- Tumor-targeting with novel non-benzoyl 6-substituted straight chain pyrrolo[2,3-d ]pyrimidine antifolates via cellular uptake by folate receptor α and inhibition of de novo purine nucleotide biosynthesis
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A new series of 6-substituted straight side chain pyrrolo[2,3-d]pyrimidines 3a-d with varying chain lengths (n = 5-8) was designed and synthesized as part of our program to provide targeted antitumor agents with folate receptor (FR) cellular uptake specificity and glycinamide ribonucleotide formyltransferase (GARFTase) inhibition. Carboxylic acids 4a-d were converted to the acid chlorides and reacted with diazomethane, followed by 48% HBr to generate the α-bromomethylketones 5a-d. Condensation of 2,4-diamino-6-hydroxypyrimidine 6 with 5a-d afforded the 6-substituted pyrrolo[2,3-d]pyrimidines 7a-d. Hydrolysis and subsequent coupling with diethyl l-glutamate and saponification afforded target compounds 3a-d. Compounds 3b-d showed selective cellular uptake via FRα and -β, associated with high affinity binding and inhibition of de novo purine nucleotide biosynthesis via GARFTase, resulting in potent inhibition against FR-expressing Chinese hamster cells and human KB tumor cells in culture. Our studies establish, for the first time, that a side chain benzoyl group is not essential for tumor-selective drug uptake by FRα.
- Wang, Yiqiang,Cherian, Christina,Orr, Steven,Mitchell-Ryan, Shermaine,Hou, Zhanjun,Raghavan, Sudhir,Matherly, Larry H.,Gangjee, Aleem
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Read Online
- Effects of structural variations of non-ionic surfactants on micellar properties and solubilization: surfactants containing very long hydrocarbon chains
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Polyoxyethylene mono-ethers of dotriacontanol (C32E41) and 4,9-dimethyltritriacontanol (C35E40) have been synthesized. The micellar weights in water at 298K were 4.82 x 105 and 5.90 x 105, the aggregation numbers 212 and 260, and the levels of hydration 290 and 283 mol water mol-1 surfactant, respectively. The solubilization of azobenzene, cortisone acetate, griseofulvin, sulphadiazine, phenylbutazone, betamethasone, tolbutamide, and menaphthone was studied in 2% solutions of the above surfactants. The presence of large micelles did not result in increased solubilization; C32E41 and C35E40 had a lower solubilizing capacity than that of cetomacrogol.
- Arnarson,Elworthy
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Read Online
- Novel (3,5-di-tert-butyl-2-hydroxy-phenylcarbamoyl)-alkanoic acids as potent antioxidants
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A series of novel phenolic antioxidants of amphiphilic structure has been synthesized. Investigations into the influence of aliphatic spacer length and nature of a hydrophilic anchor on the antioxidant activity allowed elucidating certain structure requirements for the membrane-addressed antioxidant designing.
- Lodyato, Vladimir I.,Yurkova, Irina L.,Sorokin, Viktor L.,Shadyro, Oleg I.,Dolgopalets, Vladimir I.,Kisel, Mikhail A.
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Read Online
- Synthesis and antiherpetic activity of novel purine conjugates with 7,8-difluoro-3-methyl-3,4-dihydro-2H-1,4-benzoxazine
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[Figure not available: see fulltext.] A method for the synthesis of novel purine conjugates with 7,8-difluoro-3-methyl-3,4-dihydro-2H-1,4-benzoxazine containing fragments of ω-amino acids with different lengths of the polymethylene chain as a linker has been developed. It was found in experiments in vitro that the obtained compounds are active against the herpes simplex virus type 1, including the acyclovir-resistant strain.
- Andronova, Valeriya L.,Charushin, Valery N.,Galegov, Georgii А.,Krasnov, Victor P.,Levit, Galina L.,Vozdvizhenskaya, Olga А.
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p. 490 - 497
(2021/06/26)
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- SYNTHETIC PROCESSES AND INTERMEDIATES
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The invention provides synthetic processes and synthetic intermediate compounds that can be used to prepare therapeutic conjugates. The invention also provides methods for treating HBV and/or HDV infection in a human by administering a therapeutic conjugate prepared by the synthetic methods of the invention.
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(2021/06/26)
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- Neutrophil-Selective Fluorescent Probe Development through Metabolism-Oriented Live-Cell Distinction
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Human neutrophils are the most abundant leukocytes and have been considered as the first line of defence in the innate immune system. Selective imaging of live neutrophils will facilitate the in situ study of neutrophils in infection or inflammation events as well as clinical diagnosis. However, small-molecule-based probes for the discrimination of live neutrophils among different granulocytes in human blood have yet to be reported. Herein, we report the first fluorescent probe NeutropG for the specific distinction and imaging of active neutrophils. The selective staining mechanism of NeutropG is elucidated as metabolism-oriented live-cell distinction (MOLD) through lipid droplet biogenesis with the help of ACSL and DGAT. Finally, NeutropG is applied to accurately quantify neutrophil levels in fresh blood samples by showing a high correlation with the current clinical method.
- Gao, Min,Lee, Sun Hyeok,Park, Sang Hyuk,Ciaramicoli, Larissa Miasiro,Kwon, Haw-Young,Cho, Heewon,Jeong, Joseph,Chang, Young-Tae
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supporting information
p. 23743 - 23749
(2021/10/14)
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- Defining a minimum pharmacophore for simocyclinone D8 disruption of DNA gyrase binding to DNA
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The increasing occurrence of drug-resistant bacterial infections in the clinic has created a need for new antibacterial agents. Natural products have historically been a rich source of both antibiotics and lead compounds for new antibacterial agents. The natural product simocyclinone D8 (SD8) has been reported to inhibit DNA gyrase, a validated antibacterial drug target, by a unique catalytic inhibition mechanism of action. In this work, we have used a deconstruction-reconstruction approach to prepare analogs of the coumarin subunit of SD8 and evaluated their ability to disrupt binding of the DNA gyrase enzyme to DNA in a surface plasmon resonance assay. This has led to a minimum pharmacophore required for disruption of binding. Springer Science+Business Media 2014.
- Gaskell, Lauren M.,Nguyen, Thuy,Ellis, Keith C.
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p. 3632 - 3643
(2014/08/05)
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- Palladium-catalyzed reduction of acid chlorides to aldehydes with hydrosilanes
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An efficient synthesis of aldehydes from acid chlorides with hydrosilanes as a reducing agent in the presence of a palladium catalyst has been achieved. A simple mixture of commercially available Pd(dba)2 and Mes 3P as a catalyst realized the reduction of various acid chlorides including aliphatic acid chlorides and a, P-unsaturated acid chlorides to the corresponding aldehydes in good to high yields under mild reaction conditions. Georg Thieme Verlag Stuttgart ? New York.
- Fujihara, Tetsuaki,Cong, Cong,Iwai, Tomohiro,Terao, Jun,Tsuji, Yasushi
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supporting information
p. 2389 - 2392
(2013/07/19)
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- Synthesis of novel phytosphingosine derivatives and their preliminary biological evaluation for enhancing radiation therapy
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Eight d-ribo-phytosphingosine derivatives were synthesized from d-ribo-phytosphingosine and diverse acyl chlorides with N,N-diisopropylethylamine in tetrahydrofuran for 1 h at room temperature. Effect of these compounds on IR-induced cell death was evaluated on blood cancer cells (Jurkat). Among these, 3d showed the highest enhancement of radiosensitizing effect.
- Moon, Byung Seok,Park, Moon-Taek,Park, Jeong Hoon,Kim, Sang Wook,Lee, Kyo Chul,An, Gwang Il,Yang, Seung Dae,Chi, Dae Yoon,Cheon, Gi Jeong,Lee, Su-Jae
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p. 6643 - 6646
(2008/09/17)
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- COMPOUNDS
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The invention provides a water-soluble prodrug compound comprising a therapeutically effective moiety coupled via a metabolically cleavable bond to a protein binding moiety, wherein said therapeutically effective moiety has an anticancer, antiinflammatory, antiinfective or antipain effect, said protein binding moiety binds non-covalently to blood proteins, and the protein binding of said compound is at least 100 % higher than that of the therapeutically effective moiety itself, with the exclusion of (i) the monoester of gemcitabine with azelaic acid, (ii) the monoester of dideoxycytidine with 1,12-dodecanedicarboxylic acid, (iii) 2-amino-l,9-dihydro-9(2'-(1-(10-acetyl-decanoyloxy)ethoxymethyl))-guanine, (iv) 5'-cytarabine monoester with 1,4-phenylene diacetic acid, (v) the monoester of metronidazole with 1,4-butanedicarboxylic acid, and (vi) the monoester of metronidazole with 1,6-phenylene diacetic acid; and pre-prodrugs metabolizable thereto.
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(2010/10/20)
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- PROTEIN BINDING COMPOUNDS
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The present invention provides a prodrug compound comprising a therapeutically effective moiety coupled via a metabolically cleavable bond to a blood protein binding moiety.
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Page/Page column 12
(2010/02/11)
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- Synthesis of idebenone; a synthetic analog of coenzyme Q
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Idebenone, a synthetic analog of coenzyme Q, was prepared from the tetramethoxytoluene 2. Two main transformations in this procedure are Friedel-Crafts acylation of 2 to 4 and CAN assisted oxidation of 7 to the quinone 8.
- Jung,Joe,Seong,Park
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p. 2735 - 2741
(2007/10/03)
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- Transformations of higher terpenoids: IV. Synthesis and spectral parameters of glycyrrhetinic acid derivatives containing amino acid fragments
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New glycyrrhetinic acid derivatives containing amino acid and amino ester fragments were synthesized as potential biologically active substances. NMR spectra of the newly synthesized compounds were studied, and assignment of signals of the C8 and C14 carbon atoms in the terpenoid fragment was refined.
- Petrenko,Petukhova,Shakirov,Shul'ts,Tolstikov
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p. 982 - 995
(2007/10/03)
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- Synthesis and intermembrane transfer of pyrene-labelled liponucleotides: Ceramide phosphothymidines
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Phospholipid conjugates of 3'-azido-3'-deoxythymidine (AZT) show activity against human immunodeficiency virus (HIV) in vitro. Here we report on the synthesis and characterization of two pyrene containing conjugates: 2-N-(4-(pyren-1-yl)butanoyl)ceramide 5'-phosphothymidine (Pbs-Cer-P-T) (XII) and 2-N-(10-(pyren-1-yl)decanoyl)ceramide 5'-phosphothymidine (Pds-Cer-P-T) (XIII). These fluorescent labelled conjugates served as model compounds to study incorporation of sphingoliponucleotides into membranes. The complex compounds were prepared by condensation of 3'-acetylthymidine and labelled ceramides using the phosphite triester coupling procedure. UV absorption, fluorimetry as well as 1H-, 31P-, 13C-NMR analyses were used for structure confirmation of the synthesized substances. When incorporated into small unilamellar 1-palmitoyl-2-oleoyl-glycerophosphatidylcholine (POPC) vesicles and incubated with unlabelled acceptor POPC vesicles, the compounds (XII) and (XIII) exhibited spontaneous transfer. Kinetic data suggest that transfer from donor to acceptor vesicles occurred via the intervening aqueous phase. The non-specific lipid transfer protein from bovine liver stimulated the transfer of Pds-Cer-P-T between phospholipid vesicles in a concentration dependent manner. Copyright (C) 1999 Elsevier Science Ireland Ltd.
- Oskolkova, Olga V.,Shvets, Vitaly I.,Hermetter, Albin,Paltauf, Fritz
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- A facile synthesis of 2-substituted isoflavones for immunoassay: Assembly of the isoflavonoid skeleton by means of a novel cyclisation reaction
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For the purpose of the development of immunoassays for wide-scale screening, isoflavones suitable for attachment to a hapten were prepared. A new cyclisation reaction allowed the direct conversion of 2- (acyloxy)deoxybenzoins to 2-alkylisoflavones by treatment with chlorotrimethylsilane and triethylamine in dimethylformamide.
- Pelter, Andrew,Ward, Robert S.,Whalley, Jacqueline L.
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p. 1793 - 1802
(2007/10/03)
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- Design, synthesis, and biochemical evaluation of N-substituted maleimides as inhibitors of prostaglandin endoperoxide synthases
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N-(Carboxyalkyl)maleimides are rapid as well as time-dependent inhibitors of prostaglandin endoperoxide synthase (PGHS). The corresponding N- alkylmaleimides were only time-dependent inactivators of PGHS, suggesting that the carboxylate is critical for rapid inhibition. Several N-substituted maleimide analogs containing structural features similar to those of the nonsteroidal anti-inflammatory drug aspirin were synthesized and evaluated as inhibitors of PGHS. Most of the aspirin-like maleimides inactivated the cyclooxygenase activity of purified ovine PGHS-1 in a time- and concentration-dependent manner similar to that of aspirin. The peroxidase activity of PGHS was also inactivated by the maleimide analogs. The cyclooxygenase activity of the inducible isozyme, i.e., PGHS-2, was also inhibited by these compounds. The corresponding succinimide analog of N-5- maleimido-2-acetoxy-1-benzoic acid did not inhibit either enzyme activity, suggesting that inactivation was due to covalent modification of the protein. The mechanism of inhibition of PGHS-1 by N-(carboxyheptyl)maleimide was investigated. Incubation of apoPGHS-1 with 2 equiv of N-(carboxyheptyl)[3,4- 14C]maleimide led to the incorporation of radioactivity in the protein, but no adduct was detected by reversed-phase HPLC, suggesting that it was unstable to the chromatographic conditions. Furthermore, hematin- reconstituted PGHS-1, which was rapidly inhibited by N- (carboxyheptyl)maleimide, displayed spontaneous regeneration of about 50% of the cyclooxygenase and peroxidase activities, suggesting that the adduct responsible for the inhibition breaks down to regenerate active enzyme. ApoPGHS-1, inhibited by N-(carboxyheptyl)maleimide, did not display regeneration of enzyme activity, but addition of hematin to the inhibited apoenzyme led to spontaneous recovery of about 50% of cyclooxygenase activity. These results suggest that addition of heme leads to a conformational change in the protein which increases the susceptibility of the adduct toward hydrolytic cleavage. ApoPGHS-1, pretreated with N(carboxyheptyl)maleimide, was resistant to trypsin cleavage, suggesting that the carboxylate functionality of the maleimide binds in the cyclooxygenase channel. A model for the interaction of N-(carboxyheptyl)maleimide in the cyclooxygenase active site is proposed.
- Kalgutkar, Amit S.,Crews, Brenda C.,Marnett, Lawrence J.
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p. 1692 - 1703
(2007/10/03)
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- The chemistry of pseudomonic acid. 15. Synthesis and antibacterial activity of a series of 5-alkyl, 5-alkenyl, and 5-heterosubstituted oxazoles
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The synthesis of a range of 5-alkyl, 5-alkenyl, and 5-heterosubstituted 2- (1-normon-2-yl) oxazoles is described. The antibacterial activity was determined as the minimum inhibitory concentration against a range of Gram- positive and Gram-negative organisms using a standard Agar dilution procedure. Compounds possessing an acid functionality directly on, or close to, the ring were found to be of greatly decreased potency, while increasing lipophilicity with greater chain length led to increased potency of these derivatives.
- Brown, Pamela,Davies, David T.,O'Hanlon, Peter J.,Wilson, Jennifer M.
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p. 446 - 457
(2007/10/03)
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- Photosensitive compound
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Photosensitive compounds having preferably a functional group such as --SO2 Cl, --SO3 H, --SO3 R, STR1 (R, R', R" being alkyl) on a terminal benzene or naphthalene ring connected via a methylene group and STR2 moiety are improved in sensitivity to light and thermal stability, and thus useful in a photo resist.
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- Reduction of DDHQ and TCC esters by NaBH4 - Its specificity in the presence of alkyl/aryl esters
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DDHQ/TCC esters 3a-f, 7a-g were prepared either by oxidation of spiroketones 1 with DDQ/o-chloranil or by condensation of acid chloride with DDHQ/TCC. NaBH4 reduction of unsaturated DDHQ 3a-b and TCC 7a-c esters gave the corresponding allylic alcohols in good yield without any observable 1,4-addition products. Reduction of saturated esters 3e,7d, gave the corresponding alcohols. Alkyl esters 5 and 6, methyl benzoate and phenyl benzoate remained unaffected under these reduction conditions. In the reduction of compound 7e containing both alkyl and TCC esters, TCC ester is selectively reduced. Reduction of TCC mono esters 7f-g gave the lactones. The observed facile reduction has been rationalised.
- Kasturi,Pragnacharyulu
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p. 4431 - 4438
(2007/10/02)
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- SYNTHESE DANS LA CHIMIE DES PHENANTHRIDINES. II. PREPARATION D'UNE NOUVELLE SERIE D'ω-(PHENANTHRIDINYL-6) ALCANOATES DE METHYLE OU D'ETHYLE
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A new series of methyl and ethyl ω-(6-phenanthridinyl) alkanoates is easily synthesised from the acid chloride - esters ROCO(CH2)nCOCl (n=0, 3 to 8; R=Me or Et).Reaction of these with o-aminobiphenyl leads to the expected amide-esters which are cyclised to phenanthridines quaternised to the corresponding phenanthridinium salts.
- Lion, C.,Boukou-Poba, J. P.,Charvy, C.
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p. 567 - 574
(2007/10/02)
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- Methotrexate analogues. 34. Replacement of the glutamate moiety in methotrexate and aminopterin by long-chain 2-aminoalkanedioic acids
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Eight previously unreported methotrexate (MTX) and aminopterin (AMT) analogues with the L-glutamate moiety replaced by DL-2-aminoalkanedioic acids containing up to 10 CH2 groups were synthesized from 4-amino-4-deoxy-N10-methylpteroic
- Rosowsky,Bader,Kohler,Freisheim,Moran
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p. 1338 - 1344
(2007/10/02)
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- Synthesis and Absolute Configuration of 2-Hydroxy-12-methyl Tridecanoic Acid
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The synthesis of racemic 2-hydroxy-12-methyl tridecanoic acid is described.The absolute configuration of the two enantiomers has been determined by the method of Dale and Mosher. - Keywords: 2-Hydroxy-12-methyl Tridecanoic Acid, Absolute COnfiguration
- Balzer, Th.,Budzikiewicz, H.
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p. 1367 - 1368
(2007/10/02)
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- 1-O-(13-Methyl-1-Z-tetradecenyl)-2-O-(13-methyltetradecanoyl)-glycero-3-phospho-ethanolamine, a Plasmalogen from Myxococcus stipitatus
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The structure of 1-O-(13-methyl-1-Z-tetradecenyl)-2-O-(13-methyltetradecanoyl)-glycero-3-phospho-ethanolamine isolated from Myxococcus stipitatus has been elucidated. 1H and 13C NMR as well as mass spectral data have been accumulated which allow a ready identification and structure elucidation of compounds of this type. - Keywords: Myxobacteria, Myxococcus stipitatus, Phospholipids, Plasmalogen, Structure Elucidation
- Stein, J.,Budzikiewicz, H.
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p. 1017 - 1020
(2007/10/02)
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- Regioselective Functionalization of Non-Activated CH-bonds, 2. Photochemical Functionalization of the Myristoyl Group in 1,2-Alkanediyl and o-Phenylene 1-(4-Benzoylbenzoate) 2-Myristates
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Myristic acid (1a) was linked with ethylene glycol (2a), trans-1,2-cyclohexanediol (2b), and catechol (2c) to 4-benzoylbencoic acid to form the diesters 4a-c.These cyclize by photolysis to the carbinols 12, which are converted into the methyl 7- to 13-oxomyristates (5a).The ketofunctionalization of the remote CH2-groups in 1a is more selective than in the corresponding benzoylbenzoic esters 13 without the 1,2-alkanediyl or o-phenylene link.Additionally the maximum of the functionalization is shifted from the end towards the middle of the chain.The latter observation can be explained by a higher population of gauche conformations at the beginning of the chain.In CCl4 the selectivity increases slightly from 4a to 4b, c with increasing rigidity of the link.The polarity of the solvent has only a small effect on the selectivity.
- Dors, Bernhard,Luftmann, Heinrich,Schaefer, Hans J.
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p. 761 - 776
(2007/10/02)
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- Studies of Spin Labeled Sodium Dodecyl Sulfate. I. Synthesis and Properties
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Nitroxide spin labeled surfactant, sodium salt of 2-ethyl-2--4,4-dimethyloxazolidin-3-yloxyl, was synthesized and some properties of the compound were studied by means of ESR and conductivity measurements.From conductivity measurements it was found that the critical micelle concentration of the compound was 21.6 mmol kg-1 at 25.0 +/- 0.1 deg C and the micelle consisted of a small number of labeled surfactant ions.The ESR spectra of the labeled surfactant were measured as a function of concentration and temperature.These spectra showed a typical pattern interpreted in terms of spin exchange.Regarding spin exchange as chemical reaction, second order rate constant was determined from the analysis of line width and compared with the values obtained by diffusion controlled model.
- Yamaguchi, Takeo,Yamauchi, Akira,Kimoto, Eiji,Kimizuka, Hideo
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p. 372 - 376
(2007/10/02)
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