Rapid assembly of 1,3-indanedione-based spirocyclic tetrahydroquinolines for inducing human lung cancer cell apoptosis

Abstract

The rapid collection of a library of biologically relevant molecules is essential in new drug discovery. Here we show a variety of bioactive 1,3-indanedione-based spirocyclic tetrahydroquinolines that have been concisely and efficiently constructed under the guidance of biology-oriented synthesis (BIOS). Using Pd(PPh3)4 as a catalyst, various 2-arylidene-1,3-indanediones can react with vinyl benzoxazinanones under the mild condition to afford a new class of spirocyclic tetrahydroquinolines in moderate to excellent yields (45%–99%) with high stereocontrol (>95:5 diastereoselectivity). Their structures were unambiguously confirmed by X-ray single crystal analysis. The biological evaluation revealed that two of the 1,3-indanedione-based spirocyclic tetrahydroquinolines show remarkable apoptosis-inducing activities over A549 human lung cancer cells, exceeding that of cisplatin. The antitur activities were triggered by reactive oxygen species, commonly overproduced in cancer cells. The clinical demand for antitumor chemotherapy for lung cancer has encouraged an all-out search for analogues with lower toxcity, improved therapeutic index and increased activity.

Keywords

• Spirocyclic tetrahydroquinoline
• 1,3-Indanedione
• Lung cancer
• Apoptosis
• Mitochondria