One-Pot Synthesis and Evaluation of Antioxidative Stress and Anticancer Properties of an Active Chromone Derivative.

Chromones are the structural building blocks of several natural flavonoids. The synthesis of chromones, which contain a hydroxy group on the ring, presents some challenges. We used the one-pot method to synthesize ten chromone derivatives and two related compounds using modified Baker-Venkataraman reactions. The structures were confirmed using FT-IR, 1H NMR, 13C NMR, and HRMS. The in vitro antioxidant assay revealed that compounds 2e, 2f, 2j, and 3i had potent antioxidant activity and that all these synthesized compounds, except those containing nitro groups, were harmless to normal cells. In addition, compounds 2b, 2d, 2e, 2f, 2g, 2i, and 2j had anticancer activity. Compounds 2f and 2j were used to investigate the mechanism of anticancer activity. Both 2f and 2j induced a slightly early apoptotic effect but significantly impacted the S phase in the cell cycle. The effect on cell invasion indicates that both compounds significantly inhibited the growth of cervical cancer cells. A chromone scaffold possesses effective chemoprotective and antioxidant properties, making it a promising candidate for antioxidant and future cancer treatments.

Molecular docking based screening of triterpenoids as potential G-quadruplex stabilizing ligands with anti-cancer activity.

Triterpenoids isolated from Ganoderma lucidum (GLTs) exhibit a broad spectrum of anti-cancer properties, including anti-proliferative, anti-metastatic and anti-angiogenic activities. Current research studies revealed the role by GLTs in inducing apoptosis and suppression of telomerase activity of cancer cells with much lower toxicity to healthy cells. Compounds selectively binding and stabilizing G-quadruplex structures could inhibit the telomerase or downregulate the oncogenes and may act as anti-cancer agents. Targeting human telomeric G-quadruplex DNA could be one of the mechanisms by which these GLTs exert anti-cancer activity. In this study, 208 GLTs were screened for ligands with high binding affinity and selectively to stabilize the pG4DNA by using the docking tool AutoDock4. The results showed that ganoderic acid A and ganoderic acid Df exhibit high binding affinity and selectively bind to the lateral groove of pG4DNA. Based on our findings, we suggest that the triterpenoid represents a new class of G-quadruplex groove binding ligands and thus act as potential anti-cancer agents.

Antimalarial activity of HIV-1 protease inhibitor in chromone series.

Increasing parasite resistance to nearly all available antimalarial drugs becomes a serious problem to human health and necessitates the need to continue the search for new effective drugs. Recent studies have shown that clinically utilized HIV-1 protease (HIV-1 PR) inhibitors can inhibit the in vitro and in vivo growth of Plasmodium falciparum. In this study, a series of chromone derivatives possessing HIV-1 PR inhibitory activity has been tested for antimalarial activity against P. falciparum (K1 multi-drug resistant strain). Chromone 15, the potent HIV-1 PR inhibitor (IC50=0.65µM), was found to be the most potent antimalarial compound with IC50=0.95µM while primaquine and tafenoquine showed IC50=2.41 and 1.95µM, respectively. Molecular docking study of chromone compounds against plasmepsin II, an aspartic protease enzyme important in hemoglobin degradation, revealed that chromone 15 exhibited the higher binding affinity (binding energy=-13.24kcal/mol) than the known PM II inhibitors. Thus, HIV-1 PR inhibitor in chromone series has the potential to be a new class of antimalarial agent.

Ligand-based CoMFA and CoMSIA studies on chromone derivatives as radical scavengers.

The antioxidant activity for a series of chromone compounds, evaluated by DPPH free radical scavenging assay, were subjected to 3D-QSAR studies using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). All 48 chromone derivatives were geometry optimized by AM1 and HF/6-31G(*) calculations. The CoMFA and CoMSIA results were compared between different alignment strategies. The best CoMFA model obtained from HF/6-31G(*) optimization with field fit alignment gave cross-validated r(2) (q(2))=0.821, noncross-validated r(2)=0.987, S=0.095, and F=388.255. The best CoMSIA model derived from AM1 optimized structures and superimposition alignment gave q(2)=0.876, noncross-validated r(2)=0.976, S=0.129, and F=208.073, including electrostatic, hydrophobic, hydrogen bond donor and acceptor fields. The contour maps provide the fruitful structure-radical scavenging activity relationships which are useful for designing new compounds with higher activity.

Synthesis, topoisomerase I inhibitory and cytotoxic activities of chromone derivatives.

A series of chromone derivatives were designed as potential topoisomerase I (Top I) inhibitors based on the docking simulation study. Sixteen synthesized compounds were evaluated for Top I inhibitory activity and some compounds were further tested for in vitro cytotoxic activity. The most potent inhibitor, chromone 11b showed greater inhibitory activity (IC50 = 1.46 µM) than the known Top I inhibitors, i.e., camptothecin, fisetin and morin, but inactive against breast cancer cell (MCF-7), oral cavity cancer cell (KB) and small cell lung cancer (NCI-H187). Chromone 11c, another potent inhibitor (IC50 = 6.16 µM), exhibited cytotoxic activity against KB (IC50 = 73.32 µM) and NCI-H187 (IC50 = 36.79 µM).

In vitro antioxidant activity study of novel chromone derivatives.

Forty-eight chromone derivatives were evaluated for their antioxidant activity using 2,2-diphenyl-1-picrylhydrazyl free radical scavenging assay, ferrous ions (Fe(2+) ) chelating activity test, total antioxidant activity test (Ferric thiocyanate and Thiobarbituric acid methods), and total reductive capability (potassium ferricyanide reduction). 7,8-Dihydroxy-2-(3'-trifluoromethylphenyl)-3-(3″-trifluoromethylbenzoyl) chromone 32 showed stronger radical scavenging and metal chelating activities than butylated hydroxytoluene, vitamin E, and trolox. Chromone derivatives that exhibited good radical scavenging and metal chelating also displayed strong total antioxidant and reductive power activities. The results obtained from this study indicated that the synthesized chromone derivatives have remarkable antioxidant activity.

3D-QSAR studies on chromone derivatives as HIV-1 protease inhibitors: application of molecular field analysis.

Three-dimensional quantitative structure-activity relationship (3D-QSAR) models were developed for chromone derivatives against HIV-1 protease using molecular field analysis (MFA) with genetic partial least square algorithms (G/PLS). Three different alignment methods: field fit, pharmacophore-based, and receptor-based were used to derive three MFA models. All models produced good predictive ability with high cross-validated r(2) (r(2) (cv)), conventional r(2), and predictive r(2)(r(2)(pred)) values. The receptor-based MFA showed the best statistical results with r(2) (cv) = 0.789, r(2)= 0.886, and r(2)(pred) = 0.995. The result obtained from the receptor-based model was compared with the docking simulation of the most active compound 21 in this chromone series to the binding pocket of HIV-1 protease (PDB entry 1AJX). It was shown that the MFA model related well with the binding structure of the complex and can provide guidelines to design more potent HIV-1 protease inhibitors.

3D-QSAR investigation of synthetic antioxidant chromone derivatives by molecular field analysis.

A series of 7-hydroxy, 8-hydroxy and 7,8-dihydroxy synthetic chromone derivatives was evaluated for their DPPH free radical scavenging activities. A training set of 30 synthetic chromone derivatives was subject to three-dimensional quantitative structure-activity relationship (3D-QSAR) studies using molecular field analysis (MFA). The substitutional requirements for favorable antioxidant activity were investigated and a predictive model that could be used for the design of novel antioxidants was derived. Regression analysis was carried out using genetic partial least squares (G/PLS) method. A highly predictive and statistically significant model was generated. The predictive ability of the developed model was assessed using a test set of 5 compounds (r(2) (pred) = 0.924). The analyzed MFA model demonstrated a good fit, having r(2) value of 0.868 and cross-validated coefficient r(2) (cv) value of 0.771.