Abstract
Polyfunctional N,O,O,N-type ligands such as the oxalyl dihydrazide (ODH) may induce formation of mono-, di-, and polynuclear complexes with natural monoterpene ketones, involving ligand bridging and Oxo-bridging. In this context, a novel chiral dihydrazone is designed through hemi-synthesis process by reacting oxalyldihydrazide (ODH) with (s)-carvone, the major compound of caraway's seeds essential oil. The C = N imine bi-condensation is performed without prior isolation of the natural (s)-carvone and the resulting (s)-carvone dihydrazone (s-CHD) is structurally characterized by Single-crystal X-ray diffraction, 2D-NMR spectroscopy and chiral LCMS analysis to confirm the formation of a single pure enantiomer. In-vitro cell-based assays were conducted on normal fibroblast (L929) using a presBlue (PB) fluorescence quantification method of cell-viability and by sulforhodamine B calorimetric cytotoxicity assays to determine the anti-proliferative effect on four human tumoral lines (NCI-H460, Hela, HepG2 and MCF-7) and normal PLP2. Anti-inflammatory assays were determined through NO production by Maurine LPS-stimulated macrophages (RAW 264.7). The (s)-CHD has no effect on normal cells viability (>88%) and PLP2 (GI50= 326 ug/mL), while a moderate (∼55%) to significant (∼63%) antigrowth potential was recorded against HepG2, Hela and MCF-7 tumor cell lines, where RAW 264.7 was feebly sensitive. A molecular docking was performed using Autodock vina software on the protein kinase CK2 and Epidermal Growth factor Kinase proteins EGFK and the dock scores allowed to identify significant binding affinities (lower ΔG and Ki values) and potential hydrophilic/hydrophobic interactions with (s)-CHD comparing to the clinical ellipticine as potential ligands. Molecular docking suggests that (s)-CHD possesses high affinity towards the kinase domain receptors CK2 and EGFR, being able to bind to the ATP region.
Highlights
Plant terpenoids are extremely reactive secondary metabolites [1], of large structurally diverse configurations allowing them to be hazards [6]
The dextro (d) form of carvone is mainly found in certain plant EOs, including Carum carvi L. (Apiaceae) and Zanthoxylum alatum DC. (Rutaceae) seeds [7,8,9,10], dill Anethum graveolens L. (Apiaceae) and fennel Foeniculum vulgare Mill. (Apiaceae) seeds [11], which are well documented in folk medicine for their remedies on gastric disorders [12,13]
Due to the outstanding chemical proprieties of the (S)-carvone and its potential reactivity, the current study reports an in-situ imine condensation of C. carvi seeds EOs with oxalyl dihydrazide (OHD) to obtain a new chiral (s)-carvone dihydrazone (s-CHD) structure via an hemi-synthetic approach
Summary
Plant terpenoids are extremely reactive secondary metabolites [1], of large structurally diverse configurations allowing them to be hazards [6]. Previous studies highlighted several pharmacological effects of carvone and its derivatives as antimicrobial compound [15], antifungal [16], and antitumoral [15,17,18]. Different conventional methods, such as hydrodistillation [19], soxhlet [20] and supercritical fluid extraction [21], are used to extract EOs from C. carvi seeds, where reports usually highlighted large amounts of carvone (50–60%) and limonene (30–40%) in the volatile fraction [21,22]. Post-synthetic modification of (s)-carvone present in raw plant materials, by mean of its ketone function, may exhibit interesting biologically active compounds associated with a chiral interaction that plays a crucial role in the elaboration of synthetic or hemi-synthetic anticancer drugs [ 23 , 24 ]
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