine (DEHSPM) (5 mg/kg) completely prevents diarrhea in rodents, tissue distribution studies demonstrated that the principal metabolite of DEHSPM, homospermine (HSPM), accumulates and persists in tissues for a protracted period of time. This accumulation accounts for a large part of the chronic toxicity of DEHSPM. Thus a major objective was to develop a metabolically labile analogue of DEHSPM which retained the desirable biological properties of the parent drug. Hydroxyl groups, sites vulnerable to further metabolic transformation, were introduced into the external aminobutyl segments providing N1,N14-diethyl-(3R),(12R)-dihydroxyhomospermine [(HO)2-DEHSPM]. The design concept was assisted by molecular modeling, which predicted that (HO)2DEHSPM would have a Ki for polyamine transport essentially identical with that of DEHSPM. The experimentally measured Ki and also the observed values of other biological properties of (HO)2DEHSPM were in fact identical with those of DEHSPM, including IC50 against L1210 cells, impact on the NMDA receptor, and impact on L1210 native polyamine pools. Most significantly, however, there was no accumulation of the dideethylated metabolite in tissues from mice treated chronically with (HO)2DEHSPM, and (HO)2DEHSPM was 3-fold less toxic than DEHSPM. Finally, (HO)2DEHSPM completely prevented diarrhea in the castor oil-treated rat model at a dose of 5 mg/kg, just as did DEHSPM.

Animals↗

PubMed1996

Metabolism and pharmacokinetics of N1,N14-diethylhomospermine.

The pharmacokinetics and metabolism of N1,N14-diethylhomospermine (DEHSPM) is described. Analysis of 15 min constant rate intravenous infusion data in dogs gave mean values of: plasma t1/2 = 1.04 hr; Vd = 0.514 liter/kg; CL = 0.343 liter/hr/kg; and AUC0-infinity = 43.2 mg/hr/liter. The renal t1/2 = 0.99 hr, with 36% of the drug recovered in the urine between 0-4 hr unchanged. In other experiments, the drug was administered to dogs by subcutaneous injection. Noncompartmental analysis of plasma concentration-time data showed a mean residence time (MRT) of 4.67 hr (subcutaneous) vs. 1.93 hr (intravenous). Mice and dogs received DEHSPM chronically to evaluate tissue distribution of DEHSPM and its metabolites. All tissues examined contained DEHSPM and its N-deethylated metabolites, N1-ethylhomospermine (MEHSPM) and homospermine (HSPM). On day 1 posttreatment, 35% of the total dose administered to mice was present in the liver (25%) and kidney (10%). The DEHSPM present declines rapidly (liver t1/2 = 1.6 days). The majority of the original dose was present as HSPM, which persisted in tissues for weeks (liver t1/2 = 15.4 days). These data suggest that DEHSPM and MEHSPM are metabolized by N-deethylation, but that HSPM is not susceptible to further degradation by polyamine catabolic enzymes that involves stepwise removal of aminopropyl equivalents by spermine/spermidine N1-acetyltransferase/polyamine oxidase. Thus, chronic DEHSPM dosing regimens in both dogs and mice may result in the accumulation of HSPM, which is retained by tissues for an extended period of time resulting in disruption of normal polyamine homeostasis in these tissues. These findings correlate with clinical and histopathological signs of toxicity in dogs and in mice.

Animals↗

PubMed1995

The role of charge in polyamine analogue recognition.

A series of analogues and homologues of N1,N12-diethylspermine (DESPM) was synthesized, and their biological properties were evaluated. These tetraamines include a simple linear analogue of DESPM, N1,N12-bis(2,2,2-trifluoroethyl)spermine (FDESPM), the cyclic analogues of DESPM, N,N'-bis(4-piperidinylmethyl)-1,4-diaminobutane [PIP(4,4,4)] and N,N'-bis[2-(4-piperidinyl)ethyl]-1,4-diaminobutane [PIP(5,4,5)], and their aromatic counterparts, N,N'-bis-(4-pyridylmethyl)-1,4-diaminobutane [PYR(4,4,4)] and N,N'-bis[2-(4-pyridyl)ethyl]-1,4-diaminobutane [PYR(5,4,5)]. The analogues FDESPM, PIP(4,4,4), and PYR(4,4,4) have distances between their nitrogen atoms almost identical to those of DESPM. The longer analogues PIP(5,4,5) and PYR(5,4,5) are very similar in the spacing of their amino groups. However, the pKa of the nitrogens in the groups differ; thus, the extent of protonation and the charge characteristics among the members of the groups differ. A comparison of the biological properties of these compounds clearly demonstrates that the tetraamines must be charged to be "recognized" by the cell. Analogues with low nitrogen pKa's such that the nitrogens are poorly protonated at physiological pH do not compete well with spermidine for uptake and, as expected, have high 96 h IC50 values and have little effect on S-adenosylmethionine decarboxylase, ornithine decarboxylase, and spermidine/spermine N1-acetyltransferase activities and on intracellular polyamine pools.

Acetyltransferases↗