Synthesis and In Vitro Cytotoxic Properties of Polycarbo-Substituted 4-(Arylamino)quinazolines

Herein, we describe the synthesis of novel unsymmetrical polycarbo-substituted 4-anilinoquinazolines derived from the 2-aryl-6-bromo-8-iodoquinazolines via one-pot three-step reaction sequences involving initial amination and subsequent double cross-coupling (bis-Suzuki, Sonogashira/Stille or Sonogashira/Suzuki-Miyaura) reactions with different cross coupling partners for the two carbon–carbon bond formation steps. The 4-anilinoquinazolines were evaluated for potential cytotoxicity against three cancer cell lines, namely, human breast adenocarcinoma (MCF-7) cells, human cervical cancer (HeLa) and human lung cancer (A549) cells. The most active compounds, 2b, 2c, 3c, 4a, 4c and 5a, were found to be more selective against the MCF-7 and HeLa cell lines than the human lung carcinoma (A549) cells. We selected compounds 2c, 3c and 7a as representatives for further evaluation for potential to induce apoptosis and/or necrotic properties in the three cancer cell lines. Compound 2c induced apoptosis of MCF-7 cells through cell membrane alteration. Treatment of Hela and A549 cell lines with compounds 3c and 7a, respectively, led to caspase-3 activation in both cell lines. Compound 3c, on the other hand, caused more necrosis than apoptosis induction in the membrane alteration assay.


MCF-7
HeLa A549 Figure S52. Linear regression plots and percentage cell viability graphs of MCF-7, HeLa and A549 cells exposed to different concentrations of 3a.

MCF-7
HeLa A549 Figure S54. Linear regression plots and percentage cell viability graphs of MCF-7, HeLa and A549 cells exposed to different concentrations of 3b.

MCF-7
HeLa A549 Figure S58. Linear regression plots and percentage cell viability graphs of MCF-7, HeLa and A549 cells exposed to different concentrations of 3d.

MCF-7
HeLa A549 Figure S66. Linear regression plots and percentage cell viability graphs of MCF-7, HeLa and A549 cells exposed to different concentrations of 4d.

MCF-7
HeLa A549 Figure S72. Linear regression plots and percentage cell viability graphs of MCF-7, HeLa and A549 cells exposed to different concentrations of 5c.

MCF-7
HeLa A549 Figure S74. Linear regression plots and percentage cell viability graphs of MCF-7, HeLa and A549 cells exposed to different concentrations of 5d.

MCF-7
HeLa A549 Figure S76. Linear regression plots and percentage cell viability graphs of MCF-7, HeLa and A549 cells exposed to different concentrations of 6b.

MCF-7
HeLa A549 Figure S78. Linear regression plots and percentage cell viability graphs of MCF-7, HeLa and A549 cells exposed to different concentrations of 6c.

MCF-7
HeLa A549 Figure S82. Linear regression plots and percentage cell viability graphs of MCF-7, HeLa and A549 cells exposed to different concentrations of 7a.

MCF-7
HeLa A549 Figure S84. Linear regression plots and percentage cell viability graphs of MCF-7, HeLa and A549 cells exposed to different concentrations of 7b.