RESUMO
Photodynamic therapy (PDT) and vascular-disrupting agents (VDA) each have their advantages in the treatment of solid tumors, but also present drawbacks. In PDT, hypoxia at the center of the tumor limits conversion of molecular oxygen into singlet oxygen, while VDAs are deficient at affecting the rim of the tumor. A phthalocyanine-chalcone conjugate combining the VDA properties of chalcones with the PDT properties of phthalocyanines was designed to address these deficiencies. Its vascular targeting, photophysical, photochemical, photodynamic activities are reported herein.
Assuntos
Chalcona/química , Indóis/química , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacologia , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Chalcona/farmacologia , Humanos , Indóis/farmacologia , Isoindóis , Estrutura Molecular , Fármacos Fotossensibilizantes/síntese química , Oxigênio Singlete/metabolismoRESUMO
Vascular-disrupting agents (VDA) specifically target established neovasculature which results in vascular shutdown. This therapeutic strategy could improve the outcome of pathologies involving aberrant angiogenesis. Although several classes of VDA exist, inhibitors of tubulin assembly (ITA) represent the main category. A series of 21 conformationnally-restricted analogues of E7010, a known ITA-VDA, were designed and synthesised as novel inhibitors of tubulin assembly (ITA) and vascular-disrupting agents (VDA). Among them, indole 4j exhibited good potency against HUVEC and HIG-82 cell lines, as well as a good ability to inhibit tubulin assembly. Furthermore, indole 4j reduced HUVEC migration in a dose-dependent manner, indicating a vascular disrupting activity comparable to that of the gold standard, Combretastatin A4 (CA4).
Assuntos
Antineoplásicos , Tubulina (Proteína) , Tubulina (Proteína)/metabolismo , Linhagem Celular Tumoral , Moduladores de Tubulina , Antineoplásicos/farmacologia , Indóis/farmacologia , Inibidores da Angiogênese/farmacologiaRESUMO
A short and efficient synthesis, based on a one-step double elimination, of a key intermediate in the synthesis of various glucocorticosteroids has been developed. This method can be carried out on large scale for further industrial applications. The synthesis allowed us to identify a novel prednisolone derivative 10 and its anti-inflammatory activity was determined in an in vivo model of inflammation. In order to understand the regioselectivity of the double elimination under various conditions, mechanistic studies were undertaken and confirmed the experimental results. We also propose a mechanism for the formation of the new steroid 10 studied by molecular modeling.
Assuntos
Glucocorticoides/química , Glucocorticoides/síntese química , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Técnicas de Química Sintética , Edema/tratamento farmacológico , Glucocorticoides/farmacologia , Glucocorticoides/uso terapêutico , Masculino , Camundongos , Modelos Moleculares , Conformação Molecular , Prednisolona/síntese química , Prednisolona/química , Prednisolona/farmacologia , Prednisolona/uso terapêuticoRESUMO
The TWIK-related K+ channel, TREK-1, has recently emerged as an attractive therapeutic target for the development of a novel class of analgesic drugs, suggesting that activation of TREK-1 could result in pain inhibition. Here, we report the synthesis of a series of substituted acrylic acids (1-54) based on our previous work with caffeate esters. The analogues were evaluated for their ability to modulate TREK-1 channel by electrophysiology and for their in vivo antinociceptive activity (acetic acid-induced writhing and hot plate assays), leading to the identification of a series of novel molecules able to activate TREK-1 and displaying potent antinociceptive activity in vivo. Furyl analogue 36 is the most promising of the series.
Assuntos
Analgésicos/farmacologia , Canais de Potássio de Domínios Poros em Tandem/agonistas , AnimaisRESUMO
Potassium (K(+)) channels are membrane proteins expressed in most living cells that selectively control the flow of K(+) ions. More than 80 genes encode the K(+) channel subunits in the human genome. The TWIK-related K(+) channel (TREK-1) belongs to the two-pore domain K(+) channels (K2P) and displays various properties including sensitivity to physical (membrane stretch, acidosis, temperature) and chemical stimuli (signaling lipids, volatile anesthetics). The distribution of TREK-1 in the central nervous system, coupled with the physiological consequences of its opening and closing, leads to the emergence of this channel as an attractive therapeutic target. We review the TREK-1 channel, its structural and functional properties, and the pharmacological agents (agonists and antagonists) able to modulate its gating.
Assuntos
Fármacos Neuroprotetores/farmacologia , Canais de Potássio de Domínios Poros em Tandem/agonistas , Canais de Potássio de Domínios Poros em Tandem/antagonistas & inibidores , Arritmias Cardíacas/tratamento farmacológico , Depressão/tratamento farmacológico , Epilepsia/tratamento farmacológico , Humanos , Inflamação/tratamento farmacológico , Modelos Moleculares , Estrutura Molecular , Fármacos Neuroprotetores/química , Dor/tratamento farmacológico , Canais de Potássio de Domínios Poros em Tandem/metabolismo , Relação Estrutura-AtividadeRESUMO
We are investigating the synthesis of thioanalogues of nodulation factors that will be resistant to degradation by chitinases. To study the influence of our protecting group strategy, the glycosylation of 1,6-anhydro-2-azido-3-O-benzyl-2-deoxy-beta-D-glucopyranoside (7) with two trichloroacetimidate glycosyl donors carrying an azido group at C-2 and either benzyl or benzoyl protecting groups on O-3 and O-4 was first attempted under catalysis with BF(3).Et(2)O in toluene. While glycosylation with the benzoylated glycosyl donor gave only a poor yield (27%) of the disaccharide, a similar reaction with the benzylated donor gave the corresponding disaccharide in good yield (77%). Although both products were obtained as anomeric mixtures, the benzylated donor led to improved stereoselectivity in favor of the desired beta-anomer (alpha:beta 3:7). Based on these results, a novel thiotrisaccharide was synthesized via the coupling of 7 with 6-O-acetyl-4-S-(3,4,6-tri-O-acetyl-2-benzyloxycarbonylamino-2-deoxy-beta-D-glucopyranosyl)-2-azido-3-O-benzyl-2-deoxy-4-thio-alpha-D-glucopyranosyl trichloroacetimidate (25) also newly synthesized. After optimization of the reaction conditions, the desired thiotrisaccharide 4-O-[6-O-acetyl-4-S-(3,4,6-tri-O-acetyl-2-benzyloxycarbonylamino-2-deoxy-beta-D-glucopyranosyl)-2-azido-3-O-benzyl-2-deoxy-4-thio-beta-D-glucopyranosyl]-1,6-anhydro-2-azido-3-O-benzyl-2-deoxy-beta-D-glucopyranoside (26beta) was obtained in 57% yield. These conditions led to an anomeric mixture in favor of the desired beta-anomer (alpha:beta 1:4.7) that was separated from the alpha-anomer by normal-phase HPLC on a PrepNova Pack(R) silica gel cartridge. The work described here shows that thiodisaccharide glycosyl donors behave quite differently from the analogous O-disaccharide used previously to synthesize nodulation factors.
Assuntos
Lipopolissacarídeos/química , Oligossacarídeos/síntese química , Tioglicosídeos/síntese química , Sequência de Carboidratos , Quitina/análogos & derivados , Dissacarídeos/síntese química , Glicosilação , Dados de Sequência Molecular , Oligossacarídeos/química , Tioglicosídeos/química , Trissacarídeos/síntese químicaRESUMO
The TWIK-related K(+) channel, TREK-1, has recently emerged as an attractive therapeutic target for the development of a novel class of analgesic drugs. It has been reported that TREK-1 -/- mice were more sensitive than wild-type mice to painful stimuli, suggesting that activation of TREK-1 could result in pain inhibition. Here we report the synthesis of a series of substituted caffeate esters (12a-u) based on the hit compound CDC 2 (cinnamyl 3,4-dihydroxyl-α-cyanocinnamate). These analogs were evaluated for their ability to modulate TREK-1 channel by electrophysiology and for their in vivo antinociceptive activity (acetic acid induced-writhing assay) leading to the identification a series of novel molecules able to activate TREK-1 and displaying potent analgesic activity in vivo.