RESUMO
Despite All-trans retinoic acid (ATRA) has transformed acute promyelocytic leukemia (APL) from the most fatal to the most curable hematological cancer, there remains a clinical challenge that many high-risk APL patients who fail to achieve a complete molecular remission or relapse and become resistant to ATRA. Herein, we report that 5-(4-methoxyphenethyl)-[1, 3] dioxolo [4, 5-j] phenanthridin-6(5H)-one (ZYH005) exhibits specific anticancer effects on APL and ATRA-resistant APL in vitro and vivo, while shows negligible cytotoxic effect on non-cancerous cell lines and peripheral blood mononuclear cells from healthy donors. Using single-molecule magnetic tweezers and molecule docking, we demonstrate that ZYH005 is a DNA intercalator. Further mechanistic studies show that ZYH005 triggers DNA damage, and caspase-dependent degradation of the PML-RARa fusion protein. As a result, APL and ATRA-resistant APL cells underwent apoptosis upon ZYH005 treatment and this apoptosis-inducing effect is even stronger than that of arsenic trioxide and anticancer agents including 5-fluorouracil, cisplatin and doxorubicin. Moreover, ZYH005 represses leukemia development in vivo and prolongs the survival of both APL and ATRA-resistant APL mice. To our knowledge, ZYH005 is the first synthetic phenanthridinone derivative, which functions as a DNA intercalator and can serve as a potential candidate drug for APL, particularly for ATRA-resistant APL.
Assuntos
Resistencia a Medicamentos Antineoplásicos/genética , Substâncias Intercalantes/administração & dosagem , Leucemia Promielocítica Aguda/tratamento farmacológico , Fenantridinas/administração & dosagem , Animais , Apoptose/efeitos dos fármacos , Trióxido de Arsênio/administração & dosagem , Trióxido de Arsênio/química , Caspases/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Humanos , Substâncias Intercalantes/química , Leucemia Promielocítica Aguda/genética , Leucemia Promielocítica Aguda/patologia , Camundongos , Simulação de Acoplamento Molecular , Proteínas de Fusão Oncogênica/antagonistas & inibidores , Proteínas de Fusão Oncogênica/genética , Fenantridinas/química , Proteína da Leucemia Promielocítica/genética , Proteólise/efeitos dos fármacos , Receptor alfa de Ácido Retinoico/genética , Tretinoína/administração & dosagem , Tretinoína/química , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
An efficient, silver-induced tandem radical addition/cyclization for the synthesis of 3,4-dihydroquinolinones is presented, which exhibits a good functional group tolerance. The reaction is easy to operate and amenable to a multigram-scale synthesis. Additionally, this work illustrates the formation of a key skeleton for the synthesis of biologically interesting 3,4-dihydroquinolinone alkaloids.
RESUMO
Zanthoxylum schinifolium Sieb. et Zucc. (Rutaceae), a dioecious shrub with hooked prickly branches, has been used as folk medicine for the treatment of the common cold, stomach ache, diarrhea, and jaundice in China, Korea, and Japan. In our phytochemical investigations on this genus, a new megastigmane sesquiterpenoid, which is referred to as schinifolenol A (1), was isolated from Z. schinifolium. The stereochemistry was characterized via the analyses of extensive spectra. The absolute configuration was established by the application of a modified Mosher's experiment and assisted by a time-dependent density functional theory (TD-DFT) on calculated electronic circular dichroism (ECD). Bioactivity screenings showed that compound 1 exhibited a safe hypotoxicity and a better selectivity on anti-Kaposi's sarcoma associated herpes virus (KSHV).
Assuntos
Cicloexanonas/administração & dosagem , Glucosídeos/administração & dosagem , Herpesvirus Humano 8/efeitos dos fármacos , Norisoprenoides/administração & dosagem , Sarcoma de Kaposi/tratamento farmacológico , Zanthoxylum/química , Dicroísmo Circular , Cicloexanonas/química , Glucosídeos/química , Herpesvirus Humano 8/patogenicidade , Humanos , Estrutura Molecular , Norisoprenoides/química , Compostos Fitoquímicos/administração & dosagem , Compostos Fitoquímicos/química , Extratos Vegetais/química , Sarcoma de Kaposi/virologiaRESUMO
Na2S2O8-promoted decarboxylative cyclization of biaryl-2-oxamic acid for phenanthridinones has been developed. This work illustrates the first example of intramolecular decarboxylative amidation of unactivated arene under transition-metal-free conditions. Additionally, this approach provides an efficient and economical method to access biologically interesting phenanthridinones, an important structure motif in many natural products.