RESUMO
Starting from the antimalarial drugs chloroquine and hydroxychloroquine, we conducted a structural optimization on the side chain of chloroquine by introducing amino substituted longer chains thus leading to a series of novel aminochloroquine derivatives. Anti-infectious effects against SARS-Cov2 spike glycoprotein as well as immunosuppressive and anti-inflammatory activities of the new compounds were evaluated. Distinguished immunosuppressive activities on the responses of T cell, B cell and macrophages upon mitogen and pathogenic signaling were manifested. Compounds 9-11 displayed the most promising inhibitory effects both on cellular proliferation and on the production of multiple pro-inflammatory cytokines, including IL-17, IFN-γ, IL-6, IL-1ß and TNF-α, which might be insightful in the pursuit of treatment for immune disorders and inflammatory diseases.
Assuntos
Aminas/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Antivirais/farmacologia , Cloroquina/farmacologia , SARS-CoV-2/efeitos dos fármacos , Glicoproteína da Espícula de Coronavírus/antagonistas & inibidores , Aminas/química , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Antivirais/síntese química , Antivirais/química , Linfócitos B/imunologia , Proliferação de Células/efeitos dos fármacos , Cloroquina/síntese química , Cloroquina/química , Citocinas/metabolismo , Relação Dose-Resposta a Droga , Humanos , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Testes de Sensibilidade Microbiana , Estrutura Molecular , SARS-CoV-2/metabolismo , Glicoproteína da Espícula de Coronavírus/metabolismo , Relação Estrutura-Atividade , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologiaRESUMO
A series of C-7, C-9 and C-10 modified taxane analogues were synthesized and their in vitro anticancer activities against three human cancer cell lines: A-549 (human lung cancer cell line), MDA-MB-231 (human breast cancer cell line), A-549/T (human lung cancer resistant cell line) were studied. The novel 1-deoxybaccatin VI derivatives modified with carbonate group at C-9 and C-10 positions enable the behavior of these compounds to be evidently distinct from other similar compounds. The strong cytotoxicity in the three cell lines, especially in drug-resistant cell line, showed by the newly synthesized taxane analogues indicated them as potential lead compounds for anticancer drug design.
Assuntos
Antineoplásicos/síntese química , Hidrocarbonetos Aromáticos com Pontes/química , Taxoides/química , Antineoplásicos/química , Antineoplásicos/farmacologia , Hidrocarbonetos Aromáticos com Pontes/síntese química , Hidrocarbonetos Aromáticos com Pontes/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Desenho de Fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Relação Estrutura-Atividade , Taxoides/síntese química , Taxoides/farmacologiaRESUMO
A new series of C-3'-N-sulfonyl paclitaxel analogs were designed and synthesized from 1-deoxybaccatin VI and their structures were confirmed by 1H NMR, 13C NMR and high resolution MS. The synthesized compounds were evaluated for their in vitro anti-Hepatocellular carcinoma (HCC) activity against human hepatoma (HepG2) cell line. Bioassay results showed that compounds 17c, 17d and 17f exhibited more potent inhibitory activity against HepG2 cell line in comparison with paclitaxel. It is suggested that paclitaxel analogs containing the C-3'-N-sulfonyl could be considered as a precursor structure for further synthesis of more potent analogues.
Assuntos
Antineoplásicos , Carcinoma Hepatocelular , Neoplasias Hepáticas , Antineoplásicos/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Estrutura Molecular , Relação Estrutura-Atividade , Taxoides/farmacologiaRESUMO
Hematopoietic progenitor kinase 1 (HPK1) is an important negative regulator in T-cell receptor signaling and as a promising key target for immunotherapy. Herein, based on the reported HPK1 inhibitor 2 featuring an isofuranone component, a structural optimization approach was conducted leading to several series of derivatives characterized by containing an isoindoline structural motif. Compound 49 was identified as a new potent HPK1 inhibitor with an IC50 value of 0.9 nM, more potent than compound 2 (5.5 nM). It also has an improved IV profile in rats and enhanced aqueous solubility. It effectively inhibited pSLP76 and reinvigorated T-cell receptor (TCR) signaling, promoting T-cell function and cytokine production both in naïve and antigen-specific T cells. Furthermore, compound 49 reversed the inhibition on T-cell activity mediated by classic immunosuppressive factors in the tumor microenvironment (TME). In the murine CT-26 tumor model, this compound reinvigorated the T cell and synergistically enhanced the antitumor efficacy of anti-PD1 at a well-tolerant dosage.
Assuntos
Transdução de Sinais , Linfócitos T , Camundongos , Ratos , Animais , Linfócitos T/metabolismo , Fosforilação , Ligação Proteica , Receptores de Antígenos de Linfócitos TRESUMO
The p21-activated kinase 4 (PAK4) is a member of the PAKs family. It is overexpressed in multiple tumor tissues. Pharmacological inhibition of PAK4 attenuates proliferation, migration, and invasion of cancer cells. Recent studies revealed that inhibition of PAK4 sensitizes immunotherapy which has been extensively exploited as a new strategy to treat cancer. In the past few years, a large number of PAK4 inhibitors have been reported. Of note, the allosteric inhibitor KPT-9274 has been tested in phase â clinic trials. Herein, we provide an update on recent research progress on the PAK4 mediated signaling pathway and highlight the development of the PAK4 small molecular inhibitors in recent 5 years. Meanwhile, challenges, limitations, and future developmental directions will be discussed as well.