RESUMO
A structure-activity relationship study on polyamine derivatives led to the synthesis and the determination of antikinetoplastid activity of 17 compounds. Among them, a spermidine derivative (compound 13) was specifically active in vitro against Leishmania donovani axenic amastigotes (IC50 at 5.4µM; Selectivity Index >18.5) and a spermine derivative (compound 28) specifically active against Trypanosoma brucei gambiense (IC50 at 1.9µM; Selectivity Index >52).
Assuntos
Antiprotozoários/síntese química , Desenho de Fármacos , Kinetoplastida/efeitos dos fármacos , Putrescina/síntese química , Espermidina/síntese química , Espermina/síntese química , Acilação , Antiprotozoários/farmacologia , Avaliação Pré-Clínica de Medicamentos/métodos , Leishmania donovani/efeitos dos fármacos , Putrescina/farmacologia , Espermidina/farmacologia , Espermina/farmacologia , Trypanosoma brucei brucei/efeitos dos fármacosRESUMO
The highly distorted Pt(d(G*pG*)) (G* = N7-platinated G) 17-membered macrocyclic ring formed by cisplatin anticancer drug binding to DNA alters the structure of the G*G* base pair steps, canting one base, and increases dynamic motion, complicating solution structural studies. However, the ring appears to favor the HH1 conformation (HH1 denotes head-to-head guanine bases, 1 denotes the normal direction of backbone propagation). Compared to cisplatin, analogues with NH groups in the carrier ligand replaced by bulky N-alkyl groups are more toxic and less active and form less dynamic adducts. To examine the molecular origins for the biological effects of steric bulk, we evaluate Me(4)DABPt(d(G*pG*)) models; the bulk and chirality of Me(4)DAB (N,N,N',N'-tetramethyl-2,3-diaminobutane with S,S or R,R configurations at the chelate ring carbons) impede dynamic motion and enhance the utility of NMR methods for identifying and characterizing conformers. Unlike past studies of adducts with such bulky carrier ligands, in which no HH conformer was found, the Me(4)DABPt(d(G*pG*)) adducts did form the HH1 conformer, providing compelling evidence that the sugar-phosphate backbone can impose constraints sufficient to overcome the alkyl-group steric effects. The HH1 conformer exhibits no significant canting. The (S,S)-Me(4)DABPt(d(G*pG*)) adduct has the least amount of the "normal" HH1 conformer and the greatest amount of the ΔHT1 conformer (ΔHT1 = head-to-tail G* bases with Δ chirality) ever observed (88% under some conditions). Thus, our results lead us to hypothesize that the low activity and high toxicity of analogues of cisplatin having carrier ligands with N-alkyl groups arise from the low abundance and minimal canting of the HH1 conformer and possibly from the adverse effects of an abundant ΔHT1 conformer. The new findings advance our understanding of the chemistry of the Pt(d(G*pG*)) macrocyclic ring and of the effects of carrier-ligand steric bulk on the properties of the ring.
Assuntos
Antineoplásicos/síntese química , Cisplatino/análogos & derivados , Fosfatos de Dinucleosídeos/metabolismo , Guanina/metabolismo , Compostos Macrocíclicos/síntese química , Conformação Molecular/efeitos dos fármacos , Platina/química , Putrescina/análogos & derivados , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Dicroísmo Circular , Cisplatino/efeitos adversos , Cisplatino/química , DNA/química , DNA/metabolismo , Adutos de DNA/química , Adutos de DNA/metabolismo , Fosfatos de Dinucleosídeos/química , Guanina/química , Compostos Macrocíclicos/metabolismo , Compostos Macrocíclicos/farmacologia , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Movimento (Física) , Neoplasias/tratamento farmacológico , Platina/metabolismo , Putrescina/síntese química , Putrescina/metabolismo , Putrescina/farmacologia , EstereoisomerismoRESUMO
The kinetics of oxidation of a series of para-substituted N,N'-dibenzyl-1,4-diaminobutanes by the flavoprotein polyamine oxidase from mouse have been determined to gain insight into the mechanism of amine oxidation by this member of the monoamine oxidase structural family. The k(cat)/K(m) values are maximal at pH 9, consistent with the singly charged substrate being the active form. The rate constant for flavin reduction, k(red), by N,N'-dibenzyl-1,4-diaminobutane decreases about 5-fold below a pK(a) of approximately 8; this is attributed to the need for a neutral nitrogen at the site of oxidation. The k(red) and k(cat) values are comparable for each of the N,N'-dibenzyl-1,4-diaminobutanes, consistent with rate-limiting reduction. The deuterium kinetic isotope effects on k(red) and k(cat) are identical for each of the N,N'-dibenzyl-1,4-diaminobutanes, consistent with rate-limiting cleavage of the substrate CH bond. The k(red) values for seven different para-substituted N,N'-dibenzyl-1,4-diaminobutanes correlate with a combination of the van der Waals volume and sigma value of the substrates, with rho values of -0.59 at pH 8.6 and -0.09 at pH 6.6. These results are consistent with direct transfer of a hydride from the neutral CN bond of the substrate to the flavin as the mechanism of polyamine oxidase.
Assuntos
Oxirredutases atuantes sobre Doadores de Grupo CH-NH/química , Putrescina/análogos & derivados , Animais , Catálise , Cinética , Camundongos , Oxirredução , Oxirredutases atuantes sobre Doadores de Grupo CH-NH/genética , Oxirredutases atuantes sobre Doadores de Grupo CH-NH/metabolismo , Putrescina/síntese química , Putrescina/química , Relação Estrutura-Atividade , Especificidade por Substrato , Poliamina OxidaseRESUMO
A series of tripodal ligands based on the 2-tert-butyl-4-R-6-phenol was synthesized, where R=aldehyde (HL1), R=putrescine-pyrene (HL2) and R=putrescine (HL3). A dinucleating ligand wherein a putrescine group connects two tripodal moieties was also prepared (H2L4). The corresponding copper complexes (1, 2, 3, and 4, respectively) were prepared and characterized. We determined the phenol's pKas in the range 2.47-3.93. The DNA binding constants were determined at 6×106, 5.5×105 and 2.7×106 for 2, 3 and 4, respectively. The complexes display a metal-centered reduction wave at Epc,red=-0.45 to -0.5V vs. saturated calomel electrode, as well as a ligand-centered oxidation wave above 0.57V at pH7. In the presence of ascorbate they promote an efficient cleavage of DNA, with for example a concentration required to cleave 50% of supercoiled DNA of 1.7µM for 2. The nuclease activity is affected by the nature of the R group: putrescine-pyrene≈bis-ligating>putrescine>aldehyde. The species responsible for strand scission is the hydroxyl radical. The cytotoxicity of the complexes was evaluated on bladder cancer cell lines sensitive or resistant to cis-platin. The IC50 of complexes 2 and 4 span over a short range (1.3-2µM) for the two cell lines. They are lower than those of the other complexes (3.1-9.7µM) and cis-platin. The most active compounds block the cell cycle at the G0/1 phase and promote apoptosis.
Assuntos
Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Cobre/química , Clivagem do DNA/efeitos dos fármacos , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Chlorocebus aethiops , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , DNA Super-Helicoidal/química , Desoxirribonucleases/química , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Humanos , Ligantes , Modelos Químicos , Estrutura Molecular , Oxirredução , Putrescina/análogos & derivados , Putrescina/síntese química , Putrescina/química , Putrescina/farmacologia , Pirenos/síntese química , Pirenos/química , Pirenos/farmacologia , Células VeroRESUMO
Macrocyclic hydroxamic acids coordinate Fe(III) with high affinity as part of siderophore-mediated bacterial iron acquisition. Trimeric hydroxamic acid macrocycles, such as desferrioxamine E (DFOE), are prevalent in nature, with fewer dimeric macrocycles identified, including putrebactin (pbH2), avaroferrin (avH2), bisucaberin (bsH2) and alcaligin (alH2). This work used metal-templated synthesis (MTS) to pre-assemble complexes between one equivalent of Fe(III) and two equivalents of 4-((4-aminobutyl)(hydroxy)amino)-4-oxobutanoic acid (BBH) or 4-((5-aminopentyl)(hydroxy)amino)-4-oxobutanoic acid (PBH). Following peptide coupling, the respective Fe(III) complexes of pbH2 or bsH2 were formed, which analysed by LC-MS under acidic pH as [Fe(pb)]+ ([M]+, m/zobs 426.1) or [Fe(bs)]+ ([M]+, m/zobs 454.2). The mixed-ligand 1:1:1 Fe(III):BBH:PBH system furnished [Fe(pb)]+ and [Fe(bs)]+, together with chimeric [Fe(av)]+ ([M]+, m/zobs 440.2). The deviation from the expected 1:2:1 distribution of [Fe(pb)]+:[Fe(av)]+:[Fe(bs)]+ to 1:3.2:1.6 suggested the MTS-mediated formation of dimeric macrocycles could be influenced by steric effects in the pre-complex and/or cavity size, as governed by the monomer. 21-Membered avH2 defined the lower boundary of the optimal architecture. Mixed-ligand MTS between Fe(III):PBH-d4:ret-PBH at 1:1.5:1.5, where ret-PBH=3-(6-amino-N-hydroxyhexanamido)propanoic acid, gave four Fe(III)-loaded trimeric hydroxamic acid macrocycles in a distribution of 1.0:3.0:2.9:1.1 that closely matched the expected distribution 1:3:3:1 for a system without any kinetic and/or thermodynamic bias. Apo-macrocycles pbH2, avH2 and bsH2 were produced upon incubation with diethylenetriaminepentaacetic acid (DTPA) and co-eluted with a biosynthetic mixture of the native macrocycles. The work has demonstrated the utility of single- and mixed-ligand MTS for producing a variety of homo- and heteroleptic dimeric hydroxamic acid macrocycles as Fe(III) complexes and free ligands.
Assuntos
Compostos Férricos/síntese química , Ácidos Hidroxâmicos/síntese química , Peptídeos Cíclicos/síntese química , Putrescina/análogos & derivados , Succinatos/síntese química , Cromatografia Líquida , Compostos Férricos/análise , Ácidos Hidroxâmicos/análise , Ligantes , Espectrometria de Massas , Ácido Pentético/química , Peptídeos Cíclicos/análise , Putrescina/análise , Putrescina/síntese química , Shewanella putrefaciens , Succinatos/análiseRESUMO
Methods are presented to tritiate the polyamines putrescine and spermine.
Assuntos
Produtos Biológicos/química , Produtos Biológicos/síntese química , Poliaminas/química , Poliaminas/síntese química , Trítio/química , Humanos , Espectroscopia de Ressonância Magnética , Oxirredução , Putrescina/síntese química , Putrescina/química , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/química , Espermina/síntese química , Espermina/químicaRESUMO
The purpose of this research was to employ diamines and their quaternary derivatives as carrier molecules for gamma-emitting radiation. The diamine putrescine is widespread in nature and has been reported to selectively concentrate in the rat ventral prostate and pancreas. This study confirms the selective uptake of radioactivity in the rat ventral prostate, but not in the pancreas, following administration of [14C]putrescine. The radioiodinated analogues of putrescine showed no predilection for either of these organs. On the other hand, radioactivity associated with a radioidinated quaternary derivative (3) was found to accumulate incartilaginous tissues such as trachea, intervertebral disks, and chondrosarcoma tumor in a manner simular to hexamethonium.
Assuntos
Compostos de Hexametônio/síntese química , Radioisótopos do Iodo , Marcação por Isótopo , Putrescina/análogos & derivados , Animais , Compostos de Hexametônio/metabolismo , Masculino , Putrescina/síntese química , Putrescina/metabolismo , Ratos , Distribuição TecidualRESUMO
Cancer cells have high-affinity polyamine uptake systems with a low stringency for structural features. Putrescine, spermidine, and spermine have, therefore, been considered as potential vectors for the selective accumulation in tumors of therapeutically or diagnostically useful structures and elements. We envisaged N-benzyl derivatives of the polyamines as vectors of (10)B and (18)F for boron neutron capture therapy (BNCT) and tumor imaging by positron emission tomography (PET), respectively. In the present work, the synthesis, transport characteristics, DNA-binding properties, and cytotoxicity of several N-benzyl derivatives of putrescine and spermidine are described. The fluorinated spermidine derivative N-(3-[(4-aminobutyl)amino]propyl)[(4-fluorophenyl)methyl]amine (N(1)-4-Fbz-spd) may be useful for PET because of its high accumulation in cancer cells via the polyamine transport system. Among the boron-containing benzyl polyamines, N-(4-aminobutyl)([4-(dihydroxyboryl)phenyl]methyl)amine (4-Bbz-put) and N-(3-[(4-aminobutyl)amino]propyl)([4-(dihydroxyboryl)phenyl]methyl)amine (N(1)-4-Bbz-spd) should be suitable for BNCT, because their accumulation in B16 melanoma cells was more efficient than that of borocaptate and borophenylalanine, two reference compounds used in BNCT.
Assuntos
Compostos de Boro/síntese química , Putrescina/análogos & derivados , Putrescina/síntese química , Espermidina/análogos & derivados , Espermidina/síntese química , Animais , Transporte Biológico Ativo , Compostos de Boro/metabolismo , Terapia por Captura de Nêutron de Boro , Linhagem Celular , DNA/química , Putrescina/metabolismo , Espermidina/metabolismo , Espermina/análogos & derivados , Relação Estrutura-Atividade , Tomografia Computadorizada de Emissão , Células Tumorais CultivadasRESUMO
(E)-Dehydro analogues of alpha-(fluoromethyl)putrescine and -ornithine derivatives were synthesized and evaluated in vitro as irreversible inhibitors of a preparation of ornithine decarboxylase (ODC, EC 4.1.1.17) obtained from rat liver. The key step in the synthesis of (E)-alpha-(fluoromethyl)dehydroornithine (17) and -putrescine (14) was the addition of propenylmagnesium bromide to fluoroacetonitrile. The resulting unstable conjugated imine salt was reduced regioselectively in situ with NaBH4 or was quenched with a solution of NaCN to give the corresponding unsaturated alpha-(fluoromethyl) amine and alpha-amino nitrile, respectively. These were transformed into 17 and 14 via a four-step sequence involving (a) phthaloyation of the amine function; (b) allylic bromination of the methyl group; (c) Gabriel reaction; and (d) hydrolytic cleavage of the protective groups. (E)-alpha-(Difluoromethyl)dehydroornithine (10) and -putrescine (7) were prepared from ethyl tert-butyl 2-(difluoromethyl)-2-(2-propenyl)malonate and di-tert-butyl 2-(difluoromethyl)-2-(2-propenyl)malonate, respectively, via a sequence similar to that reported previously for the synthesis of the saturated analogues. Compounds 17, 14, 10, and 7 proved to be much more potent enzyme-activated irreversible inhibitors of ODC than the corresponding saturated analogues. The increase in potency is particularly marked in the alpha-fluoromethyl series. The apparent dissociation constants (KI) and the times of half-inactivation of enzyme (tau 50) at infinite concentration of inhibitors are 2.7 microM and 2.6 min for 17 and 42 microM and 0.2 min for 14. The KI and tau 50 of the corresponding saturated analogues are 75 microM and 1.6 min for the ornithine derivative and 56 microM and 4.4 min for the putrescine derivative.
Assuntos
Eflornitina/análogos & derivados , Inibidores da Ornitina Descarboxilase , Ornitina/análogos & derivados , Putrescina/análogos & derivados , Animais , Indicadores e Reagentes , Isomerismo , Cinética , Fígado/enzimologia , Espectroscopia de Ressonância Magnética , Ornitina/síntese química , Ornitina/farmacologia , Putrescina/síntese química , Putrescina/farmacologia , Ratos , Relação Estrutura-AtividadeRESUMO
1,4-Dimethylputrescine (2,5-hexanediamine) was separated into its racemic and meso isomers by fractional crystallization of its dibenzoyl derivative. The racemic form was resolved into its (+)- and (-)-isomers with (+)- and (-)-dibenzoyltartaric acids. None of the three isomers (meso, +, and -) inhibited ornithine decarboxylase (ODC) activity in vitro, while all the three were strongly inhibitory of ODC when assayed in vivo in rats or in H-35 hepatoma cells. In rat liver the three isomers also decreased the putrescine pool while only the (+)-isomer decreased spermidine content. In the H-35 cells the (-)- and (+)-isomers decreased the spermidine and spermine content. When ODC was induced in the latter by insulin it was found that the (-)-isomer strongly inhibited protein and ODC synthesis, while the (+)-isomer and the meso isomer were less inhibitory. The meso isomer was a good inducer of ODC antizyme in rat liver, while the (+)- and (-)-isomers were poor inducers of the former.
Assuntos
Inibidores da Ornitina Descarboxilase , Putrescina/análogos & derivados , Putrescina/farmacologia , Animais , Linhagem Celular , Feminino , Isomerismo , Fígado/efeitos dos fármacos , Fígado/enzimologia , Neoplasias Hepáticas Experimentais , Proteínas de Neoplasias/biossíntese , Rotação Ocular , Poliaminas/metabolismo , Putrescina/síntese química , Putrescina/isolamento & purificação , Ratos , Ratos Endogâmicos , Relação Estrutura-Atividade , Tioacetamida/farmacologia , Células Tumorais Cultivadas/efeitos dos fármacos , Células Tumorais Cultivadas/metabolismoRESUMO
No-carrier-added [1-11C]putrescine was synthesized in 20% radiochemical yield in a synthesis time of 50 min by the Michael addition of potassium [11C]cyanide to acrylonitrile followed by reduction of the [11C]dinitrile with borane-methyl sulfide complex. Biodistribution in mice at 5, 30, and 60 min showed low uptake in normal brain tissue.
Assuntos
Radioisótopos de Carbono , Putrescina/síntese química , Animais , Camundongos , Putrescina/metabolismo , Radioquímica , Distribuição Tecidual , Tomografia Computadorizada de Emissão/métodosRESUMO
Using solid phase synthesis techniques, we have rapidly obtained a series of eight aryl sulphonamides derived from putrescine. These conjugates with various aryl groups were evaluated for their affinity towards 5-HT6 receptors in man. This evaluation revealed the interest of two compounds which present the same activity level, in the submicromolar range, as two reference derivatives. The most potent will be considered as a new lead for further investigations.
Assuntos
Receptores de Serotonina/metabolismo , Sulfonamidas/síntese química , Sulfonamidas/metabolismo , Humanos , Ligantes , Dietilamida do Ácido Lisérgico/metabolismo , Putrescina/análogos & derivados , Putrescina/síntese química , Antagonistas da Serotonina/metabolismoRESUMO
An ultrasound-assisted preparation of 1,4-diazabutadienes via smooth condensation of diketones with amines under solvent-free conditions is described. The generality of this method was examined by the synthesized N,N'-diaryl- and N,N'-dialkyl-1,4-diazabutadiene derivatives. In addition to experimental simplicity, the main advantages of the procedure are mild conditions, short reaction time (2-15 min) and high yields (71-98%).
Assuntos
Iminas/síntese química , Putrescina/síntese química , Ultrassom , Aminas/química , Iminas/química , Cetonas/química , Putrescina/químicaRESUMO
A series of symmetry-based HIV protease inhibitors was designed and synthesized. Modification of the core regiochemistry and stereochemistry significantly affected the potency, metabolic stability, and oral bioavailability of the inhibitors, as did the variation of a pendent arylmethyl P3 group. Optimization led to the selection of two compounds, 10c (A-790742) and 9d (A-792611), for advancement to preclinical studies. Both compounds displayed low nanomolar potency against wild type HIV in the presence of human serum, low rates of metabolism in human liver microsomes, and high oral bioavailability in animal models. The compounds were examined in a preclinical model for the hyperbilirubinemia observed with some HIV PIs, and both exhibited less bilirubin elevation than comparator compounds. X-ray crystallographic analyses of the new cores were used to examine differences in their binding modes. The antiviral activity of the compounds against protease inhibitor resistant strains of HIV was also determined.
Assuntos
Carbamatos/síntese química , Dipeptídeos/síntese química , Inibidores da Protease de HIV/síntese química , Putrescina/análogos & derivados , Piridinas/síntese química , Animais , Sítios de Ligação , Disponibilidade Biológica , Células CACO-2 , Carbamatos/metabolismo , Carbamatos/farmacologia , Permeabilidade da Membrana Celular , Cristalografia por Raios X , Dipeptídeos/efeitos adversos , Dipeptídeos/farmacologia , Cães , Farmacorresistência Viral , Protease de HIV/genética , Inibidores da Protease de HIV/efeitos adversos , Inibidores da Protease de HIV/farmacologia , HIV-1/efeitos dos fármacos , HIV-1/enzimologia , HIV-1/genética , Humanos , Hiperbilirrubinemia/induzido quimicamente , Hiperlipidemias/induzido quimicamente , Hiperlipidemias/metabolismo , Técnicas In Vitro , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Mutação , Putrescina/síntese química , Putrescina/metabolismo , Putrescina/farmacologia , Piridinas/efeitos adversos , Piridinas/farmacologia , Ratos , Ratos Gunn , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
The synthesis of putrescine was accomplished by decarboxylation of L-ornithine when this amino acid was heated in aqueous solution and in the absence of oxygen. Chromatographic, radioisotopic, and enzymatic techniques were used to demonstrate that one mole of non-radioactive putrescine and one mole of 14CO2 was formed during the heating of L-(l-14C)-ornithine. This work indicates that the synthesis of putrescine can occur starting with ornithine and in conditions that are presumed could have existed on the primitive Earth. The possible significance of these results in the prebiotic molecular evolution is briefly discussed.
Assuntos
Ornitina/química , Putrescina/síntese química , Descarboxilação , Planeta Terra , Putrescina/químicaRESUMO
No carrier-added 1-[11C]putrescine has been prepared using a simple two-step procedure. Radiochemical yields of 1-2% at end-of-synthesis were obtained in a synthesis time of 50-60 min. The in vivo uptake of no carrier-added 1-[11C]putrescine into rat prostate was determined and compared to the uptake of no carrier-added material containing varying amounts of non-radioactive putrescine. The in vivo results indicate that the mechanism of uptake into the prostate is saturable.
Assuntos
Próstata/metabolismo , Putrescina/síntese química , Animais , Radioisótopos de Carbono , Cromatografia Líquida de Alta Pressão , Masculino , Putrescina/metabolismo , Ratos , Ratos Endogâmicos , Distribuição TecidualRESUMO
A new radiolabeled analog of putrescine, 18F labeled 2-fluoroputrescine, has been prepared as a potential in vivo imaging agent for prostate and prostate derived tumors. The radiosynthesis yielded 1.5-4.5 mCi amounts of the 18F labeled putrescine analog (1-3% yields at end-of-synthesis), with specific activities ranging from 0.85-4.3 Ci/mmol, in a synthesis time of 2 h. The in vivo biodistribution in mature male rats showed considerable uptake by the bone, indicating defluorination of the compound. In animals pretreated with aminoguanidine, an inhibitor of diamine oxidase, the enzyme important in the metabolism of putrescine, defluorination was markedly reduced, but uptake by the prostate did not improve. These results suggest the need for development of a 18F labeled analog of putrescine which does not defluorinate in vivo, and which has biological properties similar to putrescine.
Assuntos
Putrescina/análogos & derivados , Animais , Flúor , Masculino , Próstata/diagnóstico por imagem , Putrescina/síntese química , Radioisótopos , Cintilografia , Ratos , Distribuição TecidualRESUMO
Novel alkyl-1,4-butanediamine Pt(II) complexes having a seven-membered ring structure were synthesized and characterized by fast atom bombardment mass and infrared spectra and elemental analysis. Their antitumor activities in vivo toward lymphoid leukemia L1210 and Lewis lung carcinoma LL were studied in the case where the leaving group was either dichloride or cyclobutane-1,1-dicarboxylate. 1,4-Butanediamine Pt(II) complexes (seven-membered ring) showed higher antitumor activities than those of ethylenediamine Pt(II) (five-membered ring) and 1,3-propanediamine Pt(II) (six-membered ring) complexes toward L1210 for both leaving groups. Alkyl-1,4-butanediamine Pt(II) complexes showed high antitumor activities toward L1210, except for 1,1-dimethyl-1,4-butanediamine Pt(II) complexes. In particular, 2,2-dimethyl-1,4-butanediamine and 2,3-dimethyl-1,4-butanediamine Pt(II) complexes exhibited excellent antitumor activities with T/C% values higher than 300. None of the dichloro Pt(II) complexes showed antitumor activities toward LL, but the cyclobutane-1,1-dicarboxylato Pt(II) complexes, which were moderately active toward L1210 with T/C% values around 200, also showed high antitumor activities toward LL with T/C% values of more than 200. Alkyl-1,4-butanediamine Pt(II) complexes with a seven-membered ring structure were found to be stable and to have antitumor activities in vivo.
Assuntos
Antineoplásicos/síntese química , Compostos Organoplatínicos/síntese química , Putrescina/análogos & derivados , Animais , Fenômenos Químicos , Química , Feminino , Leucemia L1210/tratamento farmacológico , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Compostos Organoplatínicos/farmacologia , Putrescina/síntese química , Putrescina/farmacologiaRESUMO
Eleven lipophilic derivatives of the title biogenic amines and 28 structurally related triamines and tetramines have been synthesized. Twenty-three of them inhibited the platelet aggregation induced by collagen at an IC50 between 8 mumol/L and 30 mumol/L. Five compounds prolonged the one stage thromboplastin time (Quick) by 7s or more at 100 mumol/L. The antiplatelet and anticoagulant effect do not run parallel. The relationship between the effects observed and the chemical structure of the oligoamines has been elucidated.
Assuntos
Anticoagulantes/síntese química , Inibidores da Agregação Plaquetária/síntese química , Putrescina/análogos & derivados , Espermidina/análogos & derivados , Espermina/análogos & derivados , Fenômenos Químicos , Química , Humanos , Técnicas In Vitro , Putrescina/síntese química , Putrescina/farmacologia , Espermidina/síntese química , Espermidina/farmacologia , Espermina/síntese química , Espermina/farmacologiaRESUMO
Bovine plasma amine oxidase (BPAO) was previously shown to be irreversibly inhibited by propargylamine and 2-chloroallylamine. 1,4-Diamine versions of these two compounds are here shown to be highly potent inactivators, with IC50 values near 20 microM. Mono-N-alkylation or N,N-dialkylation greatly lowered the inactivation potency in every case, whereas the mono-N-acyl derivatives were also weaker inhibitors and enzyme activity was recoverable. The finding that the bis-primary amines 1,4-diamino-2-butyne (a known potent inhibitor of diamine oxidases) and Z-2-chloro-1,4-diamino-2-butene are potent inactivators of BPAO is suggestive of unexpected similarities between plasma amine oxidase and the diamine oxidases and implies that it may be unwise to attempt to develop selective inhibitors of diamine oxidase using a diamine construct.