RESUMEN
2-Desoxy-4-epi-puchellin (PCL) is a sesquiterpene-lactone, which naturally occurs in many traditional Chinese medicinal plants, and has antitumor and anti-inflammatory activities. In this work, a series of 13-amino derivatives of PCL were synthesized through Michael addition reaction. Inhibition of IL-6-induced STAT3 signaling pathway and in vitro cytotoxicity of these compounds were evaluated, and their effect on the cell cycle was also studied. The methyl hydroxyethylamine derivatives showed higher potency than PCL, which could induce significant mitotic arrest via G2/M arrest in HCT116 cancer cells, indicating that these derivatives have the potential to be developed into anti-colon cancer drugs.
Asunto(s)
Aminas/farmacología , Antineoplásicos/farmacología , Puntos de Control de la Fase G2 del Ciclo Celular/efectos de los fármacos , Lactonas/farmacología , Sesquiterpenos/farmacología , Transducción de Señal/efectos de los fármacos , Aminas/síntesis química , Aminas/química , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Células HCT116 , Humanos , Lactonas/síntesis química , Lactonas/química , Estructura Molecular , Factor de Transcripción STAT3/metabolismo , Sesquiterpenos/síntesis química , Sesquiterpenos/química , Relación Estructura-ActividadRESUMEN
We investigated the function and molecular mechanisms of 2-desoxy-4ß-propylcarbamate-pulchellin (P-13), a sesquiterpene lactone derivative of 2-desoxy-4-epi-pulchellin from the traditional Chinese medicinal herb Carpesium abrotanoides L, in regulating STAT3 signaling and cancer cell growth. We found that P-13 inhibited the IL-6-induced, as well as the constitutive, STAT3 activation in a dose and time-dependent manner. In vitro kinase activity analyses demonstrated that P-13 directly inhibited JAK2 kinase activity. The inhibitory effects of P-13 on JAK2/STAT3 signaling could be blocked by reducing agents dithiothreitol (DTT) or glutathione (GSH), indicating an involvement of the thiol-reactive α-ß unsaturated carbonyl group in P-13. Further analyses with mass spectrograph, as well as molecular docking, revealed that P-13 covalently bound with the C452 in the SH2 domain of JAK2. Furthermore, P-13 inhibited growth and induced death of many cancer cell lines, particularly those expressing constitutively activated STAT3. It also inhibited in vivo growth of human cancer cell xenografts. Taken together, these findings revealed P-13 as a novel covalent inhibitor of JAK2, uncovered a new mechanism to inhibit JAK2, and provided a promising anti-cancer drug candidate.