Discovery of N-(4-Methoxyphenyl)-N,2-dimethylquinazolin-4-amine, a Potent Apoptosis Inducer and Efficacious Anticancer Agent with High Blood Brain Barrier Penetration

Abstract

As a continuation of our structure-activity relationship (SAR) studies on 4-anilinoquinazolines as potent apoptosis inducers and to identify anticancer development candidates, we explored the replacement of the 2-Cl group in our lead compound 2-chloro-N-(4-methoxyphenyl)-N-methylquinazolin-4-amine (6b, EP128265, MPI-0441138) by other functional groups. This SAR study and lead optimization resulted in the identification of N-(4-methoxyphenyl)-N,2-dimethylquinazolin-4-amine (6h, EP128495, MPC-6827) as an anticancer clinical candidate. Compound 6h was found to be a potent apoptosis inducer with EC(50) of 2 nM in our cell-based apoptosis induction assay. It also has excellent blood brain barrier penetration, and is highly efficacious in human MX-1 breast and other mouse xenograft cancer models.

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

“…The presence of the latter is further confirmed by a band in the region ν max 3413-3452 cm −1 of their IR spectra. Moreover, the molecular ion region of their mass spectra revealed the absence of the M+ and M + 2 peaks in the ratio 3:1 due to the 35 Cl and 37 Cl isotope observed in the spectra of the corresponding substrates. chloro-8-iodoquinazoline framework to serve as a template for the design of unsymmetrical polycarbosubstituted 4-anilinoquinazolines.…”

“…The presence of the latter is further confirmed by a band in the region νmax 3413-3452 cm −1 of their IR spectra. Moreover, the molecular ion region of their mass spectra revealed the absence of the M+ and M + 2 peaks in the ratio 3:1 due to the 35 Cl and 37 Cl isotope observed in the spectra of the corresponding substrates. We decided to take advantage of the trend in reactivity of the C-sp 2 -X bonds in transition metal catalyzed cross-coupling (trend: C-sp 2 -I > C(4)-Cl > C-sp 2 -Br > C(2)-Cl > C-sp 2 -Cl) [18] and subjected compounds 1a-d to one-pot successive two-and three-step reaction sequences involving initial amination and subsequent Pd catalyzed cross-coupling reactions to afford novel unsymmetrical polycarbosubstituted 4-anilinoquinazolines.…”

“…A bulky aryl group such as 4-chlorophenyl-or 4-methoxyphenyl substituent at the 2-position of the polycarbo-substituted quinazolines 5-7 resulted in loss of activity compared to derivatives bearing relatively smaller phenyl or 4-fluorophenyl group at this position. Since cytotoxicity does not define a specific cellular death mechanism and considering the literature precedent on the pro-apoptotic properties of the 2-substituted 4-anilinoquinazoline derivatives [35], we decided to evaluate how compounds 2b, 2c, 3c, 4a, 4c, 5a and 7a induce cell death in cancer 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.…”

Design, synthesis and biological evaluation of novel quinazoline derivatives as potential anti-cancer agents

“…It outlines the synthetic pathway used to obtain compounds 4-11. The starting material 2-phenyl-4H- [3,1]benzoxazin-4-one 1, 2-phenyl-3H-quinazolin-4-one 2 and 2-phenyl-4-chloroquinazoline 3 were prepared in our laboratory following a reported procedure 15 . Compound 2 was alkylated with some selected phenethyl chloride derivatives in dry dimethylformamide containing anhydrous potassium carbonate.…”

“…In spite of the substantial progress in many aspects of cancer research, the current approaches have many disadvantages, including low efficacy and high degree of toxicity. Notably, many cancer chemotherapeutic agents are themselves carcinogenic 3 . Therefore, there is an urgent need to rationally design novel, molecularly targeted anti-cancer therapies, which are more selective, ideally less toxic and ultimately more effective than traditional treatments.…”