Chalcones, potential anticancer agents, have shown promise in the suppression of multidrug resistance due to the inhibition of drug efflux driven by certain adenosine triphosphate (ATP)-binding cassette (ABC) transporters. The gene and protein expression of chosen ABC transporters (multidrug resistance protein 1, ABCB1; multidrug resistance-associated protein 1, ABCC1; and breast cancer resistance protein, ABCG2) in human colorectal cancer cells (COLO 205 and COLO 320, which overexpress active ABCB1) was mainly studied in this work under the influence of a novel synthetic acridine-based chalcone, 1C. While gene expression dropped just at 24 h, compound 1C selectively suppressed colorectal cancer cell growth and greatly lowered ABCB1 protein levels in COLO 320 cells at 24, 48, and 72 h. It also reduced ABCC1 protein levels after 48 h. Molecular docking and ATPase tests show that 1C probably acts as an allosteric modulator of ABCB1. It also lowered galectin-1 (GAL1) expression in COLO 205 cells at 24 h. Functional tests on COLO cells revealed ABCB1 and ABCC1/2 to be major contributors to multidrug resistance in both. Overall, 1C transiently lowered GAL1 in COLO 205 while affecting important functional ABC transporters, mostly ABCB1 and to a lesser extent ABCC1 in COLO 320 cells. COLO 320's absence of GAL1 expression points to a possible yet unknown interaction between GAL1 and ABCB1.
- MeSH
- ATP Binding Cassette Transporter, Subfamily G, Member 2 metabolism MeSH
- ATP-Binding Cassette Transporters * metabolism chemistry genetics MeSH
- Acridines * chemistry pharmacology MeSH
- Chalcone * pharmacology chemistry MeSH
- Chalcones * pharmacology chemistry MeSH
- Drug Resistance, Neoplasm drug effects MeSH
- Colorectal Neoplasms metabolism drug therapy MeSH
- Humans MeSH
- Cell Line, Tumor MeSH
- ATP Binding Cassette Transporter, Subfamily B metabolism genetics MeSH
- Cell Proliferation drug effects MeSH
- Multidrug Resistance-Associated Protein 2 MeSH
- Multidrug Resistance-Associated Proteins metabolism genetics MeSH
- Antineoplastic Agents * pharmacology chemistry MeSH
- Gene Expression Regulation, Neoplastic drug effects MeSH
- Molecular Docking Simulation MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
Gram-positive bacteria are responsible for a wide range of infections in humans. In most Gram-positive bacteria, sortase A plays a significant role in attaching virulence factors to the bacteria's cell wall. These cell surface proteins play a significant role in virulence and pathogenesis. Even though antibiotics are available to treat these infections, there is a continuous search for an alternative strategy due to an increase in antibiotic resistance. Thus, using anti-sortase drugs to combat these bacterial infections may be a promising approach. Here, we describe a method for targeting Gram-positive bacterial infection by combining curcumin and trans-chalcone as sortase A inhibitors. We have used curcumin and trans-chalcone alone and in combination as a sortase A inhibitor. We have seen ~78%, ~43%, and ~94% inhibition when treated with curcumin, trans-chalcone, and a combination of both compounds, respectively. The compounds have also shown a significant effect on biofilm formation, IgG binding, protein A recruitment, and IgG deposition. We discovered that combining curcumin and trans-chalcone is more effective against Gram-positive bacteria than either compound alone. The present work demonstrated that a combination of these natural compounds could be used as an antivirulence therapy against Gram-positive bacterial infection.
- MeSH
- Aminoacyltransferases * antagonists & inhibitors metabolism MeSH
- Anti-Bacterial Agents * pharmacology chemistry MeSH
- Bacterial Proteins * metabolism antagonists & inhibitors MeSH
- Biofilms * drug effects MeSH
- Chalcone * pharmacology chemistry MeSH
- Cysteine Endopeptidases * metabolism MeSH
- Virulence Factors metabolism MeSH
- Gram-Positive Bacterial Infections drug therapy microbiology MeSH
- Gram-Positive Bacteria drug effects MeSH
- Curcumin * pharmacology chemistry MeSH
- Humans MeSH
- Microbial Sensitivity Tests MeSH
- Virulence drug effects MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
Multidrug resistance (MDR) mechanisms in cancer cells are greatly influenced by glutathione transferase P1-1 (hGSTP1-1). The use of synthetic or natural compounds as hGSTP1-1 inhibitors is considered an effective approach to overcome MDR. Nine compounds consisting of coumarin-6-sulfonamide linked to chalcone derivatives were synthesized and evaluated for their ability to inhibit hGSTP1-1. Among the synthetic derivatives, compounds 5g, 5f, and 5a displayed the most potent inhibitory effect, with IC50 values of 12.2 ± 0.5 μΜ, 12.7 ± 0.7 and 16.3 ± 0.6, respectively. Kinetic inhibition analysis of the most potent molecule, 5g, showed that it behaves as a mixed-type inhibitor of the target enzyme. An in vitro cytotoxicity assessment of 5a, 5f, and 5g against the human prostate cancer cell lines DU-145 and PC3, as well as the breast cancer cell line MCF-7, demonstrated that compound 5g exhibited the most pronounced cytotoxic effect on all tested cell lines. Molecular docking studies were performed to predict the structural and molecular determinants of 5g, 5f, and 5a binding to hGSTP1-1. In agreement with the experimental data, the results revealed that 5g exhibited the lowest docking score among the three studied inhibitors as a consequence of shape complementarity, governed by van der Waals, hydrogen bonds and a π-π stacking interaction. These findings suggest that coumarin-chalcone hybrids offer new perspectives for the development of safe and efficient natural product-based sensitizers that can target hGSTP1-1 for anticancer purposes.
- MeSH
- Chalcone chemistry pharmacology MeSH
- Chalcones chemistry pharmacology MeSH
- Glutathione S-Transferase pi * antagonists & inhibitors metabolism MeSH
- Enzyme Inhibitors pharmacology chemistry MeSH
- Coumarins * chemistry pharmacology MeSH
- Humans MeSH
- MCF-7 Cells MeSH
- Cell Line, Tumor MeSH
- Antineoplastic Agents pharmacology chemistry MeSH
- Molecular Docking Simulation * MeSH
- Sulfonamides * chemistry pharmacology MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
A bis(chalcone) molecule (H2L) was synthesized via Aldol's condensation from terephthalaldehyde and 2'-hydroxyacetophenone and it was used as bridging ligand for the preparation of five dinuclear copper(II) complexes of the composition [Cu(NN)(μ-L)Cu(NN)](NO3)2⋅nH2O (n = 0-2) (1-5), where NN stands for a bidentate N-donor ligand such as phen (1,10-phenanthroline, 1), bpy (2,2'-bipyridine, 2), mebpy (5,5'-dimethyl-2,2'-dipyridine, 3), bphen (bathophenanthroline, 4) and nphen (5-nitro-1,10-phenanthroline, 5). The compounds were characterized by different suitable techniques to confirm their purity, composition, and structure. Moreover, the products were evaluated for their in vitro cytotoxicity on a panel of human cancer cell lines: ovarian (A2780), ovarian resistant to cisplatin (A2780R), prostate (PC3), osteosarcoma (HOS), breast (MCF7) and lung (A549), and normal fibroblasts (MRC-5), showing significant cytotoxicity in most cases, with IC50 ≈ 0.35-7.8 μM. Additionally, the time-dependent cytotoxicity and cellular uptake of copper, together with flow cytometric studies concerning cell-cycle arrest, induction of cell death and autophagy and induction of intracellular ROS/superoxide production in A2780 cells, were also performed. The results of biological testing on A2780 cells pointed out a possible mechanism of action characterized by the G2/M cell cycle arrest and induction of apoptosis by triggering the intrinsic signalling pathway associated with the damage of mitochondrial structure and depletion of mitochondrial membrane potential. SYNOPSIS: Dinuclear Cu(II) complexes bearing a bridging bis(chalcone) ligand revealed high in vitro cytotoxicity, initiated A2780 cell arrest at G2/M phase and efficiently triggered intrinsic pathway of apoptosis.
- MeSH
- Apoptosis MeSH
- Chalcone * pharmacology MeSH
- Chalcones * pharmacology MeSH
- Coordination Complexes * pharmacology chemistry MeSH
- Humans MeSH
- Ligands MeSH
- Copper chemistry MeSH
- Cell Line, Tumor MeSH
- Ovarian Neoplasms * MeSH
- Antineoplastic Agents * pharmacology chemistry MeSH
- Check Tag
- Humans MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
The coexistence of leishmaniasis, Chagas disease, and neoplasia in endemic areas has been extensively documented. The use of common drugs in the treatment of these pathologies invites us to search for new molecules with these characteristics. In this research, we report 16 synthetic chalcone derivatives that were investigated for leishmanicidal and trypanocidal activities as well as for antiproliferative potential on eight human cancers and two nontumor cell lines. The final compounds 8-23 were obtained using the classical base-catalyzed Claisen-Schmidt condensation. The most potent compounds as parasiticidal were found to be 22 and 23, while compounds 18 and 22 showed the best antiproliferative activity and therapeutic index against CCRF-CEM, K562, A549, and U2OS cancer cell lines and non-toxic VERO, BMDM, MRC-5, and BJ cells. In the case of K562 and the corresponding drug-resistant K562-TAX cell lines, the antiproliferative activity has shown a more significant difference for compound 19 having 10.3 times higher activity against the K562-TAX than K562 cell line. Flow cytometry analysis using K562 and A549 cell lines cultured with compounds 18 and 22 confirmed the induction of apoptosis in treated cells after 24 h. Based on the structural analysis, these chalcones represent new compounds potentially useful for Leishmania, Trypanosoma cruzi, and some cancer treatments.
- MeSH
- Chagas Disease * drug therapy MeSH
- Chalcone * pharmacology MeSH
- Leishmania * MeSH
- Leishmaniasis * drug therapy MeSH
- Humans MeSH
- Naphthalenes therapeutic use MeSH
- Trypanocidal Agents * chemistry MeSH
- Trypanosoma cruzi * MeSH
- Structure-Activity Relationship MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- MeSH
- Antidepressive Agents pharmacology MeSH
- Anti-Anxiety Agents pharmacology MeSH
- Carthamus tinctorius * chemistry metabolism growth & development MeSH
- Chalcone analogs & derivatives MeSH
- Phytotherapy MeSH
- Humans MeSH
- Neuroprotective Agents pharmacology MeSH
- Nootropic Agents pharmacology MeSH
- Plant Extracts * pharmacology therapeutic use MeSH
- Salvia miltiorrhiza MeSH
- Check Tag
- Humans MeSH
- Publication type
- Research Support, Non-U.S. Gov't MeSH
- Keywords
- Cyclo3Fort,
- MeSH
- Chalcone therapeutic use MeSH
- Chronic Disease therapy MeSH
- Phytotherapy MeSH
- Hesperidin therapeutic use MeSH
- Compression Bandages MeSH
- Ascorbic Acid therapeutic use MeSH
- Humans MeSH
- Plant Extracts therapeutic use MeSH
- Ruscus chemistry MeSH
- Sclerotherapy MeSH
- Venous Insufficiency * drug therapy MeSH
- Check Tag
- Humans MeSH
Chalcones, i.e., compounds with the chemical pattern of 1,3-diphenylprop-2-en-1-ones, exert a wide range of bio-activities, e.g., antioxidant, anti-inflammatory, anticancer, anti-infective etc. Our research group has been focused on pyrazine analogues of chalcones; several series have been synthesized and tested in vitro on antifungal and antimycobacterial activity. The highest potency was exhibited by derivatives with electron withdrawing groups (EWG) in positions 2 and 4 of the ring B. As halogens also have electron withdrawing properties, novel halogenated derivatives were prepared by Claisen-Schmidt condensation. All compounds were submitted for evaluation of their antifungal and antibacterial activity, including their antimycobacterial effect. In the antifungal assay against eight strains of selected fungi, growth inhibition of Candida glabrata and Trichophyton interdigitale (formerly T. mentagrophytes) was shown by non-alkylated derivatives with 2-bromo or 2-chloro substitution. In the panel of selected bacteria, 2-chloro derivatives showed the highest inhibitory effect on Staphylococcus sp. In addition, all products were also screened for their antimycobacterial activity against Mycobacterium tuberculosis H37RV My 331/88, M. kansasii My 235/80, M. avium 152/80 and M. smegmatis CCM 4622. Some of the examined compounds, inhibited growth of M. kansasii and M. smegmatis with minimum inhibitory concentrations (MICs) comparable with those of isoniazid.
- MeSH
- Anti-Infective Agents * chemical synthesis chemistry pharmacology MeSH
- Candida glabrata growth & development MeSH
- Chalcone * chemical synthesis chemistry pharmacology MeSH
- Hydrocarbons, Halogenated * chemical synthesis chemistry pharmacology MeSH
- Mycobacterium growth & development MeSH
- Pyrazines * chemical synthesis chemistry pharmacology MeSH
- Trichophyton growth & development MeSH
- Publication type
- Journal Article MeSH
- MeSH
- Cell Migration Assays methods utilization MeSH
- Biomedical Research MeSH
- Chalcone analogs & derivatives administration & dosage therapeutic use MeSH
- Cytotoxicity Tests, Immunologic methods utilization MeSH
- Human Umbilical Vein Endothelial Cells * cytology enzymology MeSH
- Photochemotherapy methods utilization MeSH
- Indicators and Reagents MeSH
- Angiogenesis Inhibitors * administration & dosage adverse effects therapeutic use MeSH
- Humans MeSH
- Perylene analogs & derivatives administration & dosage therapeutic use MeSH
- Antineoplastic Agents * administration & dosage adverse effects therapeutic use MeSH
- Statistics as Topic MeSH
- Check Tag
- Humans MeSH
- Publication type
- Research Support, Non-U.S. Gov't MeSH
