Synthesis and Anti-proliferative Activity of Substituted-Anilinoquinazolines and Its Relation to EGFR Inhibition

D. A. A El Ella; K. A. Saleh; M. Hassan; N. Hamdy; M. E. El-Araby; K.A. M. Abouzid

doi:10.1055/s-0032-1312601

Arzneimittelforschung, Table of Contents

Arzneimittelforschung 2012; 62(08): 360-366
DOI: 10.1055/s-0032-1312601

Original Article

Synthesis and Anti-proliferative Activity of Substituted-Anilinoquinazolines and Its Relation to EGFR Inhibition

D. A. A El Ella^*

¹Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt

,

K. A. Saleh

²Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Russian Egyptian University, Cairo, Egypt

,

M. Hassan

²Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Russian Egyptian University, Cairo, Egypt

,

N. Hamdy

³Department of Biochemistry, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt

,

M. E. El-Araby

⁴Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Helwan University, Helwan, Egypt

,

K.A. M. Abouzid^*

¹Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt

› Author Affiliations

Abstract

4-Anilinoquinazoline is a privileged scaffold in developing small molecule inhibitors of tyrosine kinases (TK) especially epidermal growth factor receptor (EGFR). 2 series belonging to 3'-substituted-4-anilinoquinazoline scaffold were synthesized and screened in vitro on isolated and a breast cancer cell line. The research aims at exploring the activity of compounds having diverse substituents at 3' position of the aniline moiety. Generally, the meta-substituted-anilinoquinazolines exhibited significant inhibitory activity against isolated enzyme as well as MCF-7 cancer cell line. For instance, compound 10b inhibited >99% of EGFR activities at 10 µM concentration. 6 of the tested compounds exhibited range of anti-proliferative activity below 10 µM potency. In particular, compounds 6e and 10b displayed the highest activity among the tested compounds with IC₅₀ values equal to 8.6 and 4.84 µM, respectively. Structure-based tools were utilized to rationalize EGFR-TK binding of compound 10b since it is the most active compound in the enzyme inhibition test.

Key words

quinazoline - anilinoquinazoline - EGFR inhibitors - tyrosine kinase inhibitors - anti-cancer - structure-based design

Full Text

References

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