RESUMO
BACKGROUND: Integrins are heterodimeric cell surface receptors that mediate cell-cell and cell-extracellular matrix adhesion. These molecules play a role in processes such as cell growth and proliferation, differentiation, migration, cell trafficking, besides contributing to angiogenesis and tumor development. Given their biological role, integrins have been proposed as amenable targets in medicinal chemistry. In particular, αvß3, αvß5, αvß6 and α5ß1, integrins involved in tumor angiogenesis and metastasis, have been the subject of studies aimed at the discovery of novel cancer therapeutics. A large number of peptides and peptidomimetics based on the RGD (Arg-Gly-Asp) recognition sequence were developed in the past two decades as integrin ligands. Though such ligands have not been satisfactory as anti-angiogenic agents, their use as tools to achieve selective tumor targeting of anticancer drugs has been explored. OBJECTIVE: In this review, we summarize recent literature and patent applications in which integrin peptidic and peptidomimetic ligands were conjugated to chemotherapeutic agents both with stable or cleavable bonds to achieve tumor targeted drug delivery. METHODS: Relevant recent patents and literature in this field have been considered spanning the search from 2000 to 2016. Literature and patents were examined according to the different classes of cytotoxic drug targeted to integrins. CONCLUSION: In spite of the promising features of the conjugates, none of them has entered clinical trials. New efforts are focused on innovative approaches in the field such as the synthesis of new integrin ligands able to target a single integrin type or the employment of nanoparticles based drug delivery systems.
Assuntos
Antineoplásicos/administração & dosagem , Integrinas/metabolismo , Neoplasias/tratamento farmacológico , Inibidores da Angiogênese/administração & dosagem , Inibidores da Angiogênese/química , Inibidores da Angiogênese/farmacologia , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Sistemas de Liberação de Medicamentos , Humanos , Nanopartículas , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/patologia , Patentes como Assunto , Peptídeos/administração & dosagem , Peptídeos/química , Peptidomiméticos/administração & dosagem , Peptidomiméticos/químicaRESUMO
We have designed a new synthetic strategy for the preparation of a new class of cyclic RGD integrin ligands in which the azabicycloalkane scaffold can be envisaged as a (γ,α) dipeptide mimic. The synthesis and in vitro biological evaluation of these RGD derivatives, as well as the computational study of their conformational properties and binding modes to αVß3 integrin are described. Compound has shown to be a promising candidate as αVß3 integrin antagonist able to interfere with both cell adhesion and movement on vitronectin with no evidence of cytotoxic effects.
Assuntos
Alcanos/farmacologia , Compostos Azabicíclicos/farmacologia , Dipeptídeos/farmacologia , Integrina alfaVbeta3/antagonistas & inibidores , Integrina alfaVbeta3/metabolismo , Alcanos/síntese química , Alcanos/química , Compostos Azabicíclicos/síntese química , Compostos Azabicíclicos/química , Adesão Celular/efeitos dos fármacos , Linhagem Celular , Dipeptídeos/síntese química , Dipeptídeos/química , Relação Dose-Resposta a Droga , Humanos , Ligantes , Modelos Moleculares , Conformação Molecular , Relação Estrutura-AtividadeRESUMO
Integrins are associated with tumour cell survival and progression, and their expression has been shown to be increased in tumours. Thus, four novel conjugates of the tripeptide integrin ligand Arg-Gly-Asp (RGD) and the cytotoxic agent paclitaxel (cRGD-PTX) were prepared to investigate the potential of the multivalent presentation of the RGD moiety in improving the antitumor efficacy of PTX by tumour targeting. PTX was conjugated to two or four integrin recognizing ligands. The influence of multivalent presentation on in vitro αvß3-receptor affinity was confirmed. For all the conjugates compared to the previously synthesized monovalent counterparts, an enhancement of the binding strength was observed; this behaviour was more pronounced when considering the tetravalent presented RGD-conjugate. Cell growth inhibition assays on a panel of human tumour cell lines showed remarkable cytotoxic activity for all conjugates with IC50 values in a nanomolar range. Among the four conjugates, the bivalent derivative 3b was selected for in vivo studies in an ovarian carcinoma cell model xenografted in immunodeficient mice. A marked antitumor activity was observed, similar to that of PTX, but with a much more favourable toxicity profile. Overall, the novel cRGD-PTX conjugates disclosed here represent promising candidates for further advancement in the domain of targeted anti-tumour therapy.
Assuntos
Sistemas de Liberação de Medicamentos , Desenho de Fármacos , Paclitaxel/síntese química , Paclitaxel/farmacologia , Peptídeos Cíclicos/síntese química , Peptídeos Cíclicos/farmacologia , Multimerização Proteica , Animais , Antineoplásicos/farmacologia , Biotinilação , Linhagem Celular Tumoral , Feminino , Humanos , Integrina alfaVbeta3/metabolismo , Camundongos Nus , Peptídeos Cíclicos/química , Vitronectina/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The rational design, synthesis and in vitro biological evaluation of dual action conjugates 11-13, containing a tumour targeting, integrin αvß3/αvß5 ligand portion and a pro-apoptotic SMAC mimetic portion (cyclo-RGD/SMAC mimetic conjugates) are reported. The binding strength of the two separate units is generally maintained by these dual action conjugates. In particular, the connection between the separate units (anchor points on each unit; nature, length and stability of the linker) influences the activity of each portion against its molecular targets (integrins αvß3/αvß5 for cyclo-RGD, IAP proteins for SMAC mimetics). Each conjugate portion tolerates different substitutions while preserving the binding affinity for each target.
Assuntos
Proteínas Inibidoras de Apoptose/metabolismo , Integrina alfaVbeta3/metabolismo , Proteínas Mitocondriais/metabolismo , Peptídeos Cíclicos/síntese química , Peptídeos Cíclicos/farmacologia , Receptores de Vitronectina/metabolismo , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Biotinilação/efeitos dos fármacos , Bovinos , Linhagem Celular Tumoral , Sistema Livre de Células , Dimerização , Doxorrubicina/farmacologia , Humanos , Concentração Inibidora 50 , Ligantes , Peptídeos Cíclicos/química , Ligação Proteica/efeitos dos fármacos , Vitronectina/metabolismoRESUMO
In recent years progress has been speeding in studies of cell-cell interaction governed by adhesion molecules, and in particular by integrins and their ligands in cells and in the extracellular matrix. Integrins are distributed in a variety of tissues and blood cells. An increased expression of integrins and of their adhesion counterparts is often observed in sites relevant to disease states. Important roles are played by integrin α(v)ß(3) in cancer angiogenesis and metastatic diffusion, in angiogenesis in ischemic tissues, in atherosclerotic damage and restenosis, and in osteoporosis; by integrin α(5)ß(1) in angiogenesis processes; by integrin α(II)bß(3), mediating adhesion of platelets to fibrinogen, in thrombotic conditions; by integrins α(4)ß(1) and α(L)ß(2) in inflammatory conditions, particularly autoimmune diseases and asthma. Therefore, medicinal chemists became attracted and engaged in research on integrins as therapeutic and diagnostic targets. Many efforts have been directed towards the development of molecular constructs including integrin ligands that can provide advanced tools for drug delivery, for imaging, or for their combination (theranostics), particularly by exploiting the new possibilities offered by nanoparticles. Here we will review the current status and the future perspective of integrin targeting of several kind of nanoparticles, going from most studied micelles, liposomes, polymeric nanoparticles to finish with inorganic nanoparticles of more recent employment. Perfluoroalkane filled microbubbles, although over the nanometric size (1-10 µm) will be shortly considered.
Assuntos
Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/metabolismo , Sistemas de Liberação de Medicamentos/métodos , Integrinas/metabolismo , Nanopartículas/administração & dosagem , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Animais , Humanos , Nanopartículas/químicaRESUMO
BACKGROUND: XIAP (X-linked inhibitor of apoptosis protein) is an anti-apoptotic protein exerting its activity by binding and suppressing caspases. As XIAP is overexpressed in several tumours, in which it apparently contributes to chemoresistance, and because its activity in vivo is antagonised by second mitochondria-derived activator of caspase (SMAC)/direct inhibitor of apoptosis-binding protein with low pI, small molecules mimicking SMAC (so called SMAC-mimetics) can potentially overcome tumour resistance by promoting apoptosis. METHODS: Three homodimeric compounds were synthesised tethering a monomeric SMAC-mimetic with different linkers and their affinity binding for the baculoviral inhibitor repeats domains of XIAP measured by fluorescent polarisation assay. The apoptotic activity of these molecules, alone or in combination with tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) and/or Bortezomib, was tested in melanoma cell lines by MTT viability assays and western blot analysis of activated caspases. RESULTS: We show that in melanoma cell lines, which are typically resistant to chemotherapeutic agents, XIAP knock-down sensitises cells to TRAIL treatment in vitro, also favouring the accumulation of cleaved caspase-8. We also describe a new series of 4-substituted azabicyclo[5.3.0]alkane monomeric and dimeric SMAC-mimetics that target various members of the IAP family and powerfully synergise at submicromolar concentrations with TRAIL in inducing cell death. Finally, we show that the simultaneous administration of newly developed SMAC-mimetics with Bortezomib potently triggers apoptosis in a melanoma cell line resistant to the combined effect of SMAC-mimetics and TRAIL. CONCLUSION: Hence, the newly developed SMAC-mimetics effectively synergise with TRAIL and Bortezomib in inducing cell death. These findings warrant further preclinical studies in vivo to verify the anticancer effectiveness of the combination of these agents.
Assuntos
Ácidos Borônicos/farmacologia , Morte Celular/efeitos dos fármacos , Peptídeos e Proteínas de Sinalização Intracelular/farmacologia , Melanoma/tratamento farmacológico , Proteínas Mitocondriais/farmacologia , Pirazinas/farmacologia , Ligante Indutor de Apoptose Relacionado a TNF/farmacologia , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/metabolismo , Proteínas Reguladoras de Apoptose , Bortezomib , Caspase 8/metabolismo , Linhagem Celular Tumoral , Regulação para Baixo , Interações Medicamentosas , Sinergismo Farmacológico , Técnicas de Silenciamento de Genes , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/administração & dosagem , Proteínas Mitocondriais/administração & dosagem , Ligante Indutor de Apoptose Relacionado a TNF/administração & dosagemRESUMO
The practical, stereoselective synthesis of the three diastereoisomeric 1,2-trans-dicarboxy-4,5-cyclohexanediols 1-3 (DCCHDs) is described, starting from a common precursor, easily available in both enantiomeric forms. The regioselective derivatization of all functional groups of 1 is also reported. The three DCCHDs are locked in a single chair conformation and thus can be used to mimic vicinally disubstituted monosaccharides of any relative configuration.
Assuntos
Cicloexanóis/química , Cicloexanóis/síntese química , Mimetismo Molecular , Monossacarídeos/química , Monossacarídeos/síntese química , Desenho de Fármacos , Conformação MolecularRESUMO
[structure: see text]. A small library of cyclic RGD pseudopentapeptides incorporating stereoisomeric 6,5- and 7,5-fused bicyclic lactams was synthesized with the aim of developing active and selective integrin antagonists. The solid-phase synthesis and activity of these RGD derivatives is described. The approach led to two of the most active known inhibitors of alpha(V)beta3 receptor.
Assuntos
Compostos Bicíclicos com Pontes/síntese química , Lactamas/síntese química , Oligopeptídeos/síntese química , Receptores de Vitronectina/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/metabolismo , Compostos Bicíclicos com Pontes/química , Compostos Bicíclicos com Pontes/metabolismo , Ciclização , Peptídeos e Proteínas de Sinalização Intercelular , Cinética , Lactamas/química , Lactamas/metabolismo , Estrutura Molecular , Oligopeptídeos/química , Oligopeptídeos/metabolismo , Biblioteca de Peptídeos , Peptídeos/metabolismo , Inibidores da Agregação Plaquetária/metabolismo , Estrutura Secundária de Proteína , Ensaio Radioligante , Receptores de Vitronectina/químicaRESUMO
Phenyl 6-O-benzyl-2-deoxy-2-tetrachlorophthalimido-1-thio-beta-D- glucopyranoside (5a) and thexyldimethylsilyl 6-O-benzyl-2-deoxy-2-tetrachlorophthalimido-beta-D- glucopyranoside (5b) gave with O-(2,3,4,6-tetra-O-acetyl-alpha-D-galactopyranosyl)trichloroacetimida te (8) in the presence of BF3.Et2O as catalyst exclusively lactosamine derivatives 7a and 7b, respectively, in high yields. Ensuing reaction with O-(3, 4-di-O-acetyl-2-O-benzyl-alpha-L-fucopyranosyl) trichloroacetimidate (9) in the presence of TMSOTf as catalyst afforded Le(x) trisaccharide intermediates 10a,b. With fucosyl donor 9 and 5a,b as acceptors in the presence of TMSOTf as catalyst glycosylation either at the 3-O or the 4-O was observed, thus leading to mixtures of disaccharides 11a/12a and 11b/12b, respectively; their reaction with 8 furnished Le(x) trisaccharide intermediates 10a,b and Le(a) trisaccharide intermediates 14a,b. Transformation of 10b into the corresponding trichloroacetimidate 17 and reaction with lactose acceptor 19 in the presence of Zn(OTf)2 as catalyst gave protected Le(x) pentasaccahride intermediate 21, which on deprotection led to unprotected Le(x) pentasaccharide 1.
Assuntos
Acetilglucosamina/análise , Antígenos do Grupo Sanguíneo de Lewis/imunologia , Antígenos CD15/química , Oligossacarídeos/síntese química , Ácidos Ftálicos/química , Sequência de Carboidratos , Dissacarídeos/química , Dados de Sequência Molecular , Trissacarídeos/químicaRESUMO
Fifty-three patients affected by Alzheimer's disease entered a longitudinal survey aimed at studying which factors influence the rate of progression, assessed by means of the Milan Overall Dementia Assessment (MODA). The second examination was carried out, on average, after 16 months from the first assessment. Only age proved to influence the decline rate, which was faster in elders.
RESUMO
D-Glucosamine can be readily transformed into 1,3,4,6-tetra-O-acetyl-2-deoxy-2-(2,2,2-trichloroethoxycarbonylamino+ ++) -D-glucopyranose (2). From this intermediate valuable glycosyl donors can be obtained; reaction with ethanethiol in the presence of boron trifluoride etherate afforded ethyl 3,4,6-tri-O-acetyl-2-deoxy-1-thio-2-(2,2, 2-trichloroethoxycarbonylamino)-beta-D-glucopyranoside (4) which gave, upon N-acetylation, the N-acetyl-N-trichloroethoxycarbonyl derivative (5). Selective removal of the 1-O-acetyl group in 2 followed by treatment with trichloroacetonitrile in the presence of base afforded 3,4,6-tri-O-acetyl-2-deoxy-2-(2,2,2-trichloroethoxycarbonylamino)- alpha -D-glucopyranosyl trichloroacetimidate (6). Reaction of 5 with five selectively protected glycosides as glycosyl acceptors in the presence of N-iodosuccinimide/trifluoromethanesulfonic acid as the promoter system furnished the corresponding beta-glycosides in good yields, thus exhibiting the valuable glycosyl donor properties of 5. Reductive removal of the trichloroethoxycarbonyl (Teoc) group afforded the corresponding N-acetyl-protected saccharides in high yields. The imidate 6 reacted with three of the above acceptors in the presence of catalytic amounts of trimethylsilyl trifluoromethanesulfonate to give the beta-linked disaccharides in even better yields. The direct replacement of the N-Teoc group by the N-acetyl group using zinc/acetic anhydride, via the free amines as transient intermediates, adds to the high efficiency and convenience of this methodology.
Assuntos
Glucosamina/análogos & derivados , Glucosamina/síntese química , Glicosídeos/síntese química , Configuração de Carboidratos , Sequência de Carboidratos , Dissacarídeos/síntese química , Espectroscopia de Ressonância Magnética , Dados de Sequência Molecular , Estrutura Molecular , Trissacarídeos/síntese químicaRESUMO
SR 27417 (CAS 136468-36-5, N-(2-dimethylaminoethyl)-N-(3-pyridinylmethyl)[4-(2,4,6-triisop ropylphenyl) thiazol-2-yl]amine), a highly potent platelet-activating factor (PAF) receptor antagonist, was tested for its ability to prevent macroscopic and histologically assessed gastrointestinal (GI) lesions in rats induced by PAF as compared to the reference compound apafant. Both compounds were orally effective but SR 27417 prevented the gut lesioning effects of PAF at lower doses than apafant. In addition, a dose of apafant (1.5 mg/kg) that showed almost maximal effect when given 30 min before PAF, had lost most of its protective action by 3 h, while SR 27417 at a comparably effective dose (0.5 mg/kg) retained substantial ability to prevent gut lesions in all the GI tract segments investigated, 18 h after administration. These findings suggest that SR 27417 is a potent and long lasting inhibitor of PAF-induced gastrointestinal lesions in rats.
Assuntos
Gastroenteropatias/prevenção & controle , Fator de Ativação de Plaquetas/antagonistas & inibidores , Tiazóis/uso terapêutico , Animais , Azepinas/farmacologia , Relação Dose-Resposta a Droga , Mucosa Gástrica/patologia , Gastroenteropatias/induzido quimicamente , Gastroenteropatias/patologia , Mucosa Intestinal/patologia , Masculino , Fator de Ativação de Plaquetas/toxicidade , Inibidores da Agregação Plaquetária/farmacologia , Ratos , Triazóis/farmacologiaRESUMO
This paper compares the effects of ramixotidine dihydrochloride (CM 57755) with those of cimetidine on gastric acid secretion and gastrin release in conscious dogs chronically fitted with Heidenhain pouches and/or gastric fistulae. At equimolar doses, intravenous (i.v.) or intragastric (i.g.) CM 57755 caused similar inhibition of dimaprit- or pentagastrin-induced secretion than cimetidine. Acid secretion stimulated by a meat meal was significantly reduced by both CM 57755 and cimetidine. Neither CM 57755 (4.5 and 9 mumol/kg) nor cimetidine (4 mumol/kg) modified gastrin release, while cimetidine (8 mumol/kg) significantly increased it. Judging from these results, while CM 57755 appears to be an inhibitor of gastric acid secretion induced by different stimulants in dogs with potency comparable to cimetidine. The increase in plasma gastrin levels seen after cimetidine but not after CM 57755 suggests that cimetidine releases gastrin by a mechanism independent of H2 receptor antagonism.
Assuntos
Antiulcerosos/farmacologia , Cimetidina/farmacologia , Niacinamida/análogos & derivados , Receptores Histamínicos H2/efeitos dos fármacos , Animais , Cães , Ácido Gástrico/metabolismo , Gastrinas/metabolismo , Masculino , Niacinamida/farmacologia , Pentagastrina/farmacologiaRESUMO
The antisecretory effects of CM 57755, a new histamine-H2 receptor antagonist, have been compared with those of cimetidine on gastric acid secretion induced by intravenous infusions of dimaprit or pentagastrin into conscious cats with chronically implanted gastric fistulae. Intravenous infusion of CM 57755 induced a parallel shift to the right of the dimaprit dose-response curve. The potency of CM 57755 was comparable with that of cimetidine as shown by similar doses causing a 5-fold displacement to the right of the dimaprit dose-response curve (4.9 mumol kg-1 h-1 for CM 57755 and 4.7 mumol kg-1 h-1 for cimetidine). Unlike that with dimaprit, the acid secretion stimulated by increasing doses of pentagastrin was inhibited by CM 57755 with depression of the maximal effect, indicating non-competitive antagonism. In a second series of experiments the time course of the anti-secretory action of intragastrically administered CM 57755 was studied from the gastric acid secretion induced by constant infusion of dimaprit. At equieffective doses, CM 57755 caused more sustained inhibition than cimetidine.
Assuntos
Ácido Gástrico/metabolismo , Antagonistas dos Receptores H2 da Histamina/farmacologia , Niacinamida/análogos & derivados , Pentagastrina/antagonistas & inibidores , Tioureia/antagonistas & inibidores , Animais , Gatos , Cimetidina/farmacologia , Dimaprit , Cinética , Masculino , Niacinamida/farmacologiaRESUMO
The pharmacological activity of CM 57755, a new gastric antisecretory compound of the anti-H2 type, was studied in certain in vivo and in vitro preparations. In stomach-lumen perfused rats it proved to be, on a molar basis, half as active as cimetidine and 1/13 as active as ranitidine in inhibiting histamine-induced gastric acid secretion. On the other hand, CM 57755 administered to conscious gastric-fistula cats, either i.v. or intragastrically, depressed the hypersecretory plateau evoked by constant infusion of dimaprit with a potency comparable to that of cimetidine. In this preparation, the inhibition at equieffective doses of antagonists was more sustained for CM 57755 than for cimetidine and ranitidine. Applied to isolated guinea-pig right atria and gastric mucosa, CM 57755 competitively antagonized histamine effects (respective pA2's: 5.4 and 5.9) but was less potent than expected from its in vivo antisecretory activity. Bioavailability and/or biotransformation are the factors most likely to account for the differences observed between species, and between in vivo and in vitro studies for this long-acting antisecretory agent.
Assuntos
Antagonistas dos Receptores H2 da Histamina/farmacologia , Niacinamida/análogos & derivados , Animais , Antiulcerosos , Gatos , Cimetidina/farmacologia , Dimaprit , Feminino , Ácido Gástrico/metabolismo , Mucosa Gástrica/efeitos dos fármacos , Mucosa Gástrica/metabolismo , Cobaias , Frequência Cardíaca/efeitos dos fármacos , Íleo , Técnicas In Vitro , Músculo Liso/efeitos dos fármacos , Niacinamida/farmacologia , Ranitidina/farmacologia , Ratos , Ratos Endogâmicos , Tioureia/antagonistas & inibidoresRESUMO
An analysis of 26,700 unselected autopsies performed consecutively over a 15-year period was made to establish the incidence of hepatocellular carcinoma (HCC) and its relationship to cirrhosis of the liver in the Trieste area. In our series, considering the period 1968-1980, the average value of the annual age and sex incidence rates of HCC standardized to the European population proved to be 10.58/100,000 in cirrhotic males and 1.3/100,000 in cirrhotic females, whereas in non-cirrhotics it was 1.14/100,000 and 0.34/100,000, respectively. In cirrhotic males autopsied during the period 1977-1980 the above incidence increases, its average value being 16.53/100,000.