Emission Tuning of Fluorescent Kinase Inhibitors: Conjugation Length and Substituent Effects

Abstract

Fluorescent N-phenyl-4-aminoquinazoline probes targeting the ATP-binding pocket of the ERBB family of receptor tyrosine kinases are reported. Extension of the aromatic quinazoline core with fluorophore “arms” through substitution at the 6- position of the quinazoline core with phenyl, styryl, and phenylbutadienyl moieties was predicted by means of TD-DFT calculations to produce probes with tunable photoexcitation energies and excited states possessing charge-transfer character. Optical spectroscopy identified several synthesized probes that are nonemissive in aqueous solutions and exhibit emission enhancements in solvents of low polarity, suggesting good performance as turn-on fluorophores. Ligand-induced ERBB2 phosphorylation assays demonstrate that despite chemical modification to the quinazoline core these probes still function as ERBB2 inhibitors in MCF7 cells. Two probes were found to exhibit ERBB2-induced fluorescence, demonstrating the utility of these probes as turn-on, fluoroescent kinase inhibitors.

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

“…The 6-vinyl-substituted 4-anilinoquinazoline derivative B (CP-724,714), on the other hand, is a selective ERBB2 angiogenesis inhibitor under investigation for the treatment of breast, ovarian and other types of cancer ( Figure 1) [13]. The analogous (E)-6-(4-dimethylaminostyryl)-N-phenylquinazolin-4-amine C was found to exhibit ERBB2-induced fluorescence thus demonstrating its utility as a turn-on fluorescence kinase inhibitor in human cervical cancer (MCF-7) cells [14]. 2-Phenyl-4-(phenylamino)quinazoline D, on the other hand, has emerged as a potent photosensitizer with anti-proliferative activity and DNA damage in L1210 cells [15].…”

“…This compound was also found to induce programmed cell death in leukemia cells through mitochondrial/caspase 9/caspase 3-dependent pathway upon UVA irradiation [15]. utility as a turn-on fluorescence kinase inhibitor in human cervical cancer (MCF-7) cells [14]. 2-Phenyl-4-(phenylamino)quinazoline D, on the other hand, has emerged as a potent photosensitizer with antiproliferative activity and DNA damage in L1210 cells [15].…”

Spectroscopic Studies of Photochemical Transformations of Cymantrenylquinazolinone Derivatives

“…In the last decades, compounds with photochromic properties have attracted considerable attention for the creation of devices for the registration and storage of optical information, molecular switches, chemical sensors, and reagents for fluorescence spectroscopy , . It is known that 2‐aryl(hetaryl)‐ and 2‐styrylquinazolinones show distinctive fluorescence properties and therefore have potential for the creation of non‐linear optical generators . Variation of the structures, namely, the substituents in the heterocyclic and aryl fragments, allows one to obtain optical systems with various spectral parameters .…”

Synthesis, photophysical properties and DFT study of novel polycarbo-substituted quinazolines derived from the 2-aryl-6-bromo-4-chloro-8-iodoquinazolines

“…3 Interest in these compounds is not only limited to the synthesis or development of more diverse and complex bioactive derivatives for structure-activity relationship evaluations, but has since been extended to focus on their photophysical properties as potential fluorescence probes. [4][5][6][7][8][9] Fluorescent carbosubstituted quinazolines such as the medicinally important Lapatinib, for example, functions as an environmentally responsive 'turn-on' fluorophore. 8 Its analogue, (E)-6-(4-dimethylaminostyryl)-Nphenylquinazolin-4-amine, acts as a turn-on fluorescence kinase inhibitor in MCF7 cells.…”