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Synthesis and Antitumor Evaluation of Novel 5-substituted-4-hydroxy-8-nitroquinazolines as EGFR Signaling-Targeted Inhibitors

Synthesis and Antitumor Evaluation of Novel 5-substituted-4-hydroxy-8-nitroquinazolines as EGFR Signaling-Targeted Inhibitors

Yi Jin, Hui-Yuan Li, Li-Ping Lin, Jinzhi Tan, Jian Ding, Xiaomin Luo, Ya-Qiu Long

Bioorg Med Chem. 2005 Oct 1;13(19):5613-22.

PMID: 15993078

Abstract:

The synthesis and biological activity of a series of novel 5-substituted-4-hydroxy-8-nitroquinazolines that may function as inhibitors of EGFR- and/or ErbB-2-related oncogenic signaling are described. These compounds were prepared by S(N)Ar reaction of 5-chloro-4-hydroxy-8-nitroquinazoline with alkyl or aryl amines, or alkyl alcohol as nucleophiles. Although the enzyme assay showed a weak inhibition effect against both EGFR and ErbB-2 tyrosine kinases, the cell-based antitumor activity turned out promising. Compounds having 5-anilino substituent exhibit high potency with 5-(4-methoxy)anilino-4-hydroxy-8-nitroquinazoline (1h) being the best dual EGFR/ErbB-2 inhibitors, which effectively inhibited the growth of both EGFR (MDA-MB-468, IC(50)<0.01microM) and ErbB-2 (SK-BR-3, IC(50)=13microM) overexpressing human tumor cell lines in vitro. More interestingly, the variation of the substituent(s) at the 3- and/or 4-position of the 5-anilino portion was found to modulate the selectivity and potency dramatically. However, compounds having an alkylamino or alkyloxy group at the 5-position of 4-hydroxy-8-nitroquinazolines are essentially inactive. These results are consistent with molecular modeling observations. This study was the first attempt to identify new structural types of dual EGFR/ErbB-2-related signaling inhibitors by incorporation of the anilino group at the 5-position of 4-hydroxy-8-nitroquinazolines' core structure, providing promising new templates for further development of potent inhibitors targeting both EGFR and ErbB-2 tyrosine kinases.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP179248614	EGFR/ErbB-2 Inhibitor - CAS 179248-61-4		179248-61-4	Price

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