Solvatochromism and linear solvation energy relationship of the kinase inhibitor SKF86002 Muhammad Khattab a , Madeline Van Dongen b , Feng Wang b, ⁎, Andrew H.A. Clayton a, ⁎ a Centre for Micro-Photonics, Faculty of Science, Engineering and Technology, Swinburne University of Technology, Melbourne, Victoria 3122, Australia b Molecular Model Discovery Laboratory, Department of Chemistry and Biotechnology, School of Science, Faculty of Science, Engineering and Technology, Swinburne University of Technology, Melbourne, Victoria 3122, Australia abstract article info Article history: Received 17 May 2016 Received in revised form 15 July 2016 Accepted 15 July 2016 Available online 17 July 2016 We studied the spectroscopic characteristics of SKF86002, an anti-inflammatory and tyrosine kinase inhibitor drug candidate. Two conformers SKF86002A and SKF86002B are separated by energy barriers of 19.68 kJ·mol −1 and 6.65 kJ·mol −1 due to H-bonds, and produce the three major UV–Vis absorption bands at 325 nm, 260 nm and 210 nm in cyclohexane solutions. This environment-sensitive fluorophore exhibited emis- sion in the 400–500 nm range with a marked response to changes in environment polarity. By using twenty-two solvents for the solvatochromism study, it was noticed that solvent polarity, represented by dielectric constant, was well correlated with the emission wavelength maxima of SKF86002. Thus, the SKF86002 fluorescence peak red shifted in aprotic solvents from 397.5 nm in cyclohexane to 436 nm in DMSO. While the emission max- imum in hydrogen donating solvents ranged from 420 nm in t-butanol to 446 nm in N-methylformamide. Employing Lippert-Mataga, Bakhshiev and Kawski models, we found that one linear correlation provided a sat- isfactory description of polarity effect of 18 solvents on the spectral changes of SKF86002 with R 2 values 0.78, 0.80 and 0.80, respectively. Additionally, the multicomponent linear regression analysis of Kamlet-Taft (R 2 = 0.94) revealed that solvent acidity, basicity and polarity accounted for 31%, 24% and 45% of solvent effects on SKF86002 emission, respectively. While Catalán correlation (R 2 = 0.92) revealed that solvatochromic change of SKF86002 emission was attributed to changes in solvent dipolarity (71%), solvent polarity (12%), solvent acid- ity (11%) and solvent basicity (6%). Plot of Reichardt transition energies and emission energies of SKF86002 in 18 solvents showed also a linear correlation with R 2 = 0.90. The dipole moment difference between excited and ground state was calculated to be 3.4–3.5 debye. © 2016 Published by Elsevier B.V. Keywords: Solvatochromism Photophysics UV–Vis spectroscopy SKF86002 Kinase inhibitor Anti-inflammatory drug 1. Introduction SKF86002, given a IUPAC name 6-(4-fluorophenyl)-2,3-dihydro-5- (4-pyridinyl)-imidazo[2,1-b]thiazole, is a low molecular weight hetero- cycle. It was first synthesized by Bender et al., and was tested for its anti- inflammatory activity [1,2]. Later, it was identified as p38α inhibitor [3]. Pargellis et al., demonstrated that SKF86002 can act as a fluorescent marker upon binding to the ATP active pocket of p38α [4]. It was re- vealed that not only is SKF86022 able to bind to the mitogen-activated protein kinase (p38α), but also to other kinases viz. Pim1, ASK1, HCK and AMPH [5]. Hence, SKF86002 is a small kinase inhibitor, able to act as a self-fluorescent reporter and/or probe for candidate ATP-competi- tive inhibitors [5]. Photophysical studies have recently received much attention, since the spectral parameters are very sensitive to the change in microenvironment [6]. Therefore, different models have been progres- sively developed for analyzing the photophysical properties of fluores- cent compounds. Lippert-Mataga (L-M) [7,8], Bakhshiev [9], and Bilot- Kawski [10,11] (often called Kawski-Chamma-Viallet) [12,13] models are commonly applied to investigate solvent effects on the spectral characteristics of dye molecule and to estimate the change in dipole mo- ment between the ground and excited state [14]. They are easily employed, however cannot account for stabilization of dyes based on hydrogen bonding [15,16]. However, it was later discovered that if apro- tic and protic solvents were plotted separately using Kawski model, then dipole moment differences for H-bond and non-H-bond environ- ments could be evaluated [17,18] This has opened the door for studying compounds capable of strong H-bond formation [19]. Models which can separately evaluate different modes of solute-sol- vent interactions have also been developed. By using Kamlet-Taft and Catalán models, one can qualitatively and quantitatively investigate the specific (H-bond) and non-specific (due to change in dipolarity and polarizability) interactions [20]. Since SKF86002 is an ATP compet- itive inhibitor, investigating the mechanism of its binding to target pro- tein relies on understanding of its physicochemical characteristics. This Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 170 (2017) 226–233 ⁎ Corresponding authors. E-mail addresses: mkhattab@swin.edu.au (M. Khattab), fwang@swin.edu.au (F. Wang), aclayton@swin.edu.au (A.H.A. Clayton). http://dx.doi.org/10.1016/j.saa.2016.07.027 1386-1425/© 2016 Published by Elsevier B.V. Contents lists available at ScienceDirect Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy journal homepage: www.elsevier.com/locate/saa