Synthesis Of Novel Benzo[α]Quinolizine Derivatives And Their Antitumor Activity

Alkaloids and their exciting pharmacological function are always one of the hot research field of medicinal chemistry and organic chemistry. Benzo[a]quinolizidine, are a class of isoquinoline derivatives with both special three-rings fused structure and biological activities. Benzo[a]quinolizidine are widely existed in natural products and pharmaceutical molecules. Many benzo[a]quinolizidine derivatives exhibit good and diverse pharmacological activities. Such as emetine, which could significantly inhibit the synthesis of protein and proved to a potent antitumor candidate; tetrabenazine, another benzo[a]quinolizidine alkaloid, has been used in the treatments for movement disorders as an inhibitor of vesicular monoamine transporter.Modification of bioactive natural products is one of the most important method for drug discovery. Considering that the benzo[a]quinolizidines with important pharmacological effects, this work developed a oxidant coupling-Michael addition type cyclization for the synthesis of 2,4-substitute benzo[a]quinolizidine analogs and their antitumor activity was also tested. We employed available tetrahydroisoquinolines as starting material. After TEMPO oxidant, the 1-ethyoxyl tetrahydroisoquinolines were used in the coupling with the silyl enol ethers. The coupling intermediates then undergo deprotection and intermolecular Michael addition to for the desired benzo[a]quinolizidine products. Next modification were used Grignard reagent or direct reduction to give a total of 103 derivatives.All the derivatives were tested for their inhibition against 6 tumor cell lines (MDA-MB-231, Hela, K562, PC3, DU145, MCF-7) and a normal cell line (RWPE-1), the structure-activity relationship was concluded as following. (ⅰ) 2-Hydroxyl-9,10-dibenzyloxy-benzo[a]quinolizidine are essential for the activity, and the only derivatives with both 9,10-dibenzyloxy are tested with the best activity. (ⅱ) C-2 position is the pharmacophore for the antiproliferative effect. Introduction of moieties or change the configuration will tremendously impact the activity. (ⅲ) Electron-rich phenyl ring or short alkyl chains at position 4 will remarkable improve the activity, and the methyl is the best choice. (ⅳ) The electron-donating substitution and contribute to better activity and the steric parameters were proved not to be the important factor influencing the antitumor activities. The 3,5-dimethyl is the best. Finally we find a potent compound SI3b with IC50=0.66 μM, and report the SI3b-induced cell death through apoptosis and paraptosis.We focused on the synthesis of benzo[a]quinolizidines and give out a detailed SAR analysis for the benzo[α]quinolizidine derivatives. This work also provided an alternative for the next anticancer drug discovery.