Bioorganic Chemistry 89 (2019) 103009 Contents lists available at ScienceDirect Bioorganic Chemistry journal homepage: www.elsevier.com/locate/bioorg Synthesis, molecular properties, anti-inflammatory and anticancer activities T of novel 3-hydroxyflavone derivatives ⁎ Mansour Znatia,b, Claire Bordesc, Valérian Forquetc, Pierre Lantéric, Hichem Ben Janneta, , ⁎ Jalloul Bouajilab, a Laboratory of Heterocyclic Chemistry, Natural Products and Reactivity (LR11ES39), Team: Medicinal Chemistry and Natural Products, Faculty of Science of Monastir, University of Monastir, Avenue of Environment, 5019 Monastir, Tunisia b University of Toulouse, Paul-Sabatier University, Faculty of Pharmacy Toulouse, Laboratory of IMRCP UMR CNRS 5623, 118 route de Narbonne, F-31062 Toulouse, France c Univ Lyon, Université Claude Bernard Lyon 1, CNRS, ISA (Institut des Sciences Analytiques), UMR CNRS n°5280, 5 rue de la Doua, F-69100 Villeurbanne, France ARTICLE INFO ABSTRACT Keywords: A new series of 3-hydroxyflavones (1–46) were synthesized according to the Claisen-Schmidt followed by Algar- 3-hydroxyflavones Flynn-Oyamada reactions (AFO) in one step. The synthesized flavonoids were characterized by 1H NMR, 13C DFT calculations NMR and DCI-HRMS. All the synthesized compounds were tested in vitro for their 15-lipoxygenase inhibitory and 15-lipoxygenase inhibitory cytotoxic activity against the human cell lines HCT-116 (Human colon carcinoma), IGROV-1 and OVCAR-3 Cytotoxic activity (human ovarian carcinoma). It has been found that the derivatives 25, 37 and 45 were the most actives against Drug likeness HCT-116 (IC = 8.0, 9.0 and 9.0 μM, respectively) and against IGROV-1 (IC = 2.4, 5.0 and 6.0 μM, respec- Molecular propreties 50 50 tively). The derivatives 14 and 21 exhibited the higher anti-inflammatory activity at 100 μM with PI values of 76.50 and 72.70%, respectively. Molecule description was performed with DFT calculations, the drug likeness and bioactivity scores. The results exhibted that some compounds are in linear correlation with Lipinski’s rule of five showing good drug likeness and bioactivity score for drug targets. 1. Introduction indications [9–11]. Flavonoids have been reported to modulate several protein kinases (e.g. protein kinase-C) and to modulate epidermal Flavonoids are phytochemical compounds that exist in two classes, growth factor receptors (EGFRs), cyclin-dependent kinases (CDKs), either as free aglycones or glycosylated. Chemically, they are poly- vascular endothelial growth factor receptors (VEGFRs) and platelet phenols and have a phenyl-benzopyrone structure (C6–C3–C6). The derived growth factor receptors (PDGFRs), which play important roles distinction of the subclasses of flavonoids is made according to the in cancer diseases [12]. The anti-inflammatory property of flavonoids conformation of the central structure (benzopyrone). It is possible to have been investigated in in vivo and in vitro models [13]. Flavonoids distinguish in particular among the flavonoids the flavones, flavanols, are also known by their capacity to inhibit several enzymes such as isoflavones, flavonols, flavanones, flavanonols and chalcones [1]. This lipoxygenase (LOX), xanthine oxidase and cyclooxygenase (COX) which structural variety confers flavonoids a wide spectrum of biological ac- are implicated in inflammatory diseases [14,15]. tivities [2], including anticarcinogenic, anti-inflammatory [3], anti- Furthermore, flavonoids are able to modulate the functional activity microbial [4], spasmolytic and antiviral activities [5]. Moreover, they of several types of cells [13]. The different steps of inflammations are inhibit the capillary permeability, the platelet aggregation and the lipid affected by the compounds including the formation of granulose tissue, peroxidation. The ability of flavonoids to block the cell cycle, to induce chronic arthritis as well as the permeability of capillaries in the early apoptosis [6], to disturb mitotic spindle formation or to inhibit angio- stages [16], the structure-activity relationship study of 3-hydroxy- genesis makes them promising agents in anti-cancer research [7,8]. The flavones are of high interest [17]. However, most research on the bio- last few years, flavonoids and their synthetic analogs have been deeply logical activity of flavonoids has been limited on natural derivatives investigated in the treatment of ovarian, breast, cervical, pancreatic, such as kaempferol, morin, galangin quercetin, fisetin, and myricetin and prostate cancers. Flavonoids such as genistein, quercetin or flavo- [18–21]. piridol have entered late phase clinical trials for several oncological Taking into account the biological importance (anti-inflammatory, ⁎ Corresponding authors. E-mail addresses: [email protected] (H. Ben Jannet), [email protected] (J. Bouajila). https://doi.org/10.1016/j.bioorg.2019.103009 Received 4 February 2019; Received in revised form 20 May 2019; Accepted 21 May 2019 Available online 22 May 2019 0045-2068/ © 2019 Elsevier Inc. All rights reserved. M. Znati, et al. Bioorganic Chemistry 89 (2019) 103009 Scheme 1. Synthetic pathway of 3-hydroxyflavones 1–46. anticancer…) of this family of natural compounds and in order to help to 92% after precipitation in ice-water [22]. The prepared flavonols enrich it with new bioactive derivatives, a series of new flavonols were were characterized by means of spectroscopic methods (1H, 13C NMR synthesized using a Claisen-Schmidt and Algar-Flynn-Oyamada reac- and DCI-HRMS). Compound 8, as an exemple, was obtained as a yellow tions (AFO) in one step, and a series of fourty-six compounds was tested solid. Its mass spectrum (DCI- HRMS) gave pseudomolecular ion peak in vitro for their 15-lipoxygenase inhibitory and cytotoxic activity [M + H]+ at m/z 359.0292 in concordance with the molecular formula 1 against the human cell lines HCT-116 (Human colon carcinoma), C18H16BrO3. The H NMR (300 MHz, DMSO‑d6) spectrum of compound IGROV-1 and OVCAR-3 (human ovarian carcinoma). Density functional 8 has shown three signals at δH 8.16 (1H, d, J = 2.4 Hz), δH 7.87 (1H, theory (DFT) calculations were performed with the PBE (Perdew, Burke dd, J1 = 9.0, J2 = 2.4 Hz) and δH 7.72 (1H, d, J = 9.0 Hz) attributable and Ernzerhof) GGA (Generalized Gradient Approximation) exchange- to H-5, H-7 and H-8, respectively of the A-ring of the flavonol skeleton. correlation functional method and a TZP (triple zeta) basis set. The drug The same 1H NMR spectrum displayed an AA'BB' system of the B-ring at likeness of all synthesized compounds as well as of their derivatives was δH 8.30 (2H, d, J = 8.4 Hz) and δH 7.39 (2H, d, J = 8.4 Hz) attributable determined and discussed. to H-2′, H-6′ and H-3′, H-5′, respectively. The presence of two signals at δH 3.02 (1H, sept, J = 6.9 Hz) and δH 1.26 (6H, d, J = 6.9 Hz) relative to the isopropyl fragment. The 13C NMR (75 MHz, DMSO‑d ) spectrum 2. Results and discussion 6 of 8 confirmed the above spectral data by the observation of signals at δ 174.8 (C-4) attribuable to the carbonyl group, seven quaternary 2.1. Synthesis C carbons at δC 153.3 (C-9), 149.4 (C-2), 145.8 (C-4′), 135.3 (C-3), 134.1 (C-7), 126.4 (C-1′), 125.5 (C-10) and five methine carbons at δ 129.6 A one-step Claisen-Schmidt condensation followed by Algar-Flynn- C (C-5), 127.2 (C-2′, C-6′), 126.6 (C-3′, C-5′), 121.4 (C-8), 116.2 (C-6). Oyamada (AFO) reaction was used to prepare the target 3-hydroxy- The isopropyl fragment was also identified by the observation of the flavones 1–46. As illustrated in Scheme 1, substituted aryl aldehydes corresponding carbon atoms at δ 33.8 (C-7′) and 24.1 (C-8′, C-9′). with substituted 2-hydroxyacetophenones were refluxed in methanol to C afford 2-hydroxychalcones, then the intramolecular cyclization ofthe ring C and the oxidation of the carbon 3 are carried out using (H2O2, NaOH) to give the desired flavonols (1–46) with yields ranging from 30 2 M. Znati, et al. Bioorganic Chemistry 89 (2019) 103009 Table 1 2.2.2. Cytotoxic activity 15-lipoxygenase inhibition capacity (percent inhibition (%)) and cytotoxicity The cytotoxic activity of the synthesized compounds (1–46) were (HCT-116, IGROV-1 and OVCAR-3 cells lines) (IC50 (μM)) of flavonols deriva- tested against three human cancer cell lines including HCT-116, tives 1–46. IGROV-1 and OVCAR-3 using the MTT assay. Doxorubicin and ** 15-lipoxygenase Cytotoxic activity (IC50 μM) Tamoxifen are employed as positive controls. The results expressed in inhibition (%) at IC50 are presented in Table 1. It was found that all the synthesized 100 μM compounds displayed cytotoxic activity towards HCT-116, IGROV-1 Sample HCT-116 IGROV-1 OVCAR-3 and OVCAR-3 with IC50 values ranging from 2.4 to > 100 μM. 1 01.1 ± 0.0 h 28.0 ± 3.0d 25.1 ± 2.3d 25.1 ± 2.3d Compounds 25, 37, 45 and 46 exhibited the highest activity against e h f g 2 34.5 ± 2.6 95.0 ± 11.0 44.7 ± 2.1 60.0 ± 3.7 HCT-116 cell line (IC50 = 8.0−9.0 μM). Furthermore, compounds 12 3 43.2 ± 5.6d 63.0 ± 7.0 g > 100i 97.0 ± 4.9 h and 20 displayed an interesting activity with an IC50 value of 10 μM. 4 46.4 ± 9.0d > 100i 40.0 ± 2.6f 25.0 ± 0.3d * d d d Most of the rest of the compounds showed activity against the same cell 5 na 26.7 ± 1.4 33.0 ± 1.3 25.0 ± 0.7 6 na* > 100i > 100i > 100i line (HCT-116) with IC50 values ranging from 18.0 to 95.0 μM. 7 22.5 ± 2.0f 51.0 ± 4.0f 21.0 ± 1.0c 94.0 ± 7.0 h Regarding the human ovarian carcinoma cell lines (IGROV-1 and 8 15.4 ± 0.6 g 25.0 ± 4.0d 31.6 ± 1.9d 40.0 ± 1.9e OVCAR-3), compound 25 showed the most potent activity against 9 01.1 ± 0.0 h 20.0 ± 3.0c 22.4 ± 1.6c 22.0 ± 0.8c IGROV-1 with an IC50 value of 2.4 μM.