Synthesis, biological evaluation, femtosecond broadband time-resolved fluorescence and transient absorption study on 8-hydroxyquinoline derivatives

Abstract

Quinoline is a promising scaffold with invaluable medicinal benefits that can be used in the development of anticancer drugs and fluorescent chemosensors. 8-hydroxyquinoline (8HQ) and its derivatives are one of the prime examples of quinoline. These interesting molecules possess a broad spectrum of biological activities, such as antimalarial, antimicrobial and anticancer activities. However, the underlying mechanism of their actions is poorly understood. Herein, with the use of chemical synthesis and bioinformatics approach, a series of molecules integrating the quinoline ring and sulfonyl moiety were designed, their anticancer activity in hepatocellular carcinoma were evaluated and their associated mechanistic targets were identified. The structure-activity relationship of these designed compounds was also studied using a diversity-oriented synthesis. A lead compound, Q5, which contained a sulfonamide group as a linker between two quinoline rings with an MTS₅₀ value of 2.91 ± 0.09 µM in Hep3B cell line, was identified. Its potential mechanism of anticancer effect exerted on Hep3B cancer cells was likely to involve NF-kB binding and regulation. 8HQ is also well-known for its ultraweak fluorescence which is the consequence of a subpicosecond timescale nonradiative intramolecular excited state proton transfer. Strong metal chelating property is another feature of 8HQ and its derivatives. Although various substructures have been reported for their sensitive and selective metal sensing properties, the excited state dynamics of 8HQ derivatives, as well as the factors governing the decay paths, are rarely investigated. Integrating the femtosecond broadband time-resolved fluorescence and transient absorption methods, this study provides a complementary documentation for the nonradiative decay paths (including intramolecular and intermolecular excited state proton transfer, intersystem crossing and internal conversion) in quinoline-type compounds. Three representative molecules, (i) 8-hydroxyquinoline dimers (8HQ dimer), (ii) 8-methoxyquinoline (8MeOQ) and (iii) the novel synthesized 8HQ derivatives containing the acetophenone group (APFP), were selected for this study. In 8HQ dimer, a combined study of time-resolved fluorescence and transient absorption provides the first observation of time-resolved broadband fluorescence of 8HQ dimer, a prototype of DNA base pair. A doubly proton transfer occurring within 0.1 ps indicates that the rate of doubly proton transfer in doubly hydrogen-bonded complexes is highly relevant to the strength of intramolecular hydrogen bonding. The intermolecular hydrogen bonding interaction of 8HQ with solvent molecule(s) was also investigated, providing an insight into the application of 8HQ as a probe for microenvironment. As a case study of the excited state proton transfer in host-guest system and the influence of this process on the excited state dynamics, experiments on 8MeOQ in solvents of various properties were conducted using a combination of time-resolved fluorescence and transient absorption. The findings address the solvent-controlled nonradiative pathways in the deactivation of excited 8MeOQ, that is, the cooperative role of solvent molecule(s) in acid-base reaction driven by the enhanced basicity of excited 8MeOQ in protic solvent and the high triplet state yield in aprotic solvent. APFP compounds were designed and synthesized for the study of substituent effect on the excited state dynamics and their metal recognizing potentials by employing transient absorption coupled with steady state absorption and fluorescence measurements. A prominent fluorescence enhancement with characteristic emission wavelength was found in the presence of biologically relevant metal cations, including zinc(II), cadmium(II) and calcium(II). The restoration of fluorescence is likely a consequence of the bypass of nonradiative process in APFP compounds. Taken together, this work discovers a lead 8HQ derivative, Q5, as anticancer agent with a molecular reason for its anticancer action. A fundamental perspective on the nature, dynamics and key factors that governed the kinetics of the excited state process in 8HQ derivatives is also provided. The deeper understanding of the photophysics of quinoline-type compounds gained through this study may be useful for the application of quinoline-type compounds in the design of fluorescent molecules that will be used for the detection and mapping of biological relevant metals. This application potential is illustrated by the novel compound, APFP4. This work, thus, demonstrates a capacity of synthesis-bioinformatics-spectroscopic integrated strategy for the design and creation of functional organic molecules to solve biological challenges.