Search

Discrimination of cancer cells/tissues from normal ones is of critical importance for early diagnosis and treatment of cancers. Herein, we present a new strategy for high-contrast fluorescence diagnosis of cancer cells/tissues based on β-Lapachone (β-Lap, an anticancer agent) triggered ROS (reactive oxygen species) amplification specific in cancer cells/tissues. With the strategy, a wide range of cancer cells/tissues, including surgical tissue specimens harvested from patients, were distinguished from normal ones by using a combination of β-Lap and a Si-rhodamine-based NIR fluorescent ROS probe PSiR3 developed in this work with average tumor-to-normal (T/N) ratios up to 15 in cell level and 24 in tissue level, far exceeding the clinically acceptable threshold of 2.0. What's more, the strategy allowed the fluorescence discrimination of tumor tissues from inflammatory ones based on whether a marked fluorescence enhancement could be induced when treated with PSiR3 and β-Lap/PSiR3 combination, respectively., (© 2021 Wiley-VCH GmbH.)

The respiratory chain of Escherichia coli contains two different types of terminal oxidase that are differentially regulated as a response to changing environmental conditions. These oxidoreductases catalyze the reduction of molecular oxygen to water and contribute to the proton motive force. The cytochrome bo 3 oxidase (cyt bo 3 ) acts as the primary terminal oxidase under atmospheric oxygen levels, whereas the bd-type oxidase is most abundant under microaerobic conditions. In E. coli, both types of respiratory terminal oxidase (HCO and bd-type) use ubiquinol-8 as electron donor. Here, we assess the inhibitory potential of newly designed and synthesized 3-alkylated Lawson derivatives through L-proline-catalyzed three-component reductive alkylation (TCRA). The inhibitory effects of these Lawson derivatives on the terminal oxidases of E. coli (cyt bo 3 and cyt bd-I) were tested potentiometrically. Four compounds were able to reduce the oxidoreductase activity of cyt bo 3 by more than 50 % without affecting the cyt bd-I activity. Moreover, two inhibitors for both cyt bo 3 and cyt bd-I oxidase could be identified. Based on molecular-docking simulations, we propose binding modes of the new Lawson inhibitors. The molecular fragment benzyl enhances the inhibitory potential and selectivity for cyt bo 3 , whereas heterocycles reduce this effect. This work extends the library of 3-alkylated Lawson derivatives as selective inhibitors for respiratory oxidases and provides molecular probes for detailed investigations of the mechanisms of respiratory-chain enzymes of E. coli., (© 2020 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.)

1,4-Naphthoquinones are exceptional building blocks in organic synthesis and have been used to synthesize several well-known pharmaceutically active agents. Herein we report the synthesis, structural characterization, and biological evaluation of new phenylaminosulfanyl-1,4-naphthoquinone derivatives. We evaluated the cytotoxic activity of the synthesized compounds against three human cancer cell lines: A549, HeLa, and MCF-7. Most of the synthesized compounds displayed potent cytotoxic activity. Specifically, compounds 5 e [3,5-dichloro-N-(4-((4-((1,4-dioxo-3-(phenylthio)-1,4-dihydronaphthalen-2-yl)amino)phenyl)sulfonyl)phenyl)benzamide], 5 f [N-(4-((4-((1,4-dioxo-3-(phenylthio)-1,4-dihydronaphthalen-2-yl)amino)phenyl)sulfonyl)phenyl)-3,5-dinitrobenzamide], and 5 p [N-(4-((4-((1,4-dioxo-3-(phenylthio)-1,4-dihydronaphthalen-2-yl)amino)phenyl)sulfonyl)phenyl)thiophene-2-carboxamide] showed remarkable cytotoxic activity. The synthesized compounds showed low toxicity in normal human kidney HEK293 cells. The cytotoxic mechanism of compounds 5 e, 5 f, and 5 p was explored in MCF-7 cells. The results confirmed that these three compounds induce apoptosis and arrest the cell cycle at the G 1 phase. In addition, compounds 5 e, 5 f, and 5 p were found to induce apoptosis via upregulation of caspase-3 and caspase-7 proteins as well as by upregulation of the gene expression levels of caspases-3 and -7. Our findings demonstrate that compounds 5 e, 5 f, and 5 p could be potent agents against a number of cancer types., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

This work reports a combination of aryl diselenides/hydrogen peroxide and carbon-nanotube (CNT)/rhodium nanohybrids (RhCNT) for naphthol oxidation towards the synthesis of 1,4-naphthoquinones and evaluation of their relevant trypanocidal activity. Under a combination of (PhSe) 2 /H 2 O 2 in the presence of O 2 in iPrOH/hexane, several benzenoid (A-ring)-substituted quinones were prepared in moderate to high yields. We also studied the contribution of RhCNT as co-catalyst in this process and, in some cases, yields were improved. This method provides an efficient and versatile alternative for preparing A-ring-modified naphthoquinonoid compounds with relevant biological profile., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Naphthalene oxidation with metal-oxygen intermediates is a difficult reaction in environmental and biological chemistry. Herein, we report that a Mn IV bis(hydroxo) complex, which was fully characterized by various physicochemical methods, such as ESI-MS, UV/Vis, and EPR analysis, X-ray diffraction, and XAS, can be employed for the oxidation of naphthalene in the presence of acid to afford 1,4-naphthoquinone. Redox titration of the Mn IV bis(hydroxo) complex gave a one-electron reduction potential of 1.09 V, which is the most positive potential for all reported nonheme Mn IV bis(hydroxo) species as well as Mn IV oxo analogues. Kinetic studies, including kinetic isotope effect analysis, suggest that the naphthalene oxidation occurs through a rate-determining electron transfer process., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

An efficient annulation involving pyrone addition to a quinone and Dieckmann condensation was developed for rapid assembly of a γ-naphthopyrone monomeric precursor to the bis-naphthoquinone natural product aurofusarin. Dimerization was achieved through Pd II -catalyzed dehydrogenative coupling. Further studies employing asymmetric nucleophilic epoxidation indicate that the atropisomers of aurofusarin and derivatives are not configurationally stable at ambient temperature., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The biological importance of microtubules in mitosis makes them an interesting target for the development of anticancer agents. In this study, a series of novel chalcone-containing shikonin derivatives was designed, synthesized, and evaluated for biological activities. Among them, derivative PMMB-259 [(R)-1-(5,8-dihydroxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-4-methylpent-3-en-1-yl (E)-2-(4-(3-oxo-3-(3-(trifluoromethoxy)phenyl)prop-1-en-1-yl)phenoxy)acetate] was identified as a potent inhibitor of tubulin polymerization. Further investigation confirmed that PMMB-259 can induce MCF-7 cell apoptosis, reduce the mitochondrial transmembrane potential, and arrest the cell cycle at the G 2 /M phase. Moreover, the morphological variation of treated cells was visualized by confocal microscopy. The results, along with docking simulations, further indicated that PMMB-259 can bind well to tubulin at the colchicine site. Overall, these studies may provide a new molecular scaffold for the further development of antitumor agents that target tubulin., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Pluripotent stem cells are uniquely positioned for regenerative medicine, but their clinical potential can only be realized if their tumorigenic tendencies are decoupled from their pluripotent properties. Deploying small molecules to remove remnant undifferentiated pluripotent cells, which would otherwise transform into teratomas and teratomacarcinomas, offers several advantages over non-pharmacological methods. Dioxonapthoimidazolium YM155, a survivin suppressant, induced selective and potent cell death of undifferentiated stem cells. Herein, the structural requirements for stemotoxicity were investigated and found to be closely aligned with those essential for cytotoxicity in malignant cells. There was a critical reliance on the quinone and imidazolium moieties but a lesser dependence on ring substituents, which served mainly to fine-tune activity. Several potent analogues were identified which, like YM155, suppressed survivin and decreased SOX2 in stem cells. The decrease in SOX2 would cause an imbalance in pluripotent factors that could potentially prompt cells to differentiate and hence decrease the risk of aberrant teratoma formation. As phosphorylation of the NF-κB p50 subunit was also suppressed, the crosstalk between phospho-p50, SOX2, and survivin could implicate a causal role for NF-κB signaling in mediating the stem cell clearing properties of dioxonaphthoimidazoliums., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The first total synthesis of hamigerans D, G, L, and N-Q has been accomplished. A convergent approach was used to build the basic tricarbocyclic ring system bearing a 5-6-6 structure. A sequence of oxidative cleavage, homologation, and ring regeneration provided access to the 5-7-6 skeleton of hamigeran G. Based on the biogenetic hypothesis, elegant and highly efficient biomimetic transformations of hamigeran G into hamigerans D, N-Q, and L were achieved., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The first principles design of manmade redox-protein maquettes is used to clarify the physical/chemical engineering supporting the mechanisms of natural enzymes with a view to recapitulate and surpass natural performance. Herein, we use intein-based protein semisynthesis to pair a synthetic naphthoquinone amino acid (Naq) with histidine-ligated photoactive metal-tetrapyrrole cofactors, creating a 100 μs photochemical charge separation unit akin to photosynthetic reaction centers. By using propargyl groups to protect the redox-active para-quinone during synthesis and assembly while permitting selective activation, we gain the ability to employ the quinone amino acid redox cofactor with the full set of natural amino acids in protein design. Direct anchoring of quinone to the protein backbone permits secure and adaptable control of intraprotein electron-tunneling distances and rates., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The first enantioselective total synthesis of griseusin A, griseusin C, 4'-deacetyl-griseusin A, and two non-native counterparts in 11-14 steps is reported. This strategy highlights a key hydroxy-directed CH olefination of 1-methylene isochroman with an α,β-unsaturated ketone followed by subsequent stereoselective epoxidation and regioselective cyclization to afford the signature tetrahydro-spiropyran ring. Colorectal cancer cell cytotoxicities of the final products highlight the impact of the griseusin tetrahydro-spiropyran ring on bioactivity. As the first divergent enantioselective synthesis, the strategy put forth sets the stage for further griseusin mechanism-of-action and SAR studies., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Naphthoquinones are considered privileged structures for anticancer drug molecules. The Heck reaction of 2-hydroxy-1,4-naphthoquinone (lawsone) with 1-bromo-3-methyl-2-butene offered easy access to lapachol. Several naturally occurring linear and angular heterocyclic quinoids (α-lapachone, β-lapachone, dunnione, and related analogues) were prepared from lapachol. Furthermore, we demonstrated that the synthetic naphthoquinones inhibit cell proliferation in human leukemia HL-60 cells. In particular, angular-type derivatives were found to possess moderate cytotoxicity and to elevate the levels of intracellular glutathione disulfide (GSSG). Our work highlights the significant potential of naturally occurring angular-series naphthoquinones as antileukemic agents., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

A new, highly efficient Lewis base catalyst for a practical enantio- and diastereoselective crotylation of unsaturated aldehydes with E- and Z-crotyltrichlorosilanes has been developed. The method was employed as a key step in a novel asymmetric synthesis of bioactive serrulatane diterpene (-)-elisabethadione. Other strategic reactions for setting up the stereogenic centers included anionic oxy-Cope rearrangement and cationic cyclization. The synthetic route relies on simple, high yielding reactions and avoids use of protecting groups or chiral auxiliaries., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Fits like a glove: Separationless and selective electrochemical oxidation of the α-naphthol (α-NAP) isomer yields naphthoquinone species on the surface of multiwalled carbon nanotubes, which can further catalyze the electro-oxidation of NADH and hydrazine at different potentials. The β-NAP isomer failed to show any such electro-oxidation., (Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Ring the changes: the direct cross-coupling of electron-deficient 1,4-benzoquinone or its derivatives with electron-rich alkyl vinyl ethers proceeds in a tandem manner to produce substituted benzene rings with good selectivity and in good to excellent yields. The reaction has the potential for the rapid synthesis of diverse substituted benzene rings as it is not limited by substituent effects., (Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

tert-Butyldimethylsilyltriflate (TBSOTf)/NEt(3) treatment of alkynyl esters tethered to bicycloalkanones led to tricyclic allenoates with total diastereoselectivity for the ring junction. The allenoates result from an intramolecular alkynylogous Mukaiyama aldol reaction promoted by a TBSOTf/NEt(3) dual activation, with key intermediates of silylalkynylketene acetals. This novel methodology was illustrated by a formal total synthesis of (+/-)-hamigeran B.

The first total synthesis of (+)-neomarinone has been achieved by following a concise and convergent route using methyl (R)-lactate and (R)-3-methylcyclohexanone as chiral building blocks. Key steps of the synthesis are the stereocontrolled formation of the two quaternary stereocenters by diastereoselective 1,4-conjugate addition and enolate alkylation reactions, and the construction of the furanonaphthoquinone skeleton by regioselective Diels-Alder reaction between a 1,3-bis(trimethylsilyloxy)-1,3-diene and a bromoquinone. The synthesis proves the relative and absolute stereochemistry of natural neomarinone.

The interesting biological properties of the hamigerans wherein hamigeran B is a potent antiviral agent with low cytotoxicity to host cells make these deceptively simple looking structures challenging synthetic targets. A strategy to hamigeran B evolved wherein the three contiguous stereocenters are established ultimately from a Pd catalyzed asymmetric allylic alkylation (AAA). The latter involves an asymmetric allylation of a non-stabilized ketone enolate in 77 % yield and 93 % ee. By using this process, (S)-5-allyl-2-isopropyl-5-methyl-1-trifluoromethanesulfonyloxycyclopentene becomes available in four steps from 2-methylcyclopentanone. Introduction of the aryl unit by cross-coupling proceeded intermolecularly but failed intramolecularly. On the other hand, reductive removal of the triflate permitted a Heck reaction to effect intramolecular introduction of the aryl ring. The unusual conformational properties of this molecular architecture are revealed by the regioselectivity of the beta-hydrogen elimination in the Heck reaction and the diastereoselectivity of the reduction establishing the stereochemistry of the carbon bearing the isopropyl group. The successful route consists of 15 steps from 2-methylcyclopentanone and dimethylorcinol illustrating the efficiency of the route based upon the Pd AAA.

Novel metal-complex assemblies constructed from the flexible hinge-like ligand H(2)bhnq (H(2)bhnq=2,2'-bi(3-hydroxy-1,4-naphthoquinone)) have been synthesized. The X-ray crystal structures of these compounds reveal that four types of architectures are accessible by variation of the metal ions. In copper(II) compounds 1-3, the chelating bhnq(2-) ions bridge copper(II) centers to form one-dimensional zigzag chains. The chains of 1-3 are arranged by hydrogen-bonding interactions and stacking interactions to produce porous structures. Cobalt(II) and zinc(II) compounds 4 and 5 form one-dimensional helical chains. In 4 and 5, the crystal packing induces spontaneous resolution of the helical chains with chiral cavities formed perpendicular to the helices. Nickel(II) compounds 6 and 7 form cyclic tetramers. The fourth architecture, a dimer (compound 8), is obtained by the reaction of zinc(II) and bhnq(2-) in MeOH. In these compounds, changes of the dihedral angles and the metal-coordination mode of the bhnq(2-) ion induce the structural versatility. The assemblies of the zigzag chains of the copper(II) compounds exhibit reversible vapochromic behavior. UV/Vis, powder X-ray diffraction, EPR, and adsorption isotherm measurements indicate that this vapochromic behavior is based on the hinge-like flexibility of the bhnq(2-) ion.

Chiral racemic vinylcyclohexenes 2, bearing oxygenated substituents and/or a methyl group at the C-5 position of the cyclohexene ring, were submitted to Diels-Alder reactions with enantiomerically pure (SS)-(2-p-tolylsulfinyl)-1,4-naphthoquinone [(+)-1]. The domino cycloaddition/pyrolytic sulfoxide elimination process led to the formation of enantiomerically enriched angularly tetracyclic quinones anti-6 and syn-7, which were obtained from the kinetic resolution of the racemic diene. In all cases, (SS)-(2-p-tolylsulfinyl)-1,4-naphthoquinone reacted from the less hindered face of the more reactive s-cis conformation, to form products in good enantiomeric excesses. Steric effects and torsional interactions in the corresponding approaches account for the observed pi-facial diastereoselectivities at both partners. The usefulness of this methodology is illustrated with the four-step totally asymmetric synthesis of the C-3-oxygenated angucyclinone derivative (-)-8-deoxytetrangomycin 10 in 26% overall yield and with 50% enantiomeric purity.