169205-64-5Relevant academic research and scientific papers
One-pot synthesis of 4-aminoquinazolines by hexamethyldisilazane-mediated reaction of quinazolin-4(3h)-ones with amines
Shen, Zhen-Lu,He, Xiao-Fei,Hong, Yi-Ming,Hu, Xin-Quan,Mo, Wei-Min,Hu, Bao-Xiang,Sun, Nan
experimental part, p. 3644 - 3653 (2011/10/09)
Hexamethyldisilazane-mediated reaction of quinazolin-4(3H)-ones with primary amines led to facile formation of 4-aminoquinazolines through tandem silylation and substitution in a single pot. Excellent yields of the products (83-97%) and environmental friendliness (avoiding the use of chlorination reagents) are the advantages of this method. Copyright Taylor & Francis Group, LLC.
The combi-targeting concept: Chemical dissection of the dual targeting properties of a series of "combi-triazenes"
Rachid, Zakaria,Brahimi, Fouad,Katsoulas, Athanasia,Teoh, Nicole,Jean-Claude, Bertrand J.
, p. 4313 - 4321 (2007/10/03)
The combi-targeting concept postulates that a molecule termed a "combi-molecule" designed to interact with an oncoreceptor on its own and allowed to further degrade to another more stable inhibitor of the latter receptor + a DNA-damaging species should be more potent than the individual combination of the same inhibitor with a DNA-damaging agent in cells expressing the targeted receptor. Recently, using the epidermal growth factor receptor (EGFR) as a target, we demonstrated the feasibility of combi-molecules with dual EGFR/DNA-targeting properties and with the ability to degrade to another potent inhibitor of EGFR. However, despite a clear demonstration of their superior potency when compared with classical combinations in EGFR-expressing cells, the true contribution of each fragment of the combi-molecules to their overall antiproliferative activity remained elusive. Here, we report a structure-function approach whereby a series of quinazoline-based "combi-triazenes" were altered to either abrogate the affinity of the EGFR-targeting quinazoline head or to suppress the DNA-damaging property of the triazene tail. The results showed that (a) inactivation of the quinazoline head by appending an N-methylaniline group to its 4-position reduced EGFR tyrosine kinase (TK) inhibitory activity by ca. 200-fold and decreased the ability of the combi-molecule to block serum-induced growth stimulation in c-erbB2 transfected NIH3T3 cells by ca. 10-fold, (b) abrogation of the alkylating activity or the DNA-damaging potential of the triazene tail by forming 3,3-dimethyltriazenes did not suppress EGFR TK inhibitory affinity but decreased the antiproliferative activity in basal growth assays, and (c) the antiproliferative activities of the monoalkyltriazenes that possessed binary EGFR TK inhibitory and alkylating activities were superior to those of their monotargeted counterparts. The results in toto suggest that each component of the dual targeting property of combi-triazenes plays a critical role in their overall antiproliferative activity.
Tyrosine kinase inhibitors. 5. Synthesis and structure-activity relationships for 4-[(phenylmethyl)amino]- and 4-(phenylamino)quinazolines as potent adenosine 5'-triphosphate binding site inhibitors of the tyrosine kinase domain of the epidermal growth factor receptor
Rewcastle,Denny,Bridges,Zhou,Cody,McMichael,Fry
, p. 3482 - 3487 (2007/10/02)
A series of 4-substituted quinazolines and related compounds have been prepared and evaluated for their ability to inhibit the tyrosine kinase activity of the epidermal growth factor receptor on a phospholipase C-γ1- derived substrate. The results show a narrow structure-activity relationship (SAR) for the basic ring system, with quinazoline being the preferred chromophore and benzylamino and anilino the preferred side chains. In the 4- anilino series, substitution on the 3-position of the phenyl ring with small lipophilic electron-withdrawing groups provided analogues with enhanced potency. Two series of compounds [4-(phenylmethyl)amino and 4-(3- bromophenyl)amino] were studied to determine SARs for quinazoline substituents. In the more active 4-(3-bromophenyl)amino series, electron- donating groups (NH2, OMe) at the 6- or 7-position increased activity, in a pattern consistent with a requirement for high electron density in the vicinity of the 8-position of the quinazoline ring. The 6,7-dimethoxy derivatives were the most effective in both series, with the 4-(3- bromophenyl)amino derivative (3) having an IC50 of 0.029 nM, making it by far the most potent reported inhibitor of the tyrosine kinase activity of the epidermal growth factor receptor enzyme.
