Design, synthesis and anticancer activity of β-carboline based pseudo-natural products by inhibiting AKT/mTOR signaling pathway

Non-small cell lung cancer (NSCLC) is the most common type of lung cancer and remains the leading cause of cancer deaths. Much progress has been made to treat NSCLC, however, only limited patients can benefit from current treatments. Thus, more efforts are needed to pursue novel molecular modalities for NSCLC treatment. It was demonstrated that pseudo-natural products (PNP) are a critical source for antitumor drug discovery. Herein, we describe a CH activation protocol for the expedient construction of a focused library utilizing the PNP rational design strategy. This protocol features a rhodium-catalyzed CH activation/ [4+2] annulation reaction between N-OAc-indole-2-carboxamide and alkynyl quinols, enabling facile access to diverse quinol substituted β-carboline derivatives (31 examples). The anticancer activities were assessed in vitro against NSCLC cell line A549, yielding a potent antiproliferative β-carboline derivative (8r) with an IC