Quinolones in Medicinal Chemistry
1.4.1. Properties of 3-substituted 2-quinolones
The ubiquitous, naturally occurring, 3-substituted 2-quinolones exhibit a broad range of pharmacological activities and physiochemical properties.86 Their strong fluorescent properties and high stability enables them to be employed in laser dyes and optical probes and as donor chromophores in fluorescence resonance energy transfer (FRET) systems.87 A series of synthetic protocols that include conventional methods, such as Vilsmeier-Haack, Knorr, Friedlander, Larock and various metal-catalysed transformations, have been developed to access 3-substituted 2-quinolones. These methods often involve the use of costly substrates, and 4-substituted 2-quinolones are usually obtained.88 The 2-quinolones are valuable synthetic intermediates for accessing 2,3-disubstituted quinolines since they can undergo chlorination under Vilsmeier-Haack conditions to afford 2-chloroquinolines which are susceptible to nucleophilic substitution.77
24 1.4.1.1.Fluorescence properties of 2-quinolones
Since protein kinases play a central role in virtually all cell physiology and are therefore involved in the life cycles of antigens, they are ideal targets for therapeutic agents.89 Several costly methods to screen kinase inhibitors have been reported and include scintillation proximity assay (SPA), which requires radioisotope (RI)-labelled adenosine triphosphate (ATP), and time-resolved fluorescence resonance energy transfer (TR-FRET) demanding luminescent lanthanide complex-labelled antibodies.90, 91 A non-RI, low cost, convenient and homogeneous method that involves use of fluorescence correlation spectroscopy (FCS) for high-throughput screening of kinase inhibitors has also been developed.92 Fluorescence correlation spectrometry (Figure 12) is an important and powerful sensing method owing to its high selectivity and ease of operation.93 It is a single molecule detection technique using a fluorescent probe that sensitively measures fluctuation of the fluorescence intensity emitted from only a few fluorescent molecules that diffuse in and out of a small molecule receptor at the sub-femtolitre level in solution.92 In addition to screening of kinase inhibitors, FCS has been extensively used in a wide range of applications that include the detection of fluoride ions and mercury and for medical diagnosis.93, 94
The fluorescence correlation spectroscopy (FCS) assay is based on competitive binding between a standard fluorescent probe and an inhibitor candidate; if the candidate has low affinity for the kinase or is absent, the probe binds with the target enzyme resulting in fluorescence change.92, 95 However, if the probe is released from the enzyme to make way for the candidate, and initial fluorescence is restored. FCS is applicable to both active and inactive kinases.92
25 Figure 12. A schematic representation of the fundamentals of the fluorescence spectrometry assay.92 (Reproduced with permission.)
In 1980, Knierzinger and Wolfbeis96 demonstrated the fluorescence of a series of 3-substituted 2-quinolone derivatives. Electron-withdrawing groups in the 3-position enhance fluorescence;
compound 27, for example, showed strong fluorescence whereas the unsubstituted 2-quinolone showed suppressed fluorescence. In 2008, Wall et al.,97 using the FCS screening technique, revealed the inhibitory activity of ethyl 4-phenyl-2-(1H)-quinolone-3-carboxylate 28 against the macrophage colony-stimulating factor-1 (CSF-1) receptor responsible for controlling growth and differentiation of macrophage lineage. Boron difluoride complexes of 3- cinnamoyl-4-hydroxy-1-methyl-2-quinolone derivatives, such as compound 29, were recently evaluated as probes for the detection of native proteins using bovine serum albumin (BSA).98
Figure 13. Examples of 2-quinolone-based fluorophores.96-9896,97,98
26 1.4.2. Synthesis and reactivity of 3-substituted 2-quinolones.
The development of metal-catalysed chemical transformations has significantly expanded the methodology arsenal for synthetic organic chemistry, permitting the formation of various carbon-carbon and carbon-heteroatom bonds and providing one-step access to complex molecular structures from simple reagents. For instance, palladium complexes are employed as catalysts in the annulation of unsaturated molecules such as 1,3-dienes, allenes and alkynes with o-halogenoanilines or vinylic halides.99, 100 Introduction of carbon monoxide expands the utility of the procedure. Inspired by successful carbonylative annulation of o-iodophenol with an internal alkyne, annulation involving an aniline 30 and an internal alkyne 31 in the presence of carbon monoxide afforded a 3,4-disubstituted-2-quinolone 32 (Scheme 1). The method, however, requires use of a protecting agent because primary anilines yield unwanted by- products due their nucleophilicity.77,101
Scheme 1.
In 2015, Zhang et al.100 reported a serendipitous palladium(II)-catalysed synthesis of 3-acetyl- 2(1H)-quinolone 33 from N-(2-formylphenyl)but-2-ynamide 34 in the presence of 2,2’- bipyridine (bpy) in a mixture of acetic acid (AcOH) and 1,2-dichloroethane (Scheme 2). The minor product 35 can, under basic conditions, undergo an intra-molecular aldol condensation to yield a 2(1H)-quinolone core. In 2014, Mai et al.102 reported a silver-catalysed, radical, tandem cyclisation to synthesise 3,4-disubstituted dihydro-2(1H)-quinolones 36 using alkyl or keto acids 37 as the source of the radicals. Dihydro-2(1H)-quinolones have been shown to act as HIV-1 integrase inhibitors, anticancer and antihypertensive agents. In 2013, Ishida et al.99 successfully explored use of silver salts, such as AgNO3, AgBF4, AgOC(O)CF3 and AgOAc, for the synthesis of medicinally important 4-hydroxy-3-phenyl-2(1H)-quinolone 40 via oxidative cyclocarbonylation of acetylenic anilines 41 with carbon dioxide (CO2) in the presence of 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU). See Scheme 2.
27 Scheme 2. Recent metal-catalysed syntheses of 2(1H)-quinolones
It is synthetically challenging to prepare 3-substituted 2(1H)-quinolones since substitution on the quinolone core is favoured at the 6-position. Because of their diverse biological activities, developing routes to access 3-substituted 2(1H)-quinolones is of particular interest.103 The transformation of 4-hydroxyquinolone 42 into the corresponding 3-substituted quinolone 43 has been achieved using the reaction pathway outlined in Scheme 3, the final step involving regioselective lithiation of 4-methoxy-2(1H)-quinolone 44.103
Scheme 3. Pathways to 3-formyl-4-hydroxy-2(1H)-quinolone.103
28 Various metal-free chemical transformations to access such 2(1H)-quinolones have been developed and include the use of readily available 2-substituted indoles and β-nitroalkenes in the presence of polyphosphoric acid (PPA), a process which proceeds through an unprecedented transannulation pathway (Scheme 4).88, 82, 85 In addition, reaction of 3- substituted coumarins with amines or 2-substituted indoles may also be used to access 3- substituted 2-quinolones as illustrated in Scheme 4. 82, 88