RESUMO
Bortezomib has been successful for treatment of multiple myeloma, but not against solid tumors, and toxicities of neuropathy, thrombocytopenia and the emergence of resistance have triggered efforts to find alternative proteasome inhibitors. Bis-benzylidine piperidones such as RA190 covalently bind ADRM1/RPN13, a ubiquitin receptor that supports recognition of polyubiquitinated substrates of the proteasome and their subsequent deububiqutination and degradation. While these candidate RPN13 inhibitors (iRPN13) show promising anticancer activity in mouse models of cancer, they have suboptimal drug-like properties. Here we describe Up284, a novel candidate iRPN13 possessing a central spiro-carbon ring in place of RA190's problematic piperidone core. Cell lines derived from diverse cancer types (ovarian, triple negative breast, colon, cervical and prostate cancers, multiple myeloma and glioblastoma) were sensitive to Up284, including several lines resistant to bortezomib or cisplatin. Up284 and cisplatin showed synergistic cytotoxicity in vitro. Up284-induced cytotoxicity was associated with mitochondrial dysfunction, elevated levels of reactive oxygen species, accumulation of very high molecular weight polyubiquitinated protein aggregates, an unfolded protein response and the early onset of apoptosis. Up284 and RA190, but not bortezomib, enhanced antigen presentation in vitro. Up284 cleared from plasma in a few hours and accumulated in major organs by 24 h. A single dose of Up284, when administered to mice intra peritoneally or orally, inhibited proteasome function in both muscle and tumor for >48 h. Up284 was well tolerated by mice in repeat dose studies. Up284 demonstrated therapeutic activity in xenograft, syngeneic and genetically-engineered murine models of ovarian cancer.
Assuntos
Mieloma Múltiplo , Neoplasias Ovarianas , Humanos , Masculino , Feminino , Animais , Camundongos , Cisplatino , Complexo de Endopeptidases do Proteassoma , Bortezomib/farmacologia , Peptídeos e Proteínas de Sinalização IntracelularRESUMO
The syntheses of glycolytically stable galactosides and lactosides have been made toward the selective inhibition of human galectins-1 and -3. Transition metal-catalyzed cross-coupling reactions were used to create carbon-carbon bond formation (Sonogashira, Suzuki, Heck, Glaser). Additionally, Hantzsch condensation was used to create novel 2-aminothiazoles which reacted with a panel of acylating and sulfonylating reagents. Moreover, dimeric galactosides and lactosides bearing triazoles, regiospecifically prepared using copper-catalyzed Huisgen azide-alkyne [1,3]-dipolar cycloaddition, provided efficient galectins-1 and -3 inhibitors. Best monovalent inhibitor among the tested series was (E)-methyl 2-phenyl-4-(beta-D-galactopyranosyl)-but-2-enoate 15 with inhibitory potency of 313 microM against galectin-1 and best dimers were bis-lactoside 68 and 75 having both inhibitory properties of 160 microM against Galectin-3.
Assuntos
Galactosídeos/síntese química , Galectina 1/antagonistas & inibidores , Galectina 3/antagonistas & inibidores , Glicosídeos/síntese química , Estabilidade de Medicamentos , Galactosídeos/química , Galactosídeos/farmacologia , Glicosídeos/química , Glicosídeos/farmacologia , Testes de Inibição da Hemaglutinação , Humanos , Espectroscopia de Ressonância Magnética , Espectrometria de Massas por Ionização por ElectrosprayRESUMO
A furanocoumarin glycoside new named turbinatocoumarin (1) was isolated from the twigs of Dorstenia turbinata. The structure of turbinatocoumarin (1) was assigned as 5-methoxy-3-[3-(beta-glucopyranosyloxy)-2-hydroxy-3-methylbutyl]psoralen by means of spectroscopic analysis. Known compounds have also been isolated from this genus and identified as (2'S, 3'R)-3'-hydroxymarmesin (2), 5-methoxy-3-(3-methyl-2,3-dihydroxybutyl)psoralen (3), psoralen (4), kanzonol C (5) which was isolated for the first time from this genus, 4-hydroxylonchocarpin (6), umbelliferone, 4-hydroxy-3-methoxybenzaldehyde and 4-methoxyphenol. As part of our continuing search for potential naturally-occurring antitumor drug candidates, the inhibition of matrix metalloproteinase (MMP)-2 secretion from brain tumor-derived glioblastoma cells by the isolated compounds 1, 3, 5, and 6 was evaluated by zymography and compared to the documented naturally-occurring MMP secretion inhibitors chlorogenic acid (CHL) and epigallocatechin-3-gallate (EGCg). Among the compounds tested, the inhibiting MMP secretion concentrations ranged from 0.025 to 250 microM with up to 80% inhibition. The inhibitory activities of compounds 5 and 6 were found comparable to the common reference compounds CHL and EGCg. This suggests that alternate sources can be explored and exploited for the availability of chemopreventive molecules.
Assuntos
Neoplasias Encefálicas/metabolismo , Chalconas/farmacologia , Furocumarinas/farmacologia , Glicosídeos/farmacologia , Metaloproteinase 2 da Matriz/metabolismo , Moraceae/metabolismo , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/metabolismo , Antineoplásicos Fitogênicos/farmacologia , Linhagem Celular Tumoral , Chalconas/química , Chalconas/metabolismo , Furocumarinas/química , Furocumarinas/metabolismo , Glioblastoma/enzimologia , Glicosídeos/química , Glicosídeos/metabolismo , Humanos , Estrutura Molecular , Moraceae/químicaRESUMO
[reaction: see text] Stereoselective isomerization of C-allyl glycosides into (E)-C-vinyl glycosides or (Z)-exo-glycals was carried out in the presence of the cationic iridium(I) catalyst [(Ph(2)MeP)(2)Ir(cod)PF(6)]. The products of the isomerization were affected by the relative 1,2-stereochemical relationships and by the nature of the protecting groups. These effects are discussed along with a plausible reaction mechanism.
Assuntos
Glicosídeos/química , Irídio/química , Monossacarídeos/síntese química , Catálise , Estrutura Molecular , Paládio/química , Estereoisomerismo , Compostos de Vinila/químicaRESUMO
Galactosides and lactosides bearing triazoles or isoxazoles, regiospecifically prepared by [1,3]-dipolar cycloadditions between alkynes, azides or nitrile oxides, provided specific galectin-1 and -3 inhibitors with potencies as low as 20 microM.
Assuntos
Carboidratos/química , Galectina 1/antagonistas & inibidores , Galectina 3/antagonistas & inibidores , Isoxazóis/química , Triazóis/química , Carboidratos/farmacologia , Hemaglutinação/efeitos dos fármacos , Isoxazóis/síntese química , Isoxazóis/farmacologia , Estrutura Molecular , Estereoisomerismo , Relação Estrutura-Atividade , Triazóis/síntese química , Triazóis/farmacologiaRESUMO
The unusual chlorinated coumarinolignan, 5-chloropropacin, along with several other known compounds have been isolated from the roots of Mondia whitei. The structure of the chlorinated coumarinolignan was determined by NMR and mass spectroscopic analyses.
Assuntos
Apocynaceae/química , Cumarínicos/isolamento & purificação , Lignanas/isolamento & purificação , África , Cumarínicos/química , Lignanas/química , Estrutura Molecular , Raízes de Plantas/química , Plantas MedicinaisRESUMO
Quinazolinones, 2-substituted and 3-substituted, mainly synthesized by microwave irradiation, were subjected to anti-platelet aggregation and inhibition of superoxide anion generation assays. Interestingly, 2-phenyl-4-quinazolinone (4) exhibited significant inhibitory activities toward platelet aggregation and neutrophil activation, and it might therefore serve as a prototype lead compound.
Assuntos
Neutrófilos/efeitos dos fármacos , Neutrófilos/fisiologia , Inibidores da Agregação Plaquetária/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Quinazolinas/farmacologia , Superóxidos/antagonistas & inibidores , Adolescente , Adulto , Animais , Humanos , Neutrófilos/metabolismo , Agregação Plaquetária/fisiologia , Inibidores da Agregação Plaquetária/química , Quinazolinas/química , Coelhos , Superóxidos/metabolismo , Tecnologia Farmacêutica/métodosRESUMO
Oxidation of 1-benzyl-3,4-dihydroisoquinolines with cerium(IV) ammonium nitrate (CAN) under mild condition yielded the mixture of corresponding 1-benzylisoquinolines (b-type) and 1-benzoylisoquinolines (a- or c-type) in an equal yields. The selective oxidation products (c-type) can be prepared by using MeCN instead of MeOH. In the antiplatelet assays, four inducers were employed, including AA, Col, PAF, and Thr. In the PAF or Col induced platelet aggregation, compounds belonging to a- and b-type showed stronger inhibitory effects than aspirin.