The phosphoinositide 3-kinase/3-phosphoinositide-dependent kinase 1 (PDK1)/Akt signaling pathway plays a key role in cancer cell growth, invasion, and survival. Moreover, its pivotal role in carcinogenesis and tumor progression has been definitely established (1). Aberrant activation of this pathway has been implicated in many cancers such as ovarian, lung, breast, colon cancer and glioblastoma (2), therefore it could be considered as an attractive target for cancer therapy. Starting from an analysis of recent patented Akt pathway inhibitors chosen as lead structures, we designed and synthesised a new collection of oxyindolone derivatives (OXIDs). Although the 2-oxyindole nucleus has been widely investigated, and in particular as regards the effects induced by different type of substitutions in 3- position, only few cases regarded the insertion of electron reach groups in 5-position.The absence of a detailed study of this kind of modification prompted us to explore it. Then, we synthesised new OXIDs in which the C5 carbon was substituted by aromatic moieties anchored to the 2-oxyindole nucleus through different amidoalkyl chains. A preliminary evaluation on human NSCLC showed a significant antiproliferative effects, and a marked suppression of Akt phosphorylation at P-Thr308. Finally a flow cytometry analysis showed that OXIDs lead to a G1 phase arrest associated to a reduction of G2/M phase and a relative loss of S-phase population. OXIDs
Targeting the upregulated PI3K-PDK1-Akt pathway: a drug discovery approach of treating cancer.
NESI, GIULIA;DANESI, ROMANO;LAPUCCI, ANNALINA;SESTITO, SIMONA;RAPPOSELLI, SIMONA
2012-01-01
Abstract
The phosphoinositide 3-kinase/3-phosphoinositide-dependent kinase 1 (PDK1)/Akt signaling pathway plays a key role in cancer cell growth, invasion, and survival. Moreover, its pivotal role in carcinogenesis and tumor progression has been definitely established (1). Aberrant activation of this pathway has been implicated in many cancers such as ovarian, lung, breast, colon cancer and glioblastoma (2), therefore it could be considered as an attractive target for cancer therapy. Starting from an analysis of recent patented Akt pathway inhibitors chosen as lead structures, we designed and synthesised a new collection of oxyindolone derivatives (OXIDs). Although the 2-oxyindole nucleus has been widely investigated, and in particular as regards the effects induced by different type of substitutions in 3- position, only few cases regarded the insertion of electron reach groups in 5-position.The absence of a detailed study of this kind of modification prompted us to explore it. Then, we synthesised new OXIDs in which the C5 carbon was substituted by aromatic moieties anchored to the 2-oxyindole nucleus through different amidoalkyl chains. A preliminary evaluation on human NSCLC showed a significant antiproliferative effects, and a marked suppression of Akt phosphorylation at P-Thr308. Finally a flow cytometry analysis showed that OXIDs lead to a G1 phase arrest associated to a reduction of G2/M phase and a relative loss of S-phase population. OXIDsI documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
