- Synthesis and bioactivity investigation of quinone-based dimeric cationic triazolium amphiphiles selective against resistant fungal and bacterial pathogens
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A series of synthetic dimeric cationic anthraquinone analogs (CAAs) with potent antimicrobial activities against a broad range of fungi and bacteria were developed. These compounds were prepared in 2–3 steps with high overall yield and possess alkyl chain, azole, quinone, and quaternary ammonium complexes (QACs). In vitro biological evaluations reveal prominent inhibitory activities of lead compounds against several drug-susceptible and drug-resistant fungal and bacterial strains, including MRSA, VRE, Candida albicans and Aspergillus flavus. Mode of action investigation reveals that the synthesized dimeric CAA's can disrupt the membrane integrity of fungi. Computational studies reveal possible designs that can revive the activity of QACs against drug-resistant bacteria. Cytotoxicity assays in SKOV-3, a cancer cell line, show that the lead compounds are selectively toxic to fungi and bacteria over human cells.
- Shrestha, Jaya P.,Baker, Coleman,Kawasaki, Yukie,Subedi, Yagya P.,Vincent de Paul, Nzuwah Nziko,Takemoto, Jon Y.,Chang, Cheng-Wei Tom
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- Synthesis, characterization, and reaction studies of pd(Ii) tripeptide complexes
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The aqueous synthesis of Pd(II) complexes with alkylated tripeptides led to the hydrolysis of the peptides at low pH values and mixtures of complexed peptides were formed. A non-aqueous synthetic route allowed the formation and isolation of single products and their characterization. Pd(II) complexes with α-Asp(OR)AlaGly(OR), β-Asp(OR)AlaGly(OR), and TrpAlaGly(OR) (R = H or alkyl) as tri and tetradentate chelates were characterized. The tridentate coordination mode was accompanied by a fourth monodentate ligand that was shown to participate in both ligand exchange reactions and a direct removal to form the tetradentate coordination mode. The tetradentate coordination revealed a rare a hemi labile carbonyl goup coordination mode to Pd(II). Reactivity with small molecules such as ethylene, acids, formate, and episulfide was investigated. Under acidic conditions and in the presence of ethylene; acetaldehyde was formed. The Pd(II) is a soft Lewis acid and thiophilic and the complexes abstract sulfur from episulfide at apparent modest catalytic rates. The complexes adopt a square planar geometry according to a spectroscopic analysis and DFT calculations that were employed to evaluate the most energetically favorable coordination geometry and compared with the observed infrared and NMR data.
- Bjornsson, Ragnar,Monger, Lindsey J.,Razinkov, Dmitrii,Suman, Sigridur G.
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- Lysine Ethylation by Histone Lysine Methyltransferases
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Biomedicinally important histone lysine methyltransferases (KMTs) catalyze the transfer of a methyl group from S-adenosylmethionine (AdoMet) cosubstrate to lysine residues in histones and other proteins. Herein, experimental and computational investigations on human KMT-catalyzed ethylation of histone peptides by using S-adenosylethionine (AdoEth) and Se-adenosylselenoethionine (AdoSeEth) cosubstrates are reported. MALDI-TOF MS experiments reveal that, unlike monomethyltransferases SETD7 and SETD8, methyltransferases G9a and G9a-like protein (GLP) do have the capacity to ethylate lysine residues in histone peptides, and that cosubstrates follow the efficiency trend AdoMet>AdoSeEth>AdoEth. G9a and GLP can also catalyze AdoSeEth-mediated ethylation of ornithine and produce histone peptides bearing lysine residues with different alkyl groups, such as H3K9meet and H3K9me2et. Molecular dynamics and free energy simulations based on quantum mechanics/molecular mechanics potential supported the experimental findings by providing an insight into the geometry and energetics of the enzymatic methyl/ethyl transfer process.
- Al Temimi, Abbas H. K.,Martin, Michael,Meng, Qingxi,Lenstra, Danny C.,Qian, Ping,Guo, Hong,Weinhold, Elmar,Mecinovi?, Jasmin
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p. 392 - 400
(2019/11/13)
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- Tuning the biological activity of cationic anthraquinone analogues specifically toward Staphylococcus aureus
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Development of new antibacterial agents against drug resistant bacteria is an imminent task, especially against methicillin-resistant Staphylococcus aureus (MRSA). While MRSA can still be treated with broad spectrum antibiotics, the use of which often leads to the disruption of normal microbial flora leading to Clostridium difficile infection (CDI). Herein, a new class of antibacterial agent, cationic anthraquinone analogues specifically against MRSA, has been developed. Through the variation and optimization of substituents, these agents are selective toward MRSA, and not Gram negative bacteria which may avoid the problem of CDI. In addition, newly discovered lead compounds also show significantly reduced cytotoxicity against normal mammalian cells than cancerous cells. This interesting finding can alleviate the toxicity and side effect problems often associate with the use of antibiotics.
- Subedi, Yagya Prasad,Alfindee, Madher N.,Shrestha, Jaya P.,Chang, Cheng-Wei Tom
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p. 683 - 690
(2018/08/23)
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- A continuous preparation method of triflic acid ethyl ester
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A disclosed method for continuously preparing ethyl trifluoromethanesulfonate comprises the following steps: (1) adding trifluoromethanesulfonic acid and diethyl sulfate with the molar ratio of (1-2):1 into a reaction kettle, switching on a stirring apparatus, raising the temperature of the reaction kettle to 50-100 DEG C, and keeping the temperature for reacting for 2-6 h; and (2) raising the temperature of the reaction kettle to 100-150 DEG C, switching on a rectifying apparatus, controlling the reflux ratio of the rectifying apparatus at (1-3):(3-1), continuously introducing trifluoromethanesulfonic acid and diethyl sulfate into the reaction kettle, controlling the speed of trifluoromethanesulfonic acid introduced into the reaction kettle at 30-70 g/min, controlling the speed of diethyl sulfate introduced into the reaction kettle at 10-50 g/min, and collecting a distillation fraction and condensing to obtain ethyl trifluoromethanesulfonate. The preparation method is short in production period and low in energy consumption, and prepared ethyl trifluoromethanesulfonate has the purity larger than 99%, the yield is 90% or more, and industrialized production can be realized.
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Paragraph 0018; 0019
(2017/02/09)
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- Anthraquinone Analogs
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Anthraquinone analogs, methods for synthesizing anthraquinone analogs, and methods for inhibiting growth of one or more types of cells using anthraquinone analogs. Anthraquinone analogs can be synsthesized according to methods described herein. Optionally, the synthesis methods described herein include choosing an appropriate leaving group for selectively producing 1-alkyl-1H-naphtho[2,3-d]triazole-4,9-diones or 2-alkyl-2H-naphtho[2,3-d]triazole-4,9-diones. Anthraquinone analogs can include various functional groups that affect their ability to inhibit the growth of various cell types. For example, some anthraquinone analogs disclosed herein have antimicrobial activity while seemingly similar compounds demonstrate anticancer activity but lesser antimicrobial activity.
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Page/Page column 17
(2012/03/09)
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- Library synthesis and antibacterial investigation of cationic anthraquinone analogs
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We report the parallel synthesis of a series of novel 4,9-dioxo-4,9- dihydro-1H-naphtho[2,3-d][1,2,3]triazol-3-ium chloride salts, which are analogs to cationic anthraquinones. Three synthetic protocols were examined leading to a convenient and facile library synthesis of the cationic anthraquinone analogs that contain double alkyl chains of various lengths (C2-C 12) at N-1 and N-3 positions. The antibacterial activities of these compounds were evaluated against Gram-positive bacterium Staphylococcus aureus and Gram-negative bacterium Escherichia coli. The antibacterial activities of these compounds were expected to be associated with the structural features of naphthoquinone, cation and lypophilic alkyl chain and, interestingly, they showed much higher levels of antibacterial activities against G+ than G- bacteria. In addition, when the total number of carbon atoms of the alkyl groups at both N-1 and N-3 positions lies between 9 and 18, the bactericidal activity against S. aureus increased with increasing alkyl chain length at both N-atoms with MIC ≥ 1 μg/mL.
- Fosso, Marina Y.,Chan, Ka Yee,Gregory, Rylee,Chang, Cheng-Wei Tom
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experimental part
p. 231 - 235
(2012/05/20)
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- A convenient synthesis of triflate anion ionic liquids and their properties
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A solvent- and halogen-free synthesis of high purity triflate ionic liquids via direct alkylation of organic bases (amines, phosphines or heterocyclic compounds) with methyl and ethyl trifluoromethanesulfonate (methyl and ethyl triflate) has been developed. Cheap and non-toxic dimethyl and diethyl carbonate serve as source for the methyl and ethyl groups in the preparation of methyl and ethyl triflate by this invented process. The properties of ionic liquids containing the triflate anion are determined and discussed.
- Ignat'ev, Nikolai V.,Barthen, Peter,Kucheryna, Andryi,Willner, Helge,Sartori, Peter
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experimental part
p. 5319 - 5338
(2012/08/28)
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- Mode of action investigation for the antibacterial cationic anthraquinone analogs
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Reported previously by our group, we have developed a novel class of antibacterial cationic anthraquinone analogs with superb potency (MIC 1 μg/mL) against Gram positive (G+) pathogens including Methicillin-resistant Staphylococcus aureus (MRSA). However, most of these compounds only manifest modest antibacterial activity against Gram negative (G-) bacteria. Further investigation on the antibacterial mode of action using fluorogenic dyes reveals that these compounds exert two different modes of action that account for the difference in their antibacterial profile. It was found that most of the compounds exert their antibacterial activity by disrupting the redox processes of bacteria. At high concentration, these compounds can also act as membrane disrupting agents. This information can help to design new therapeutics against various bacteria.
- Chan, Ka Yee,Zhang, Jianjun,Chang, Cheng-Wei Tom
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supporting information; experimental part
p. 6353 - 6356
(2011/12/02)
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- Synthesis of enantiopure 1-r-alkyl-2-c,5-t-diphenylphospholanes and phospholanium salts through direct alkylation of phospholane
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Chiral enantiopure 1-alkyl-2,5-diphenylphospholanium salts were obtained in one step through alkylation of phospholane with alkyl triflates. The resulting air-stable phosphonium salts are electron-rich trialkylphosphane precursor ligands for transition metals, and they offer a convenient route toward chiral quaternary phosphonium salts as phase-transfer agents. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.
- Dobrota, Cristian,Duraud, Amelie,Toffano, Martial,Fiaud, Jean-Claude
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body text
p. 2439 - 2445
(2009/04/10)
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- Transannular and intermolecular interactions between chalcogen atoms: Syntheses and properties of dichalcogena dications and trichalcogena hypervalent dications
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Intramolecular (transannular) and intermolecular through-space interactions between chalcogen atoms have been described. This account includes the following three topics. (1) Various types of bis-chalcogenides and their mono-oxides, which have the two chalcogen atoms in close proximity in a molecule, give the dichalcogena dications upon the oxidation with two equivalents of NOBF4 or treatment with one equivalent of triflic anhydride (Tf2O). The stability of the dichalcogena dications increases in the order S N1 type reaction to form chalcogenachalcogenonium salts and alkyl cations. (2) The reaction of 2,6-bis[(phenylthio- or phenylseleno)methyl]phenyl phenyl telluride or the corresponding Te-oxide with NOBF4 or Tf2O affords the positively-charged hypervalent species, dicationic telluranes. Dicationic telluranes can be prepared by the remote oxidation through π-conjugation. The stable sulfenium cation can be isolated by taking advantage of 2,6-bis[(dimethylamino)methyl]phenyl ligand. (3) The remote oxygen migration and Pummerer reactions of p-bis(methylthio)-aromatic mono-oxides are discussed in light of an intermolecular through-space interaction between sulfur atoms, and a cyclic bis(dithia dication) dimer is proposed as an intermediate.
- Furukawa, Naomichi,Kobayashi, Kenji,Sato, Soichi
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p. 116 - 126
(2007/10/03)
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- Unusually facile dealkylation of alkyl 2-(methylthiomethyl)phenyl sulfoxides with triflic anhydride via dithia dications: Stereochemical and kinetic studies
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Alkyl 2-(methylthiomethyl)phenyl sulfoxides undergo facile monodealkylation on treatment with triflic anhydride in CH3CN to afford the corresponding thiasulfonium salts and alkyl iminium salts quantitatively. The dealkylation proceeds by an S(N)1 process which gives thiasulfonium salt and alkyl cation via an initial formation of the corresponding dithia dication species.
- Naka, Hiroyuki,Maruyama, Tetsushi,Sato, Soichi,Furukawa, Naomichi
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p. 345 - 348
(2007/10/03)
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- Scavenger assisted combinatorial process for preparing libraries of tertiary amine compounds
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This invention relates to a novel solution phase process for the preparation of tertiary amine combinatorial libraries. These libraries have utility for drug discovery and are used to form wellplate components of novel assay kits.
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- Activation and facile dealkylation of monooxides of 1,8-bis(alkylthio)naphthalene and 2,2′-bis(alkylthio)biphenyl with triflic anhydride via dithiadications
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Dithiadications bearing 1,8-bis(alkylthio)naphthalene 2A(a-e) and 2,2′-bis(alkylthio)biphenyl 2B(a-e) structure undergo either the facile deprotonation from the methyl group or dealkylation from the methylene groups by the triflate anion. Dications 2A(a) and 2B(a) having methyl groups were deprotonated readily to afford cyclic sulfonium salts 3A(a) and 3B(a). However, dithiadications 2A(b-e) and 2B(b-e) having ethyl, propyl, isopropyl and benzyl groups were readily dealkylated even at -45°C to give thiasulfonium salts 4A(b-e) and 4B(b-e) and alkyl triflates 5(a-e) in good yields. The intermediary formation of dithiadications 2A(a-e) and 2B(a-e) were confirmed by direct observation using NMR spectroscopy, D-labelled experiments and trapping experiments.
- Shima, Hidetaka,Kobayashi, Ryoji,Furukawa, Naomichi
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p. 437 - 438
(2007/10/03)
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- Formation of sulfinate esters in the synthesis of triflates
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On standard treatment of sterically congested alcohols and phenols with triflic anhydride in the presence of amines, trifluoromethanesulfinyl esters were unexpectedly found. Depending on the reaction conditions and the structures of both hydroxy compound and base, esterified products (yields 5% to 99%) containing 0% to 89% (!) of sulfinates were obtained. The mechanisms of these reactions are discussed. The results of the present study indicate how to avoid unwanted sulfinate formation in triflate synthesis.
- Netscher, Thomas,Bohrer, Patrick
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p. 8359 - 8362
(2007/10/03)
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- Activation and facile dealkylation of monooxides of 2,2′-bis(alkylthio)biphenyl with triflic anhydride via dithiadications: A new method for preparation of thiasulfonium salts
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Monooxides of 2,2′-bis(alkylthio)biphenyl undergo facile monodealkylation on treatment with triflic anhydride to afford the corresponding thiasulfonium salts except bis(methylthio) derivative. The reaction proceeds via an initial formation of the corresponding dithiadications.
- Shima, Hidetaka,Kobayashi, Ryoji,Nabeshima, Tatsuya,Furukawa, Naomichi
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p. 667 - 670
(2007/10/02)
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- A large-scale preparation of (3S,4S)-3-(tert-butoxycarbonyl)amino-4-methylpyrrolidine and its analogs from L-aspartic acid
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(3S,4S)-3-(tert-Butoxycarbonyl)amino-4-methylpyrrolidine (12a) was synthesized from L-aspartic acid (4) on a large scale. Methylation of dimethyl (2S)-N-benzyl-N-(9-phenylfluoren-9-yl)aspartate (5), easily derived from 4, with methyl iodide gave (3R)-3-methylaspartate (6a) in 91% yield with high diastereoselectivity. Reduction of 6a with lithium aluminum hydride, followed by hydrogenolysis, protection with di-tert-butyl dicarbonate, and mesylation gave 10a in 89% overall yield. Subsequently, reaction of 10a with benzylamine under a nitrogen atmosphere at room temperature, followed by hydrogenolysis, gave the target compound (12a) in 65% overall yield. In a similar manner to that described for the preparation of 12a from 5, compound 5 was converted into 4-ethyl and 4-propyl derivatives (12b,c) in 34% and 38% overall yields.
- Yoshida, Toshihiko,Takeshita, Makoto,Orita, Hitomi,Kado, Noriyuki,Yasuda, Shingo,Kato, Hideo,Itoh, Yasuo
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p. 1128 - 1131
(2007/10/03)
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- SYNTHESIS OF TRIFLATE AND CHLORIDE SALTS OF ALKYL N,N-BIS(2,2,2-TRIFLUOROETHYL)AMINES
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Triflate and chloride salts have been prepared in high yield by using the triflate displacement reaction.
- Anderson, Gloria L.,Harruna, Issifu
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p. 111 - 114
(2007/10/02)
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- Reactions of the Readily Accessible Electrophile, Trifluoroacetyl Triflate: A Very Reactive Agent for Trifluoroacetylations at Oxygen, Nitrogen, Carbon, or Halogen Centers
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Trifluoroacetyl triflate (TFAT) is readily prepared in 82percent yield by the dehydration (phosphorus pentoxide) of a 2:1 mixture of trifluoroacetic acid and trifluoromethanesulfonic (triflic) acid.Reactions of this highly electrophilic trifluoroacetylating reagent with alcohols, ketones, ethers, amines, and pyridines give esters, enol esters, ether cleavage, amides, and acylpyridinium ions, respectively.Reactions with ionic or easily ionizable alkyl halides give the very volatile trifluoroacetyl halides and the ionic triflate.Triphenylmethyl chloride, for example, is quantitatively converted to triphenylcarbenium triflate in a very convenient synthetic procedure.Trifluoroacetyl triflate is used in the synthesis of the first member of a new class of pyrylium salts, 2,6-dimethoxypyrylium triflate.
- Forbus, T. R.,Taylor, S. L.,Martin, J. C.
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p. 4156 - 4159
(2007/10/02)
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- Synthesis of 1-Substituted-7-hydroxyquinolinium Salts
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The reaction of 7-acetoxyquinoline with trifluorosulfonate esters of primary alcohols in methylene chloride or acetonitrile, followed by acid hydrolysis, provides a general synthesis of 1-substituted-7-hydroxyquinolines, whose phenolate anions are fluorescent.
- Ranganathan, N.,Storey, B. T.
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p. 1069 - 1072
(2007/10/02)
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