Oxidized Juncuenin B Analogues with Increased Antiproliferative Activity on Human Adherent Cell Lines: Semisynthesis and Biological Evaluation.

Phenanthrenes have become the subject of intensive research during the past decades because of their structural diversity and wide range of pharmacological activities. Earlier studies demonstrated that semisynthetic derivatization of these natural compounds could result in more active agents, and oxidative transformations are particularly promising in this regard. In our work, a natural phenanthrene, juncuenin B, was transformed by hypervalent iodine(III) reagents using a diversity-oriented approach. Eleven racemic semisynthetic compounds were produced, the majority containing an alkyl substituted p-quinol ring. Purification of the compounds was carried out by chromatographic techniques, and their structures were elucidated by 1D and 2D NMR spectroscopic methods. Stereoisomers of the bioactive derivatives were separated by chiral-phase HPLC and the absolute configurations of the active compounds, 2,6-dioxo-1,8a-dimethoxy-1,7-dimethyl-8-vinyl-9,10-dihydrophenanthrenes (1a-d), and 8a-ethoxy-1,7-dimethyl-6-oxo-8-vinyl-9,10-dihydrophenanthrene-2-ols (7a,b) were determined by ECD measurements and TDDFT-ECD calculations. The antiproliferative activities of the compounds were tested on different (MCF-7, T47D, HeLa, SiHa, C33A, A2780) human gynecological cancer cell lines. Compounds 1a-d, 4a, 6a, and 7a possessed higher activity than juncuenin B on several tumor cell lines. The structure-activity relationship studies suggested that the p-quinol (2,5-cyclohexadien-4-hydroxy-1-one) moiety has a considerable effect on the antiproliferative properties, and substantial differences could be identified in the activities of the stereoisomers.

Synthesis and In Vitro Antitumor Activity of Naringenin Oxime and Oxime Ether Derivatives.

Naringenin is one of the most abundant dietary flavonoids exerting several beneficial biological activities. Synthetic modification of naringenin is of continuous interest. During this study our aim was to synthesize a compound library of oxime and oxime ether derivatives of naringenin, and to investigate their biological activities. Two oximes and five oxime ether derivatives were prepared; their structure has been elucidated by NMR and high-resolution mass spectroscopy. The antiproliferative activity of the prepared compounds was evaluated by MTT assay against human leukemia (HL-60) and gynecological cancer cell lines isolated from cervical (HeLa, Siha) and breast (MCF-7, MDA-MB-231) cancers. Tert-butyl oxime ether derivative exerted the most potent cell growth inhibitory activity. Moreover, cell cycle analysis suggested that this derivative caused a significant increase in the hypodiploid (subG1) phase and induced apoptosis in Hela and Siha cells, and induced cell cycle arrest at G2/M phase in MCF-7 cells. The proapoptotic potential of the selected compound was confirmed by the activation of caspase-3. Antioxidant activities of the prepared molecules were also evaluated with xanthine oxidase, DPPH and ORAC assays, and the methyl substituted oxime ether exerted the most promising activity.

Stereoselective Synthesis, Synthetic and Pharmacological Application of Monoterpene-Based 1,2,4- and 1,3,4-Oxadiazoles.

Stereoselective synthesis of monoterpene-based 1,2,4- and 1,3,4-oxadiazole derivatives was accomplished starting from α,ß-unsaturated carboxylic acids, obtained by the oxidation of (-)-2-carene-3-aldehyde and commercially available (-)-myrtenal. 1,2,4-Oxadiazoles were prepared in two steps via the corresponding O-acylamidoxime intermediates, which then underwent cyclisation induced by tetrabutylammonium fluoride (TBAF) under mild reaction conditions. Stereoselective dihydroxylation in highly stereospecific reactions with the OsO4/NMO (N-methylmorpholine N-oxide) system produced α,ß-dihydroxy 1,2,4-oxadiazoles. Pinane-based 1,3,4-oxadiazoles were obtained similarly from acids by coupling with acyl hydrazines followed by POCl3-mediated dehydrative ring closure. In the case of the arane counterpart, the rearrangement of the constrained carane system occurred with the loss of chirality under the same conditions. Stereoselective dihydroxylation with OsO4/NMO produced α,ß-dihydroxy 1,3,4-oxadiazoles. The prepared diols were applied as chiral catalysts in the enantioselective addition of diethylzinc to aldehydes. All compounds were screened in vitro for their antiproliferative effects against four malignant human adherent cell lines by means of the MTT assay with the O-acylated amidoxime intermediates exerting remarkable antiproliferative action.

Thymoquinone-protoflavone hybrid molecules as potential antitumor agents.

We describe herein the synthesis of eight new ester-coupled hybrid compounds from thymoquinone and protoflavone building blocks, and their bioactivity testing against multiple cancer cell lines. Among the hybrids, compound 14 showed promising activities in all cell lines studied. The highest activities were recorded against breast cancer cell lines with higher selectivity to MDA-MB-231 as compared to MCF-7. Even though the hybrids were found to be completely hydrolysed in 24 h under cell culture conditions, compound 14 demonstrated a ca. three times stronger activity against U-87 glioblastoma cells than a 1:1 mixture of its fragments. Further, compound 14 showed good tumour selectivity: it acted 4.4-times stronger on U-87 cells than on MRC-5 fibroblasts. This selectivity was much lower, only ca. 1.3-times, when the cells were co-treated with a 1:1 mixture of its non-coupled fragments. Protoflavone-thymoquinone hybrids may therefore serve as potential new antitumor leads particularly against glioblastoma.

Preparation of dearomatized p-coumaric acid derivatives as DNA damage response inhibitors with potent in vitro antitumor effect.

Our research group previously identified graviquinone (1) as a promising antitumor metabolite that is formed in situ when the antioxidant methyl caffeate scavenges free radicals. Furthermore, it exerted a DNA damaging effect on cancer cells and a DNA protective effect on normal keratinocytes. To expand and explore chemical space around qraviquinone, in the current work we synthesized 9 new alkyl-substituted derivatives and tested their in vitro antitumor potential. All new compounds bypassed ABCB1-mediated multidrug resistance and showed highly different cell line specificity compared with 1. All compounds were more potent in MDA-MB-231 than on MCF-7 cells. The n-butyl-substituted derivatives 2 and 8 modulated the cell cycle and inhibited the ATR-mediated phosphorylation of checkpoint kinase-1 in MCF-7 cells. As a significant expansion of our previous findings, our results highlight the potential antitumor value of alkyl-substituted graviquinone derivatives.

Preparation and Evaluation of 6-Gingerol Derivatives as Novel Antioxidants and Antiplatelet Agents.

Ginger (Zingiber officinale) is widely used as a spice and a traditional medicine. Many bioactivities have been reported for its extracts and the isolated compounds, including cardiovascular protective effects. Different pathways were suggested to contribute to these effects, like the inhibition of platelet aggregation. In this study, we synthesised fourteen 6-gingerol derivatives, including eight new compounds, and studied their antiplatelet, COX-1 inhibitor, and antioxidant activities. In silico docking of selected compounds to h-COX-1 enzyme revealed favourable interactions. The investigated 6-gingerol derivatives were also characterised by in silico and experimental physicochemical and blood-brain barrier-related parameters for lead and preclinical candidate selection. 6-Shogaol (2) was identified as the best overall antiplatelet lead, along with compounds 3 and 11 and the new compound 17, which require formulation to optimize their water solubility. Compound 5 was identified as the most potent antioxidant that is also promising for use in the central nervous system (CNS).

Medicinal chemistry inspired by ginger: exploring the chemical space around 6-gingerol.

Ginger (Zingiber officinale Roscoe) has been used as a spice and as a traditional remedy since ancient times, especially in traditional Chinese medicine. It has been applied as a treatment for many diseases either alone or in combination with other remedies. Many studies were conducted on ginger and its constituents and a wide array of bioactivities were reported, e.g., antioxidant, anti-inflammatory, antiemetic, and anticancer activity. Most of these had been correlated to gingerols and shogaols, the most abundant secondary metabolites in ginger. This inspired several research groups to explore the biomedical value of the chemical space around these compounds, and many of their synthetic or semi-synthetic analogues have been prepared and studied for various bioactivities. Thanks to this, many valuable structure activity relationships have been revealed for such compounds. Herein, we provide a brief summary on the synthetic derivatization efforts that had so far been implemented on 6-gingerol, the main constituent of fresh ginger. This review covers 160 natural, semisynthetic, or synthetic 6-gingerol derivatives and their reported bioactivities.