Evaluation of the anti-inflammatory effects of synthesised tanshinone I and isotanshinone I analogues in zebrafish

Abstract

During inflammation, dysregulated neutrophil behaviour can play a major role in a range of chronic inflammatory diseases, for many of which current treatments are generally ineffective. Recently, specific naturally occurring tanshinones have shown promising anti-inflammatory effects by targeting neutrophils in vivo, yet such tanshinones, and moreover, their isomeric isotanshinone counterparts, are still a largely underexplored class of compounds, both in terms of synthesis and biological effects. To explore the anti-inflammatory effects of isotanshinones, and the tanshinones more generally, a series of substituted tanshinone and isotanshinone analogues was synthesised, alongside other structurally similar molecules. Evaluation of these using a transgenic zebrafish model of neutrophilic inflammation revealed differential anti-inflammatory profiles in vivo, with a number of compounds exhibiting promising effects. Several compounds reduce initial neutrophil recruitment and/or promote resolution of neutrophilic inflammation, of which two also result in increased apoptosis of human neutrophils. In particular, the methoxy-substituted tanshinone 39 specifically accelerates resolution of inflammation without affecting the recruitment of neutrophils to inflammatory sites, making this a particularly attractive candidate for potential pro-resolution therapeutics, as well as a possible lead for future development of functionalised tanshinones as molecular tools and/or chemical probes. The structurally related β-lapachones promote neutrophil recruitment but do not affect resolution. We also observed notable differences in toxicity profiles between compound classes. Overall, we provide new insights into the in vivo anti-inflammatory activities of several novel tanshinones, isotanshinones, and structurally related compounds.

β-Lapachone Increases Survival of Septic Mice by Regulating Inflammatory and Oxidative Response

“…We found that 24 h after CLP, the prophylactic treatment with β -Lap was able to reduce neutrophil recruitment. The transgenic zebrafish model was also observed that the β -Lap compound caused reduced recruitment of neutrophils to the injury site, without affecting the resolution of inflammation [ 39 ]. Moreover, it was demonstrated that the topical treatment of Leishmania major -infected BALB/c mice with β -Lap loaded in lecithin-chitosan nanoparticles downregulated IL-1 β and cyclooxygenase (COX-2) in the draining lymph nodes and reduced the cutaneous lesion size and neutrophil infiltration, without affecting parasites burdens [ 40 ].…”

Research and Development of Natural Product Tanshinone I: Pharmacology, Total Synthesis, and Structure Modifications

“…Researchers ( Jiao et al, 2014 ; Foulkes et al, 2020 ) synthesized tanshinone I using a relatively mild method ( Figure 5 ). Sodium percarbonate was used to oxidize 5-bromovanillin ( 40 ), and the ester functional group was hydrolyzed to obtain 1,4-hydroquinone ( 41 ).…”

“…The first modification method of the o-quinone structure of tanshinone I involves the reduction of o -quinone ( 45 ) ( Foulkes et al, 2020 ), followed by acylation of the phenolic hydroxyl group ( 46 ) ( Foulkes et al, 2020 ) or alkylate ( 47 ) ( Foulkes et al, 2020 ). The second modification method uses amine compounds to react with 11 and 12 o-dicarbonyl groups to generate imidazole ( 48 ) ( Li et al, 2018 ), oxazole ( 49 , 50 ) ( Li et al, 2018 ), and pyrazine ( 51 ) ( Li et al, 2018 ).…”

“…In the total synthesis of tanshinone I, changing the reaction conditions can result in derivatives with great structural changes, including dearomatization of the furan ring of tanshinone I ( 62 ) ( Ding et al, 2018 ), changes in the substituents on the phenyl group of the A ring ( 63 ) ( Jiao et al, 2014 ; Foulkes et al, 2020 ), and in the structure of the B ring ( 64 , 65 ) ( Ding et al, 2018 ).…”

“…Reports have been published on the structural modification of tanshinone I, including the introduction of groups at the C-15 position, such as phenyl ( Jiao et al, 2015 ). The introduction of other substituents on the A ring ( Jiao et al, 2014 ; Foulkes et al, 2020 ), or o -quinone moiety forms a heterocyclic ring such as an imidazole ring ( Li et al, 2018 ). However, most of these derivatives do not exhibit strong in vitro anti-tumor activity.…”