Asunto(s)
Azetidinas/uso terapéutico , Betacoronavirus/efectos de los fármacos , Infecciones por Coronavirus/tratamiento farmacológico , Neumonía Viral/tratamiento farmacológico , Sulfonamidas/uso terapéutico , COVID-19 , Humanos , Pandemias , Purinas , Pirazoles , SARS-CoV-2 , Tratamiento Farmacológico de COVID-19RESUMEN
Pulmonary metastasis is a frequent cause of poor outcome in cancer patients. The formation of pulmonary metastasis is greatly facilitated by recruitment of myeloid cells, which are crucial for tumor cell survival and extravasation. During inflammation, homing of myeloid cells is mediated by endothelial activation, raising the question of a potential role for endothelial activation in myeloid cell recruitment during pulmonary metastasis. Here, we show that metastatic tumor cell attachment causes the induction of the endothelial activation markers vascular cell adhesion molecule-1 (VCAM-1) and vascular adhesion protein-1 (VAP-1). Induction of VCAM-1 is dependent on tumor cell-clot formation, decreasing upon induction of tissue factor pathway inhibitor or treatment with hirudin. Furthermore, inhibition of endothelial activation with a VCAM-1 blocking antibody or a VAP-1 small molecule inhibitor leads to reduced myeloid cell recruitment and diminished tumor cell survival and metastasis without affecting tumor cell adhesion. Simultaneous inhibition of VCAM-1 and VAP-1 does not result in further reduction in myeloid cell recruitment and tumor cell survival, suggesting that both act through closely related mechanisms. These results establish VCAM-1 and VAP-1 as mediators of myeloid cell recruitment in metastasis and identify VAP-1 as a potential target for therapeutic intervention to combat early metastasis.
Asunto(s)
Amina Oxidasa (conteniendo Cobre)/inmunología , Moléculas de Adhesión Celular/inmunología , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/secundario , Pulmón/patología , Células Mieloides/patología , Molécula 1 de Adhesión Celular Vascular/inmunología , Animales , Coagulación Sanguínea , Adhesión Celular , Línea Celular Tumoral , Células Endoteliales/inmunología , Células Endoteliales/patología , Humanos , Pulmón/inmunología , Neoplasias Pulmonares/sangre , Neoplasias Pulmonares/inmunología , Macrófagos/inmunología , Macrófagos/patología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones SCID , Células Mieloides/inmunologíaRESUMEN
The doubly diastereoselective [3,3]-sigmatropic aza-Claisen rearrangement of silylketene aminals derived from 5-substituted (3S,4E,alphaR)-1-benzyloxy-3-[N-acyl-N-(alpha-methylbenzyl)amino]pent-4-enes furnishes 2,3-disubstituted (R)-N-alpha-methylbenzyl (2S,3R,4E)-7-benzyloxyhept-4-enamides in >90% de under the "matched" control of both stereogenic centres. Rearrangement of the "mismatched" diastereomeric (3R,4E,alphaR)-substrates proceeds with low diastereoselectivity. The substrate scope of the doubly diastereoselective rearrangement of the "matched" substrates in which two new stereogenic centres are created has been delineated.
RESUMEN
Asymmetric [3,3]-sigmatropic aza-Claisen rearrangement of the (Z)-N-allyl-N,O-silylketene aminal of (3S,4E,alphaR)-1-benzyloxy-3-(N-propionyl-N-alpha-methylbenzylamino)hex-4-ene furnishes (2S,3R,4E,alphaR)-N-alpha-methylbenzyl-2,3-dimethyl-7-benzyloxyhept-4-enamide in > 92% d.e.; rearrangement of the diastereomeric (3R,4E,alphaR)-(Z)-N,O-silylketene aminal proceeds with low diastereoselectivity.
RESUMEN
Integration of a (13)C-(1)H satellite peak of a given (12)C-(1)H parent resonance within a quantitative (1)H NMR spectrum and comparison to the minor component represents a simple protocol for the accurate determination of diastereoisomeric ratios of up to 1000:1 (i.e., 99.8% de).
RESUMEN
The incorporation of a gem-dimethyl group at the 5-position of a chiral oxazolidinone biases the conformation of the adjacent C(4)-stereodirecting group such that the gem-dimethyl-4-iso-propyl combination mimics a C(4)-tert-butyl group, providing higher levels of stereocontrol than a simple 4-iso-propyloxazolidinone. The generality of this principle is demonstrated with applications in stereoselective enolate alkylations, kinetic resolutions, Diels-Alder cycloadditions and Pd-catalysed asymmetric acetalisation reactions.
RESUMEN
Conjugate addition of lithium dibenzylamide to methyl 5-isopropyl, 5-phenyl- and 5-tert-butyl-cyclopentene-1-carboxylates occurs with high levels of substrate control (>88% de), with preferential addition to the face of the cyclic alpha,beta-unsaturated acceptor anti- to the stereodirecting 5-alkyl substituent. Treatment of a range of methyl (+/-)-5-alkyl-cyclopentene-1-carboxylates with both lithium (+/-)-N-benzyl-N-alpha-methylbenzylamide and lithium (+/-)-N-3,4-dimethoxybenzyl-N-alpha-methylbenzylamide indicates significant enantiorecognition in their mutual kinetic resolutions, with preferential addition anti- to the 5-alkyl substituent, giving the 1,2-syn-1,5-anti-arrangement (E >16) after enolate protonation anti- to the amino functionality. The kinetic resolution of a range of methyl (+/-)-5-alkyl-cyclopentene-1-carboxylates with lithium (S)-N-benzyl-N-alpha-methylbenzylamide, and their efficient parallel kinetic resolution with a pseudoenantiomeric mixture of lithium (S)-N-benzyl-N-alpha-methylbenzylamide and lithium (R)-N-3,4-dimethoxybenzyl-N-alpha-methylbenzylamide are also demonstrated, giving a range of 5-alkyl-cispentacin derivatives in >98% de and high ee after N-deprotection.
RESUMEN
Diketopiperazinespirocyclopropane 12 is prepared in > 98% d.e. via the conjugate addition of a phosphorus ylide to (6S)-N,N'-bis(p-methoxybenzyl)-3-methylenepiperazine-2,5-dione 2. Deprotection and hydrolysis of adduct 12 and subsequent peptide coupling demonstrate the applicability of this methodology to the asymmetric synthesis of 1-aminocyclopropane-1-carboxylic acids for incorporation into novel peptides. A model for the high level of diastereofacial selectivity observed in the cyclopropanation reaction is presented. A highly selective asymmetric approach (> 98% d.e.) to (S)-[2,2-(2)H2]-1-aminocyclopropane-1-carboxylic acid 29 is also reported via a deuterated sulfur ylide addition to acceptor 2.