RESUMO
Naturally occurring polyamines like Putrescine, Spermidine, and Spermine are polycations which bind to the DNA, hence stabilizing it and promoting the essential cellular processes. Many synthetic polyamine analogues have been synthesized in the past few years, which have shown cytotoxic effects on different tumours. In the present study, we evaluated the antiproliferative effect of a novel, acylspermidine derivative, (N-(4-aminobutyl)-N-(3-aminopropyl)-8-hydroxy-dodecanamide) (AAHD) on HepG2 cells. Fluorescence staining was performed with nuclear stain (Hoechst 33342) and acridine orange/ethidium bromide double staining. Dose and the time-dependent antiproliferative effect were observed by WST-1 assays, and radical scavenging activity was measured by ROS. Morphological changes such as cell shrinkage & blebbing were analyzed by fluorescent microscopy. It was found that AAHD markedly suppressed the growth of HepG2 cells in a dose- and time-dependent manner. It was also noted that the modulation of ROS levels confirmed the radical scavenging activity. In the near future, AAHD can be a promising drug candidate in chalking out a neoplastic strategy to control the proliferation of tumour cells. This study indicated that AAHD induced anti-proliferative and pro-apoptotic activities on HCC. Since AAHD was active at micromolar concentrations without any adverse effects on the healthy cells (Fibroblasts), it is worthy of further clinical investigations.
Assuntos
Antineoplásicos/farmacologia , Butilaminas/farmacologia , Espermidina/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Butilaminas/síntese química , Butilaminas/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Cricetinae , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células Hep G2 , Humanos , Estrutura Molecular , Espermidina/síntese química , Espermidina/química , Relação Estrutura-Atividade , Cicatrização/efeitos dos fármacosRESUMO
A pentavalent branched-chain polyamine, N4 -bis(aminopropyl)spermidine 3(3)(3)4, is a unique polycation found in the hyperthermophilic archaeon Thermococcus kodakarensis, which grows at temperatures between 60 and 100 °C. We studied the effects of this branched-chain polyamine on DNA structure at different temperatures up to 80 °C. Atomic force microscopic observation revealed that 3(3)(3)4 induces a mesh-like structure on a large DNA (166â kbp) at 24 °C. With an increase in temperature, DNA molecules tend to unwind, and multiple nano-loops with a diameter of 10-50â nm are generated along the DNA strand at 80 °C. These results were compared to those obtained with linear-chain polyamines, homocaldopentamine 3334 and spermidine, the former of which is a structural isomer of 3(3)(3)4. These specific effects are expected to neatly concern with its role on high-temperature preference in hyperthermophiles.
Assuntos
DNA/química , Espermidina/análogos & derivados , Espermidina/química , Animais , Bacteriófago T4/genética , Bovinos , DNA/genética , Genoma , Temperatura Alta , Microscopia de Força Atômica , Conformação de Ácido Nucleico , Poliaminas/química , Espermidina/síntese química , Thermococcus/químicaRESUMO
This study describes the synthesis and the biological evaluation of twenty-four original bis(benzyl)spermidines. Structural modifications of the polyamine scaffold were performed in order to avoid easily metabolized bonds. Some bis(benzyl)polyamine derivatives have demonstrated promising activity in vitro against Trypanosoma brucei gambiense and Leishmania donovani. From the enzymatic experiments on trypanothione reductase, we observed that this enzyme was not targeted by our compounds. In vivo evaluation on Swiss mice model infected by T. b. gambiense or L. donovani was done with the most interesting compound of the series.
Assuntos
Antiprotozoários/farmacologia , Espermidina/farmacologia , Antiprotozoários/síntese química , Antiprotozoários/química , Relação Dose-Resposta a Droga , Leishmania donovani , Estrutura Molecular , Testes de Sensibilidade Parasitária , Espermidina/síntese química , Espermidina/química , Relação Estrutura-Atividade , Trypanosoma brucei gambienseRESUMO
Thirteen new polyamine derivatives coupled to hydroxybenzotriazole have been synthesized and evaluated for their in vitro antikinetoplastid activity. Trypanosoma Trypanothione reductase (TryR) was envisioned as a potential target. Among all tested molecules, only one compound, a N3-spermidine-benzotriazole derivative, displayed relevant inhibitory activity on this enzyme but was not active on parasites. The corresponding Boc-protected spermidine-benzotriazole was however trypanocidal against Trypanosoma brucei gambiense with an IC50 value of 1µM and was completely devoid of cytotoxicity. On the intramacrophage amastigotes of Leishmania donovani, a N2-spermidine conjugate of this series, exhibited an interesting IC50 value of 3µM associated with both low cytotoxicity against axenic Leishmania donovani. These new compounds are promising leads for the development of antikinetoplastid agents and their targets have to be deciphered.
Assuntos
Antiprotozoários/química , Antiprotozoários/farmacologia , Leishmania donovani/efeitos dos fármacos , Triazóis/química , Triazóis/farmacologia , Trypanosoma brucei brucei/efeitos dos fármacos , Animais , Antiprotozoários/síntese química , Humanos , Leishmania donovani/enzimologia , Leishmaniose Visceral/tratamento farmacológico , NADH NADPH Oxirredutases/antagonistas & inibidores , NADH NADPH Oxirredutases/metabolismo , Espermidina/análogos & derivados , Espermidina/síntese química , Espermidina/farmacologia , Triazóis/síntese química , Tripanossomicidas/síntese química , Tripanossomicidas/química , Tripanossomicidas/farmacologia , Trypanosoma brucei brucei/enzimologia , Tripanossomíase Africana/tratamento farmacológicoRESUMO
A novel synthetic route to the chemoselectively protected N,S-ditritylglutathione monomethyl ester is described involving the chemical modification of the commercially available glutathione (GSH). The synthetic value of this building block in the facile preparation of GSH bioconjugates in a satisfying overall yield was exemplified by the case of trypanothione disulfide (TS2), a GSH-spermidine bioconjugate, involved in the antioxidative stress protection system of parasitic protozoa, such as trypanosoma and leishmania parasites.
Assuntos
Antiprotozoários/química , Glutationa/análogos & derivados , Glutationa/química , Espermidina/análogos & derivados , Animais , Antioxidantes/síntese química , Antioxidantes/farmacologia , Antiprotozoários/síntese química , Antiprotozoários/farmacologia , Glutationa/síntese química , Glutationa/farmacologia , Leishmania/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Espermidina/síntese química , Espermidina/química , Espermidina/farmacologia , Estereoisomerismo , Trypanosoma/efeitos dos fármacosRESUMO
Earlier unknown enantiomerically pure (R)- and (S)-1,8-diamino-3-methyl-4-azaoctane's (3-MeSpd's) were synthesized with high overall yields and optical purity starting from commercially available R- and S-isomers of N-Boc-2-aminopropanol-1. Application of R- and S-isomers of 3-MeSpd for the investigation of the stereospecificity of spermidine transporter and peculiarities of deoxyhypusine synthase reaction are discussed.
Assuntos
Espermidina/análogos & derivados , Espermidina/síntese química , Catálise , Linhagem Celular Tumoral , Humanos , Estrutura Molecular , Oxirredutases atuantes sobre Doadores de Grupo CH-NH/química , Espermidina/química , Espermidina/metabolismo , EstereoisomerismoRESUMO
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
Natural and synthetic membrane active antibacterial agents offer hope as potential solutions to the problem of bacterial resistance as the membrane-active nature imparts low propensity for the development of resistance. In this report norspermidine based antibacterial molecules were developed that displayed excellent antibacterial activity against various wild-type bacteria (Gram-positive and Gram-negative) and drug-resistant bacteria (methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus faecium, and ß-lactam-resistant Klebsiella pneumoniae). In a novel structure-activity relationship study it has been shown how incorporation of an aromatic amino acid drastically improves selective antibacterial activity. Additionally, the effect of stereochemistry on activity, toxicity, and plasma stability has also been studied. These rapidly bactericidal, membrane active antibacterial compounds do not trigger development of resistance in bacteria and hence bear immense potential as therapeutic agents to tackle multidrug resistant bacterial infections.
Assuntos
Antibacterianos/química , Farmacorresistência Bacteriana , Testes de Sensibilidade Microbiana , Fenilalanina/química , Espermidina/análogos & derivados , Infecções Bacterianas/tratamento farmacológico , Desenho de Fármacos , Enterococcus faecium , Humanos , Cinética , Klebsiella pneumoniae , Staphylococcus aureus Resistente à Meticilina , Micelas , Conformação Molecular , Fenilalanina/síntese química , Plasma/efeitos dos fármacos , Plasma/microbiologia , Soro/efeitos dos fármacos , Soro/microbiologia , Espermidina/síntese química , Espermidina/química , Sais de Tetrazólio/química , Tiazóis/química , Vancomicina/química , beta-Lactamas/químicaRESUMO
Three functional groups (2-propenyl, 2-propynyl, and 2,3-butadienyl) were introduced onto one of the terminal amino groups of spermidine. Of the six compounds synthesized, N-(3-aminopropyl)-N'-2,3-butadienyl-1,4-butanediamine (N(8)-butadienyl Spd) and N-[3-(2,3-butadienylamino)propyl]-1,4-butanediamine (N(1)-butadienyl Spd) irreversibly inactivated human spermine oxidase (SMO) and N(1)-acetylpolyamine oxidase (APAO). Interestingly, N(8)-butadienyl Spd inactivated SMO far more potently than N,N'-di-2,3-butadienyl-1,4-butanediamine (MDL 72527).
Assuntos
Inibidores Enzimáticos/farmacologia , Oxirredutases atuantes sobre Doadores de Grupo CH-NH/antagonistas & inibidores , Espermidina/farmacologia , Espermina/metabolismo , Inibidores Enzimáticos/síntese química , Humanos , Espermidina/análogos & derivados , Espermidina/síntese química , Poliamina OxidaseRESUMO
Convenient two-step synthesis of conjugates of HS-CoA and D-pantetheine with aminooxy analogues of Spm, Spd and Put was suggested. The use of acetone linker provided target conjugates with quantitative yields. The activity of CoA-derived "bisubstrate" inhibitors being active at microM concentrations was at least 100 times better than that of corresponding derivatives of D-pantetheine.
Assuntos
Acetiltransferases/síntese química , Poliaminas/metabolismo , Espermidina/síntese química , Espermina/síntese química , Acetilcoenzima A/química , Acetiltransferases/química , Bactérias/química , Bactérias/metabolismo , Bactérias/patogenicidade , Cinética , Panteteína/química , Poliaminas/química , Espermidina/química , Espermina/químicaRESUMO
Polyamines are small essential polycations involved in many biological processes. Enzymes of polyamine metabolism have been extensively studied and are attractive drug targets. Nevertheless, the reversible acetylation of polyamines remains poorly understood. Although eukaryotic N(8)-acetylspermidine deacetylase activity has already been detected and studied, the specific enzyme responsible for this activity has not yet been identified. However, a zinc deacetylase from Mycoplana ramosa, acetylpolyamine amidohydrolase (APAH), has been reported to use various acetylpolyamines as substrates. The recently solved crystal structure of this polyamine deacetylase revealed the formation of an 'L'-shaped active site tunnel at the dimer interface, with ideal dimensions and electrostatic properties for accommodating narrow, flexible, cationic polyamine substrates. Here, we report the design, synthesis, and evaluation of N(8)-acetylspermidine analogues bearing different zinc binding groups as potential inhibitors of APAH. Most of the synthesized compounds exhibit modest potency, with IC50 values in the mid-micromolar range, but compounds bearing hydroxamate or trifluoromethylketone zinc binding groups exhibit enhanced inhibitory potency in the mid-nanomolar range. These inhibitors will enable future explorations of acetylpolyamine function in both prokaryotes and eukaryotes.
Assuntos
Aminoidrolases/antagonistas & inibidores , Espermidina/análogos & derivados , Aminoidrolases/química , Poliaminas/metabolismo , Espermidina/síntese química , Espermidina/químicaRESUMO
Earlier unknown 1,8-diamino-3-methyl-4-azaoctane (gamma-MeSpd) was synthesized. The analogue was not a substrate of ether spermine/spermidine N1-acetyltransferase, or spermine synthase, but was capable to support the growth of DU145 cells with depleted polyamine pool. Such a combination of y-MeSpd properties discloses novel opportunities to study cellular functions of catabolically unstable and easily interconvertible spermine and spermidine.
Assuntos
Materiais Biomiméticos/síntese química , Neoplasias da Próstata/metabolismo , Estabilidade Proteica , Espermidina/síntese química , Espermina/metabolismo , Acetiltransferases/metabolismo , Processos de Crescimento Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Masculino , Neoplasias da Próstata/patologia , Espermidina/análogos & derivados , Espermidina/metabolismo , Espermidina/farmacologia , Espermina Sintase/metabolismo , Especificidade por SubstratoRESUMO
Divergent route: a direct C-C bond-forming approach to the key aryl-substituted all-carbon quaternary stereogenic center present in bioactive hydrodibenzofuran alkaloids has been discovered. This approach involves an unprecedented organocatalytic enantioselective Michael addition of α-cyanoketones with acrylates and was used in a novel and divergent synthetic strategy for the title compounds in asymmetric fashion.
Assuntos
Alcaloides/síntese química , Alcaloides de Amaryllidaceae/síntese química , Benzofuranos/química , Galantamina/síntese química , Espermidina/análogos & derivados , Alcaloides/química , Alcaloides de Amaryllidaceae/química , Brassicaceae/química , Carbono/química , Catálise , Ciclização , Galantamina/química , Liliaceae/química , Espermidina/síntese química , Espermidina/química , EstereoisomerismoRESUMO
The polyamines are organic polycations present at millimolar concentrations in eukaryotic cells where they participate in the regulation of vital cellular functions including proliferation and differentiation. Biological evaluation of rationally designed polyamine analogs is one of the cornerstones of polyamine research. Here we have synthesized and characterized novel C-methylated spermidine analogs, that is, 2-methylspermidine, 3-methylspermidine, and 8-methylspermidine. 3-Methylspermidine was found to be metabolically stable in DU145 cells, while 8-methylspermidine was a substrate for spermidine/spermine N(1)-acetyltransferase (SSAT) and 2-methylspermidine was a substrate for both SSAT and acetylpolyamine oxidase. All the analogs induced the splicing of the productive mRNA splice variant of SSAT, overcame growth arrest induced by 72-h treatment with ornithine decarboxylase (ODC) inhibitor α-difluoromethylornithine, and were transported via the polyamine transporter. Surprisingly, 2-methylspermidine was a weak downregulator of ODC activity in DU145 cells. Our data demonstrates that it is possible to radically alter the biochemical properties of a polyamine analog by changing the position of the methyl group.
Assuntos
Poliaminas/metabolismo , Espermidina/análogos & derivados , Espermidina/síntese química , Acetiltransferases/química , Acetiltransferases/genética , Processamento Alternativo , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Eflornitina/farmacologia , Humanos , Camundongos , Inibidores da Ornitina Descarboxilase , Oxirredutases atuantes sobre Doadores de Grupo CH-NH/química , Precursores de RNA/genética , RNA Mensageiro/genética , Proteínas Recombinantes/química , Espermidina/química , Espermidina/farmacologia , Relação Estrutura-AtividadeRESUMO
Unusual long polyamines such as caldopentamine and caldohexamine, and branched polyamines such as tetrakis(3-aminopropyl)ammonium and N (4)-aminopropylspermidine were often found in cells of extreme thermophiles and hyperthermophiles belonging to both Bacteria and Archaea domains. Some of these unusual polyamines are essential for life at extreme temperatures. In some cases, the unusual polyamines also exist in cells of nonthermophilic organisms and play important physiological roles under normal conditions. Methods for chromatographic analysis, isolation, and chemical syntheses of unusual polyamines as well as experimental methods for measuring their physiological roles are discussed. Especially, many newly improved methods for chemical syntheses are presented in this article.
Assuntos
Bioquímica/métodos , Poliaminas/síntese química , Poliaminas/metabolismo , Thermus thermophilus/metabolismo , Vias Biossintéticas/genética , Cromatografia Líquida de Alta Pressão , Espectroscopia de Ressonância Magnética , Ácidos Nucleicos/química , Plasmídeos/genética , Poliaminas/química , Biossíntese de Proteínas , Compostos de Amônio Quaternário/química , Recombinação Genética/genética , Espermidina/análogos & derivados , Espermidina/síntese química , Espermidina/química , Espermina/análogos & derivados , Espermina/síntese química , Espermina/química , Thermus thermophilus/citologiaRESUMO
The most widely used methods for measuring polyamine enzyme activities are radioisotope methods that measure the radioactivity of compounds produced from radiolabeled substrate by the enzyme reaction. Several fluorescent polyamines have been developed for the measurement of the polyamine transport system (PTS) or transglutaminase. Although fluorophores in the fluorescent polyamines may affect the affinity of the polyamine moiety to the enzyme protein, the assays that use fluorescent substrate are sensitive and simple for common laboratory usage.In this chapter, the uses of dansyl polyamines with a simple high-performance liquid chromatography system for the measurement of the PTS and polyamine catabolic enzymes including spermidine/spermine N¹-acetyltransferase and N¹-acetylpolyamine oxidase are described.
Assuntos
Acetiltransferases/metabolismo , Bioquímica/métodos , Corantes Fluorescentes/metabolismo , Oxirredutases atuantes sobre Doadores de Grupo CH-NH/metabolismo , Poliaminas/metabolismo , Animais , Transporte Biológico , Linhagem Celular Tumoral , Cromatografia Líquida de Alta Pressão , Compostos de Dansil/síntese química , Ensaios Enzimáticos , Humanos , Fígado/enzimologia , Ratos , Espermidina/síntese química , Espermidina/metabolismo , Espermina/síntese química , Espermina/metabolismo , Especificidade por SubstratoRESUMO
The polyamine transport system (PTS) whose activity is up-regulated in cancer cells is an attractive target for drug design. Two heterocyclic (azepine and benzazepine) systems were conjugated to various polyamine moieties through an amidine bound to afford 18 compounds which were evaluated for their affinity for the PTS and their ability to use the PTS for cell delivery. Structure-activity relationship studies and lead optimization afforded two attractive PTS targeting compounds. The azepine-spermidine conjugate 14 is a very selective substrate of the PTS that may serve as a vector for radioelements used for diagnoses or therapeutics in nuclear medicine. The nitrobenzazepine-spermine conjugate 28 is a very powerful PTS inhibitor with very low intrinsic cytotoxicity, able to prevent the growth of polyamine depleted cells in presence of exogenous polyamines.
Assuntos
Antineoplásicos/síntese química , Azepinas/síntese química , Benzazepinas/síntese química , Poliaminas/síntese química , Poliaminas/metabolismo , Espermidina/análogos & derivados , Espermina/análogos & derivados , Animais , Antineoplásicos/farmacologia , Azepinas/farmacologia , Benzazepinas/farmacologia , Transporte Biológico/efeitos dos fármacos , Células CHO , Proliferação de Células/efeitos dos fármacos , Cricetinae , Cricetulus , Ensaios de Seleção de Medicamentos Antitumorais , Leucemia L1210 , Poliaminas/farmacologia , Espermidina/síntese química , Espermidina/farmacologia , Espermina/síntese química , Espermina/farmacologia , Relação Estrutura-AtividadeRESUMO
A series of artemisinin-spermidine conjugates designed to utilise the upregulated polyamine transporter found in cancer cells have been prepared. These conjugates were evaluated against human promyelocytic leukaemia HL-60 cells and chloroquine-sensitive 3D7 Plasmodium falciparum and several show promising anticancer and antimalarial activity. Although some limitations in this vector-based approach are apparent, a number of high potency Boc-protected analogues were identified with activity against malaria parasites as low as 0.21nM.
Assuntos
Antimaláricos/síntese química , Antimaláricos/farmacologia , Antineoplásicos Fitogênicos/síntese química , Antineoplásicos Fitogênicos/farmacologia , Artemisininas/síntese química , Artemisininas/farmacologia , Poliaminas Biogênicas/metabolismo , Proteínas de Transporte/efeitos dos fármacos , Proteínas de Transporte/metabolismo , Plasmodium falciparum/metabolismo , Espermidina/análogos & derivados , Espermidina/farmacologia , Animais , Corantes , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Células HL-60 , Humanos , Plasmodium falciparum/efeitos dos fármacos , Espermidina/síntese química , Sais de Tetrazólio , TiazóisRESUMO
The first total synthesis of amino sugar antibiotic glycocinnasperimicin D (1) has been achieved by a convergent, three-component coupling strategy. The key steps involve the Heck-Mizoroki reaction by using the iodophenyl glycoside 50 and acryl amide 32 to furnish the right core structure of 1, and the construction of the urea glycoside employing the reaction of glycosyl isocyanate 8 with amino sugar 9. Glycosyl isocyanate 8 was prepared by the oxidation of isonitrile 10, which displayed excellent reactivity in the coupling event. Synthetic roadblocks, encountered during this synthetic effort, have led to the development of the alpha-selective, Lewis acid catalyzed phenyl glycosylation process with 2-amino-hexopyranose and a procedure for acetonide deprotection without affecting the silyl ethers.
Assuntos
Antibacterianos/síntese química , Antibacterianos/química , Catálise , Glicosilação , Estrutura Molecular , Espermidina/análogos & derivados , Espermidina/síntese química , Espermidina/química , EstereoisomerismoRESUMO
We describe here the syntheses and the biological properties of new alkylaminooxysterols. Compounds were synthesized through the trans-diaxial aminolysis of 5,6-alpha-epoxysterols with various natural amines including histamine, putrescine, spermidine, or spermine. The regioselective synthesis of these 16 new 5alpha-hydroxyl-6beta-aminoalkylsterols is presented. Compounds were first screened for dendrite outgrowth and cytotoxicity in vitro, and two leads were selected and further characterized. 5alpha-Hydroxy-6beta-[2-(1H-imidazol-4-yl)ethylamino]cholestan-3beta-ol, called dendrogenin A, induced growth control, differentiation, and the death of tumor cell lines representative of various cancers including metastatic melanoma and breast cancer. 5alpha-Hydroxy-6beta-[3-(4-aminobutylamino)propylamino]cholest-7-en-3beta-ol, called dendrogenin B, induced neurite outgrowth on various cell lines, neuronal differentiation in pluripotent cells, and survival of normal neurones at nanomolar concentrations. In summary, we report that two new alkylaminooxysterols, dendrogenin A and dendrogenin B, are the first members of a class of compounds that induce cell differentiation at nanomolar concentrations and represent promising new leads for the treatment of cancer or neurodegenerative diseases.