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1.
Bioorg Med Chem Lett ; 60: 128586, 2022 03 15.
Article in English | MEDLINE | ID: mdl-35085721

ABSTRACT

Menadione (VK3) is used as a powerful inducer of cellular reactive oxygen species (ROS) for many years and displays the high anti-cancer activities in vivo. Recently, the development of mitochondria-targeted drugs has been more and more appreciated. Here, the thirteen derivatives of VK3 were synthesized, which could localize in mitochondria by the triphenylphosphonium (TPP) cation or the nitrogen-based cation. The results of cytotoxicity from six human cancer cell lines showed that the targeted compounds T1-T13 displayed higher activity than VK3 with the average IC50 value around 1 µM. The results of cytotoxicity indicated that the substitutes on C-2, the linear alkyl chains on C-3 and cation moiety all could affect the cytotoxicity. The mechanistic studies showed that five representative compounds (T2, T3, T5, T8 and T13) could localize in cellular mitochondria, elicit ROS burst and collapse mitochondrial membrane potential (ΔΨm), leading to cytochrome C release and apoptosis in MGC-803 cells. Particularly, they could obviously inhibit mitochondrial thioredoxin reductase TrxR2 expression, thus leading to aggravate cellular oxidative stress.


Subject(s)
Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Mitochondria/drug effects , Thioredoxin Reductase 2/antagonists & inhibitors , Vitamin K 3/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cations/chemical synthesis , Cations/chemistry , Cations/pharmacology , Cell Line , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Mitochondria/metabolism , Molecular Structure , Structure-Activity Relationship , Thioredoxin Reductase 2/metabolism , Vitamin K 3/chemical synthesis , Vitamin K 3/chemistry
2.
Eur J Med Chem ; 209: 112859, 2021 Jan 01.
Article in English | MEDLINE | ID: mdl-33010635

ABSTRACT

Tuberculosis (TB) is one of the most fatal diseases and is responsible for the infection of millions of people around the world. Most recently, scientific frontiers have been engaged to develop new drugs that can overcome drug-resistant TB. Following this direction, using a designed scaffold based on the combination of two separate pharmacophoric groups, a series of menadione-derived selenoesters was developed with good yields. All products were evaluated for their in vitro activity against Mycobacterium tuberculosis H37Rv and attractive results were observed, especially for the compounds 8a, 8c and 8f (MICs 2.1, 8.0 and 8.1 µM, respectively). In addition, 8a, 8c and 8f demonstrated potent in vitro activity against multidrug-resistant clinical isolates (CDCT-16 and CDCT-27) with promising MIC values ranging from 0.8 to 3.1 µM. Importantly, compounds 8a and 8c were found to be non-toxic against the Vero cell line. The SI value of 8a (>23.8) was found to be comparable to that of isoniazid (>22.7), which suggests the possibility of carrying out advanced studies on this derivative. Therefore, these menadione-derived selenoesters obtained as hybrid compounds represent promising new anti-tubercular agents to overcome TB multidrug resistance.


Subject(s)
Antitubercular Agents/pharmacology , Mycobacterium tuberculosis/drug effects , Selenium/pharmacology , Vitamin K 3/pharmacology , Animals , Antitubercular Agents/chemical synthesis , Antitubercular Agents/chemistry , Chlorocebus aethiops , Humans , Models, Molecular , Selenium/chemistry , Tuberculosis/drug therapy , Vero Cells , Vitamin K 3/analogs & derivatives , Vitamin K 3/chemical synthesis
3.
Org Biomol Chem ; 16(15): 2647-2665, 2018 04 18.
Article in English | MEDLINE | ID: mdl-29542786

ABSTRACT

Malaria is a tropical parasitic disease threatening populations in tropical and sub-tropical areas. Resistance to antimalarial drugs has spread all over the world in the past 50 years, thus new drugs are urgently needed. Plasmodione (benzylmenadione series) has been identified as a potent antimalarial early lead drug, acting through a redox bioactivation on asexual and young sexual blood stages. To investigate its metabolism, a series of plasmodione-based tools, including a fully 13C-labelled lead drug and putative metabolites, have been designed and synthesized for drug metabolism investigation. Furthermore, with the help of UHPLC-MS/MS, two of the drug metabolites have been identified from urine of drug-treated mice.


Subject(s)
Antimalarials/chemical synthesis , Vitamin K 3/analogs & derivatives , Vitamin K 3/chemical synthesis , Animals , Antimalarials/metabolism , Antimalarials/pharmacology , Carbon Isotopes , Drug Resistance, Multiple , Humans , Isotope Labeling , Mice , Oxidation-Reduction , Plasmodium berghei/drug effects , Plasmodium falciparum/drug effects , Vitamin K 3/metabolism , Vitamin K 3/pharmacology
4.
Chem Biol Drug Des ; 91(1): 220-233, 2018 01.
Article in English | MEDLINE | ID: mdl-28734085

ABSTRACT

A series of novel menadione-based triazole hybrids were designed and synthesized by employing copper-catalyzed azide-alkyne cycloaddition (CuAAC). All the synthesized hybrids were characterized by their spectral data (1 H NMR, 13 C NMR, IR, and HRMS). The synthesized compounds were evaluated for their anticancer activity against five selected cancer cell lines including lung (A549), prostate (DU-145), cervical (Hela), breast (MCF-7), and mouse melanoma (B-16) using MTT assay. The screening results showed that majority of the synthesized compounds displayed significant anticancer activity. Among the tested compounds, the triazoles 5 and 6 exhibited potent activity against all cell lines. In particular, compound 6 showed higher potency than the standard tamoxifen and parent menadione against MCF-7 cell line. Flow cytometric analysis revealed that compound 6 arrested cell cycle at G0/G1 phase and induced apoptotic cell death which was further confirmed by Hoechst staining, measurement of mitochondrial membrane potential (ΔΨm) and Annexin-V-FITC assay. Thus, compound 6 can be considered as lead molecule for further development as potent anticancer therapeutic agent.


Subject(s)
Antineoplastic Agents/chemical synthesis , Vitamin K 3/chemistry , A549 Cells , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Catalysis , Cell Line, Tumor , Copper/chemistry , Cycloaddition Reaction , Drug Screening Assays, Antitumor , G1 Phase Cell Cycle Checkpoints/drug effects , HeLa Cells , Humans , MCF-7 Cells , Membrane Potential, Mitochondrial/drug effects , Mice , Structure-Activity Relationship , Triazoles/chemistry , Vitamin K 3/chemical synthesis , Vitamin K 3/pharmacology
5.
Food Chem ; 213: 336-343, 2016 Dec 15.
Article in English | MEDLINE | ID: mdl-27451189

ABSTRACT

The synthesis of aminomethylphosphine-metal complexes have opened a new perspective to the catalytic applications of organic compounds. Magnetic Fe3O4 nano-core was synthesized using the closed quartz tube with Teflon cover and microwaved 200°C for 1h with power controlled instrument set to max. 600W. Novel nano-composite supported; Fe3O4@SiO2(CH2)3NHArN(CH2PPh2)2 and Fe3O4@SiO2(CH2)3N(CH2PPh2)2 type bis(diphenylphosphinomethyl)amino ligands and their Pd(II) complexes have been synthesized and characterized with FT-IR, SEM, EDX, TEM, UV-Visible, XRD and TG/DTA techniques. All the complexes were used as heterogeneous catalysts in the oxidation of 2-methyl naphthalene (2MN) to 2-methyl-1, 4-naphthoquinone (vitamin K3, menadione, 2MNQ) in the presence of hydrogen peroxide and acetic acid. Selectivity reached about 55-60% with a conversion of 90-96% using the nano-magnetite supported aminomethylphosphine-Pd(II) complexes. The complexes were very active in three times in the catalytic recycling experiments in five catalytic cycles.


Subject(s)
Coordination Complexes/chemical synthesis , Ferric Compounds/chemical synthesis , Nanocomposites , Silicon Dioxide/chemical synthesis , Spectroscopy, Fourier Transform Infrared/methods , Vitamin K 3/chemical synthesis , Catalysis , Oxidation-Reduction
6.
Org Lett ; 16(12): 3320-3, 2014 Jun 20.
Article in English | MEDLINE | ID: mdl-24918110

ABSTRACT

A sequential Diels-Alder reaction/silicon-directed [4 + 2]-annulation was developed to assemble hydroisochromene-type ring systems from menadione 2. In the first step, a Diels-Alder of the 1-silyl-substituted butadiene 1 with 2 furnished an intermediate cyclic allylsilane. Subsequently, TMSOTf promoted a [4 + 2]-annulation through trapping of an oxonium, generated by condensation between an aldehyde and the TBS protected alcohol resulted in the formation of a cis-fused hydroisochromene 13.


Subject(s)
Alkenes/chemistry , Benzopyrans/chemical synthesis , Silanes/chemistry , Vitamin K 3/chemical synthesis , Aldehydes/chemistry , Benzopyrans/chemistry , Butadienes/chemistry , Cycloaddition Reaction , Molecular Structure , Polyenes/chemistry , Stereoisomerism , Vitamin K 3/chemistry
7.
Org Biomol Chem ; 11(36): 6108-12, 2013 Sep 28.
Article in English | MEDLINE | ID: mdl-23921718

ABSTRACT

Amphiphilic calix[4]arenes were designed as phospholipid mimics by incorporating PO3H2 or NMe3(+) head groups. Using PC12 cells and three stressors (H2O2, menadione and glutamate), we established safe calix[4]arene levels that are able not only to deliver antioxidant payloads of curcumin, but intriguingly also have inherent antioxidant properties. The calix[4]arenes appear to be potent synthetic antioxidants that could be used as nano-carriers for drug delivery.


Subject(s)
Antioxidants/chemistry , Calixarenes/chemistry , Drug Delivery Systems , Micelles , Phenols/chemistry , Phospholipids/chemistry , Animals , Antioxidants/chemical synthesis , Antioxidants/metabolism , Calixarenes/chemical synthesis , Calixarenes/metabolism , Glutamic Acid/chemical synthesis , Glutamic Acid/chemistry , Glutamic Acid/metabolism , Hydrogen Peroxide/chemical synthesis , Hydrogen Peroxide/chemistry , Hydrogen Peroxide/metabolism , Molecular Structure , PC12 Cells , Phenols/chemical synthesis , Phenols/metabolism , Phospholipids/chemical synthesis , Phospholipids/metabolism , Rats , Reactive Oxygen Species/metabolism , Surface-Active Agents/chemical synthesis , Surface-Active Agents/chemistry , Surface-Active Agents/metabolism , Vitamin K 3/chemical synthesis , Vitamin K 3/chemistry , Vitamin K 3/metabolism
8.
Dalton Trans ; 41(32): 9633-8, 2012 Aug 28.
Article in English | MEDLINE | ID: mdl-22797675

ABSTRACT

Well hexagonally ordered NbSBA-15 catalysts synthesized by an efficient hydrothermal method were used, for the first time, for the selective synthesis of vitamin K(3) by liquid-phase oxidation of 2-methyl-1-naphthol (2MN1-OH) under various reaction conditions. The recyclable NbSBA-15 catalysts were also reused to find their catalytic activities. To investigate the leaching of non-framework niobium species on the surface of silica networks, the results of original and recyclable NbSBA-15 catalysts were correlated and compared. To find an optimum condition for the selective synthesis of vitamin K(3), the washed NbSBA-15(2.2pH) was extensively used in this reaction with various reaction parameters such as temperature, time and ratios of reactant (2M1N-OH to H(2)O(2)), and the obtained results were also demonstrated. Additionally, the liquid-phase oxidation of 2M1N-OH was carried out with different solvents to find the best solvent with a good catalytic activity. Based on the all catalytic studies, the vitamin K(3) selectivity (97.3%) is higher in NbSBA-15(2.2pH) than that of other NbSBA-15 catalysts, and the NbSBA-15(2.2pH) is found to be a highly active and eco-friendly heterogeneous catalyst for the selective synthesis of vitamin K(3).


Subject(s)
Naphthols/chemistry , Niobium/chemistry , Silicon Dioxide/chemistry , Vitamin K 3/chemical synthesis , Catalysis , Oxidation-Reduction , Porosity , Temperature
9.
Org Biomol Chem ; 10(24): 4795-806, 2012 Jun 28.
Article in English | MEDLINE | ID: mdl-22618151

ABSTRACT

Menadione is the 2-methyl-1,4-naphthoquinone core used to design potent antimalarial redox-cyclers to affect the redox equilibrium of Plasmodium-infected red blood cells. Exploring the reactivity of fluoromethyl-1,4-naphthoquinones, in particular trifluoromenadione, under quasi-physiological conditions in NADPH-dependent glutathione reductase reactions, is discussed in terms of chemical synthesis, electrochemistry, enzyme kinetics, and antimalarial activities. Multitarget-directed drug discovery is an emerging approach to the design of new antimalarial drugs. Combining in one single 1,4-naphthoquinone molecule, the trifluoromenadione core with the alkyl chain at C-3 of the known antimalarial drug atovaquone, revealed a mechanism for CF(3) as a leaving group. The resulting trifluoromethyl derivative 5 showed a potent antimalarial activity per se against malarial parasites in culture.


Subject(s)
Antimalarials/chemical synthesis , Enzyme Inhibitors/chemical synthesis , Fluorine Compounds/chemical synthesis , Glutathione Reductase/antagonists & inhibitors , Vitamin K 3/chemical synthesis , Antimalarials/pharmacology , Biocatalysis , Drug Design , Enzyme Inhibitors/pharmacology , Fluorine Compounds/pharmacology , Humans , Molecular Structure , Oxidation-Reduction , Plasmodium falciparum/drug effects , Plasmodium falciparum/enzymology , Structure-Activity Relationship , Vitamin K 3/pharmacology
10.
Bioorg Med Chem ; 18(17): 6305-9, 2010 Sep 01.
Article in English | MEDLINE | ID: mdl-20688522

ABSTRACT

Ten vitamin K(3) derivatives were synthesized and screened for anti-angiogenic activity. Results indicated that amine derivatives (1a-d) exerted a stronger inhibition effect on angiogenesis compared to alkyl derivatives (2a-d). In addition to being the most potent inhibitor, 1b also suppressed human umbilical vein endothelial cell tube formation and proliferation. These results suggest that vitamin K(3) amine derivatives with shorter alkyl chains, such as 1b, could be useful for developing anti-angiogenic agents.


Subject(s)
Angiogenesis Inhibitors/chemical synthesis , Angiogenesis Inhibitors/pharmacology , Vitamin K 3/analogs & derivatives , Vitamin K 3/pharmacology , Animals , Aorta/cytology , Aorta/drug effects , Cell Proliferation/drug effects , Cells, Cultured , Endothelial Cells/drug effects , Humans , Male , Rats , Rats, Wistar , Vitamin K 3/chemical synthesis
12.
Biochim Biophys Acta ; 1787(6): 601-8, 2009 Jun.
Article in English | MEDLINE | ID: mdl-19265668

ABSTRACT

2-methyl-1,4-naphtoquinone 1 (vitamin K(3), menadione) derivatives with different substituents at the 3-position were synthesized to tune their electrochemical properties. The thermodynamic midpoint potential (E(1/2)) of the naphthoquinone derivatives yielding a semi radical naphthoquinone anion were measured by cyclic voltammetry in the aprotic solvent dimethoxyethane (DME). Using quantum chemical methods, a clear correlation was found between the thermodynamic midpoint potentials and the calculated electron affinities (E(A)). Comparison of calculated and experimental values allowed delineation of additional factors such as the conformational dependence of quinone substituents and hydrogen bonding which can influence the electron affinities (E(A)) of the quinone. This information can be used as a model to gain insight into enzyme-cofactor interactions, particularly for enzyme quinone binding modes and the electrochemical adjustment of the quinone motif.


Subject(s)
Vitamin K 3/analogs & derivatives , Crystallography, X-Ray , Electrochemistry , Hydrogen Bonding , Magnetic Resonance Spectroscopy , Molecular Conformation , Molecular Structure , Thermodynamics , Vitamin K 3/chemical synthesis , Vitamin K 3/chemistry
13.
Bioorg Med Chem Lett ; 12(19): 2729-32, 2002 Oct 07.
Article in English | MEDLINE | ID: mdl-12217364

ABSTRACT

Novel vitamin K(3) analogues were synthesized and evaluated for their anticancer activity. Compound 6, 9, 10, 11, 14, and (+/-)15 demonstrated a strong inhibitory activity against the tumor cells of A-549, Hep G2, MCF7, MES-SA, MES-SA/Dx5, MKN45, SW-480, and TW-039. Compound (+/-)15 displayed potent tumor cell cytotoxicity, and compound 14 selectively affected MCF7, even though it did not influence normal cells Detroit551 and WI-38. Compound (+/-)15 inhibited MES-SA and MES-SA/Dx5, and this specific result shows that compound (+/-)15 may become a good anticancer drug candidate.


Subject(s)
Antineoplastic Agents/pharmacology , Vitamin K 3/analogs & derivatives , Vitamin K 3/pharmacology , Antineoplastic Agents/chemical synthesis , Genes, MDR , Humans , Indicators and Reagents , Tumor Cells, Cultured , Vitamin K 3/chemical synthesis
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