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Rational Design and Synthesis of Methyl-β- d -galactomalonyl Phenyl Esters as Potent Galectin-8 N Antagonists
Galectin-8 is a β-galactoside-recognizing protein having an important role in the regulation of bone remodeling and cancer progression and metastasis. Methyl β-d-galactopyranoside malonyl aromatic esters have been designed to target and engage with particular amino acid residues of the galectin-8N extended carbohydrate-binding site. The chemically synthesized compounds had in vitro binding affinity toward galectin-8N in the range of 5-33 μM, as evaluated by isothermal titration calorimetry. This affinity directly correlated with the compounds' ability to inhibit galectin-8-induced expression of chemokines and proinflammatory cytokines in the SUM159 breast cancer cell line. X-ray crystallographic structure determination revealed that these monosaccharide-based compounds bind galectin-8N by engaging its unique arginine (Arg59) and simultaneously cross-linking to another arginine (Arg45) located across the carbohydrate-binding site. This structure-based drug design approach has led to the discovery of novel monosaccharide galactose-based antagonists, with the strongest-binding compound (Kd 5.72 μM) holding 7-fold tighter than the disaccharide lactose.
Patel, Brijesh,Kishor, Chandan,Houston, Todd. A.,Shatz-Azoulay, Hadas,Zick, Yehiel,Vinik, Yaron,Blanchard, Helen
supporting information
p. 11573 - 11584
(2020/12/02)

Design, Synthesis, and Activity Study of Water-Soluble, Rapid-Release Propofol Prodrugs
In this work, a series of water-soluble propofol prodrugs were synthesized, and their propofol release rate and pharmacodynamic characteristics were measured. We found that inserting glycolic acid as a linker between propofol and the cyclic amino acid accelerated the release of propofol from prodrugs into the plasma while preserving its safety. In animal experiments, prodrugs (3e, 3g, and 3j) were significantly better than fospropofol (the only water-soluble propofol prodrug that has been used clinically) in terms of safety, onset, and duration time of anesthesia. Their molar dose, onset time, and anesthesia duration time were comparable to those of propofol, helping to maintain the clinical benefits of propofol. The experimental results showed the potential of such compounds as water-soluble prodrugs of propofol.
Liu, Liang-Quan,Hong, Pei-Xi,Song, Xing-Hai,Zhou, Chang-Cui,Ling, Rui,Kang, Yi,Qi, Qing-Rong,Yang, Jun
supporting information
p. 7857 - 7866
(2020/08/21)

Design and synthesis of Coenzyme A analogues as Aurora kinase A inhibitors: An exploration of the roles of the pyrophosphate and pantetheine moieties
Coenzyme A (CoA) is a highly selective inhibitor of the mitotic regulatory enzyme Aurora A kinase, with a novel mode of action. Herein we report the design and synthesis of analogues of CoA as inhibitors of Aurora A kinase. We have designed and synthesised modified CoA structures as potential inhibitors, combining dicarbonyl mimics of the pyrophosphate group with a conserved adenosine headgroup and different length pantetheine-based tail groups. An analogue with a -SH group at the end of the pantotheinate tail showed the best IC50, probably due to the formation of a covalent bond with Aurora A kinase Cys290.
Bellany, Fiona,Tsuchiya, Yugo,Tran, Trang M.,Chan, A.W. Edith,Allan, Helen,Gout, Ivan,Tabor, Alethea B.
supporting information

(2020/09/16)

Synthesis and characterization of CAPE derivatives as xanthine oxidase inhibitors with radical scavenging properties
Inhibitors of the enzyme xanthine oxidase (XO) with radical scavenging properties hold promise as novel agents against reperfusion injuries after ischemic events. By suppressing the formation of damaging reactive oxygen species (ROS) by XO or scavenging ROS from other sources, these compounds may prevent a buildup of ROS in the aftermath of a heart attack or stroke. To combine these two properties in a single molecule, we synthesized and characterized the non-purine XO inhibitor caffeic acid phenethylester (CAPE) and 19 derivatives using a convenient microwave-assisted Knoevenagel condensation protocol. Varying systematically the number and positions of the hydroxyl groups at the two phenyl rings, we derived structure-activity relationships based on experimentally determined XO inhibition data. Molecular docking suggested that critical enzyme/inhibitor interactions involved π-π interactions between the phenolic inhibitor ring and Tyr914, hydrogen bonds between inhibitor hydroxyl groups and Glu802, and hydrophobic interactions between the CAPE phenyl ring and non-polar residues located at the entrance of the binding site. To effectively scavenge the stable radical DPPH, two hydroxyl groups in 1,2- or 1,4-position at the phenyl ring were required. Among all compounds tested, E-phenyl 3-(3,4-dihydroxyphenyl)acrylate, a CAPE analog without the ethyl tether, showed the most promising properties.
Choi, Wonbeen,Villegas, Valente,Istre, Hannah,Heppler, Ben,Gonzalez, Niki,Brusman, Nicole,Snider, Lindsey,Hogle, Emily,Tucker, Janelle,O?ate, Alma,O?ate, Sandra,Ma, Lili,Paula, Stefan
p. 686 - 695
(2019/03/05)

Design, synthesis and biological screening of N-(substituted pyridine-2-yl)-N-(quinoline-2-yl) malonamide as novel anti-HIV-I agents
A novel series of N1-(substiruted pyridine-2-yl)-N3-(quinoline-2-yl) malonamide derivatives (AK1-AK24) has been rationally designed, synthesized and biologically screened for in vitro anti HIV activity by using reverse transcriptase assay kit (Roche). Out of the synthesized compounds, compound AK1, AK2 and AK3 show potent reverse transcriptase (RT) inhibitor activity and compounds AK4 to AK9, AK11, AK12, AK13 and AK14 show RT inhibitory activity comparable with standard rilpivirine. In docking studies, those compounds show higher G-Score which indicates higher percentage of inhibition of reverse transcriptase during in vitro screening. Insilico pharmacokinetic studies imply that synthesized derivatives have no CYP450 inhibition, no BBB penetration and good oral absorption. Virtual toxicity studies performed by using Toxtree-v 2.6.6 in various computational animal models show high LD50 values and the compounds are found to be non-carcinogenic.
Kashid, Arun Maruti,Dhawale, Shasbikant
p. 870 - 879
(2019/05/21)

Development of catalytic deacylative alkylations (DaA) of 3-acyl-2-oxindoles: total synthesis of meso-chimonanthine and related alkaloids
We present an effective deacylative alkylation strategy for the construction of a variety of 2-oxindoles bearing an all-carbon quaternary center at the pseudobenzylic position. A wide variety of products with quaternary centers could be accessed by employing simple Pd(0) catalysis under mild reaction conditions. Importantly, the same strategy works equally well for the dimeric 2-oxindole system, furnishing products with a vicinal quaternary center in favour of meso-isomer as the major product. Eventual application to the total syntheses of meso-chimonanthine and meso-folicanthine very well demonstrates the synthetic potential of this strategy.
Kumar, Nivesh,Das, Mrinal Kanti,Ghosh, Santanu,Bisai, Alakesh
supporting information
p. 2170 - 2173
(2017/02/19)

Synthesis of 2-oxindoles via 'transition-metal-free' intramolecular dehydrogenative coupling (IDC) of sp2 C-H and sp3 C-H bonds
The synthesis of a variety of 2-oxindoles bearing an all-carbon quaternary center at the pseudo benzylic position has been achieved via a 'transition-metal-free' intramolecular dehydrogenative coupling (IDC). The construction of 2-oxindole moieties was carried out through formation of carbon-carbon bonds using KOt-Bu-catalyzed one pot C-alkylation of β-N-arylamido esters with alkyl halides followed by a dehydrogenative coupling. Experimental evidences indicated toward a radical-mediated path for this reaction.
Kumar, Nivesh,Ghosh, Santanu,Bhunia, Subhajit,Bisai, Alakesh
supporting information
p. 1153 - 1169
(2016/07/06)

Syntheses and evaluation of substituted aromatic hydroxamates and hydroxamic acids that target Mycobacterium tuberculosis
Tuberculosis (TB) continues to remain one of the most threatening diseases in the world. With the emergence of multi-drug resistant (MDR) and extensively drug resistant (XDR) strains, the need to develop new therapies is dire. The syntheses of a focused library of hydroxamates and hydroxamic acids is described, as well as anti-TB activity in the microplate alamar blue assay (MABA). A number of compounds exhibited good activity against Mtb, with notable compounds exhibiting MIC values in the range of 20-0.71 μM. This work suggests that both hydroxamates and their free acids may be incorporated into more complex scaffolds and serve as potential leads for the development of anti-TB agents.
Majewski, Mark W.,Cho, Sanghyun,Miller, Patricia A.,Franzblau, Scott G.,Miller, Marvin J.
supporting information
p. 4933 - 4936
(2015/10/28)

Synthesis and antitumor activity of feruloyl and caffeoyl derivatives This paper is dedicated to Prof. Wei-xiao Hu for his lifelong commitment to mentoring graduate students
We developed two efficient protocols for the synthesis of feruloyl and caffeoyl derivatives from commercial vanillin and veratraldehyde. Pharmacological activities were assessed against a panel of human cancer cell lines in vitro. Most synthesized compounds demonstrated attractive cytotoxicity. Several new compounds demonstrated significant antiproliferative and cytotoxic activities against HeLa and Bewo tumor cell lines. In particular, 5-nitro caffeic adamantyl ester showed broad spectrum of tumor inhibition in 10 cell lines, and reduced tumor weight by 36.7% in vivo when administered at a dose of 40 mg kg-1.
Chen, Hui-Zhen,Chen, You-Bao,Lv, Ya-Ping,Zeng, Fang,Zhang, Juan,Zhou, Yong-Lie,Li, Han-Bing,Chen, Li-Fei,Zhou, Bin-Jie,Gao, Jian-Rong,Xia, Chun-Nian
supporting information
p. 4367 - 4371
(2015/02/06)

DDQ-mediated direct Intramolecular-Dehydrogenative-Coupling (IDC): Expeditious approach to the tetracyclic core of ergot alkaloids
An efficient route to 2-oxindoles bearing an all-carbon quaternary center at the pseudobenzylic position has been developed via a DDQ-mediated Intramolecular-Dehydrogenative-Coupling (IDC). The methodology involves a one-pot C-alkylation of β-N-arylamido esters (7) concomitant with dehydrogenative-coupling in the presence of stoichiometric amount of DDQ. A tentative mechanistic route has been proposed for the oxidative coupling. The methodology provides a two-step entry to the ergoline structure of ergot alkaloids.
Bhunia, Subhajit,Ghosh, Santanu,Dey, Dhananjay,Bisai, Alakesh
supporting information
p. 2426 - 2429
(2013/06/27)

Antimicrobial N-(2-chlorobenzyl)-substituted hydroxamate is an inhibitor of 1-deoxy-d-xylulose 5-phosphate synthase
N-(2-Chlorobenzyl)-substituted hydroxamate, readily produced by hydrolysis of ketoclomazone, was identified as an inhibitor of 1-deoxy-d-xylulose 5-phosphate synthase (DXS), with an IC50 value of 1.0 μM. The compound inhibited the growth of Haemophilus influenzae. A convenient spectroscopic method for assaying DXS using NADPH-lactate dehydrogenase (LDH) is also reported.
Hayashi, Daisuke,Kato, Nobuo,Kuzuyama, Tomohisa,Sato, Yasuo,Ohkanda, Junko
supporting information
p. 5535 - 5537
(2013/07/26)

Design, synthesis, and biological evaluation of novel estradiol-bisphosphonate conjugates as bone-specific estrogens
Bone deficiency causes osteoporosis and often decreases quality of life in patients with rheumatoid arthritis. Estrogens are known to protect elderly women from bone loss. Synthesis of new estradiol-bisphosphonate conjugates (E2-BPs) was accomplished and their in vivo activity as bone-specific estrogens were examined. Among them, MCC-565 showed selective estrogenic activity in bones; but it showed little estrogenic activity in the uterus. We also found that the linker moiety in E2-BPs was essential for the absorption and specificity of the conjugates.
Morioka, Masahiko,Kamizono, Akihito,Takikawa, Hirosato,Mori, Akihisa,Ueno, Hiroaki,Kadowaki, Shu-ichiro,Nakao, Yoshihide,Kato, Kuniki,Umezawa, Kazuo
experimental part
p. 1143 - 1148
(2010/04/24)

Synthesis of bis(tetronic acid)s via double Dieckmann condensation
A practical, straightforward synthesis of several bis(tetronic acid)s from a common precursor, dimethyl l-tartrate, is described. It involves a double Dieckmann condensation using tetrabutylammonium fluoride. The radical scavenging capacities of these compounds are measured. Georg Thieme Verlag Stuttgart - New York.
Thetiot-Laurent, Sophie A.-L.,Nadal, Brice,Le Gall, Thierry
experimental part
p. 1697 - 1701
(2010/07/04)

Synthesis of trans-caffeate analogues and their bioactivities against HIV-1 integrase and cancer cell lines
Forty caffeate analogues were synthesized via a convenient method starting from vanillin with moderate to good yields. The testing of biological activity of these compounds against HIV-1 integrase indicates that four compounds: bornyl caffeate, bornyl 2-nitrocaffeate, 5-nitrocaffeic acid and 5-nitrocaffeic acid phenethyl ester (5-nitroCAPE) possess a good HIV integrase inhibitory activity, IC50 19.9, 26.8, 25.0 and 13.5 μM, respectively. Twelve caffeate analogues were tested by MTT assay on growth of human hepatocellular carcinoma BEL-7404, human breast MCF-7 adenocarcinoma, human lung A549 adenocarcinoma and human gastric cancer BCG823 cell lines, respectively. And the best result is IC50 5.5 μM for CAPE against BEL-7404.
Xia, Chun-nian,Li, Hai-bo,liu, Feng,Hu, Wei-xiao
supporting information; experimental part
p. 6553 - 6557
(2009/09/06)

Polysacchocride prodrug of 5-fluorouracil (5-FU) with enhanced target specificity for galectin-3 expressing cancers
This application discloses embodiments of a novel prodrug and its method of synthesis. The prodrug comprises a galactose-containing polysaccharide covalently linked to 5-fluorouracil (5-FU). The galactose residues that are part of the backbone of the gala
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(2008/06/13)

Novel polysaccharide pro-drug 5-fluorouracil (5-FU) with enhanced target specificity for colorectal cancer and its preparation methods
This invention describes a novel polysaccharide prodrug of 5-fluorouracil (5-FU) with enhanced target specificity for colorectal cancer treatment, and its preparation methods. The prodrug is synthesized by chemically linking anti-cancer drug 5-fluorouraci
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(2008/06/13)

Selective monoesterification of malonic acid catalyzed by boric acid
Boric acid catalyzes the monoesterification of malonic acid, likely through a chelation mechanism that is not available to the monoester product. Under more forcing conditions, diesters form to some extent, but conditions can be optimized to favour the monoester product (56?80%). With the easily handled solid acid catalyst, these reactions can be run with excess alcohol as solvent or with stoichiometric amounts of alcohol in acetonitrile with moderate heating. CSIRO 2007.
Levonis, Stephan M.,Bornaghi, Laurent F.,Houston, Todd A.
p. 821 - 823
(2008/03/12)

One-pot preparation of caffeic acid esters from 3,4-dihydroxybenzaldehyde
A convenient one-pot process for preparing various esters of caffeic acid from 3,4-dihydroxybenzaldehyde has been developed. The alcohols or phenols react with Meldrum's acid to form malonic acid mono-esters, which, without separating, immediately react with 3,4-dihydroxybenzaldehyde to afford the desired esters in good yield. The 1H NMR data and X-ray diffraction analyses indicate that these α,β-unsaturated esters are in trans (E) form in accord with natural esters.
Hu, Wei-Xiao,Xia, Chun-Nian,Wang, Guo-Hong,Zhou, Wei
p. 586 - 588
(2007/10/03)

Aqueous phosphoric acid as a mild reagent for deprotection of tert-butyl carbamates, esters, and ethers
(Chemical Equation Presented) Aqueous phosphoric acid (85 wt %) is an effective, environmentally benign reagent for the deprotection of tert-butyl carbamates, tert-butyl esters, and tert-butyl ethers. The reaction conditions are mild and offer good selectivity in the presence of other acid-sensitive groups, including CBZ carbamates, azetidine, benzyl and methyl esters, TBDMS, and methyl phenyl ethers. The mildness of the reaction is further demonstrated in the synthesis of clarithromycin derivative 4, in which a tert-butyl ester is removed in the presence of cyclic carbamate, lactone, ketal, acetate ester, and epimerizable methyl ketone functionalities. The reaction preserves the stereochemical integrity of the substrates. The reactions are high yielding, and the workup is convenient.
Li, Bryan,Berliner, Martin,Buzon, Richard,Chiu, Charles K.-F.,Colgan, Stephen T.,Kaneko, Takushi,Keene, Nandell,Kissel, William,Le, Tung,Leeman, Kyle R.,Marquez, Brian,Morris, Ronald,Newell, Lisa,Wunderwald, Silke,Witt, Michael,Weaver, John,Zhang, Zhijun,Zhang, Zhongli
p. 9045 - 9050
(2007/10/03)

Synthesis of caffeic acid esters
A new method for the preparation of caffeic acid esters was investigated. Ten caffeic acid esters were prepared by condensation of protocatechualdehyde with malonic acid mono-esters in moderate yield. Malonic acid mono-esters were prepared from the corresponding malonate di-esters. The conformations of compounds are trans (E) form.
Xia, Chun-Nian,Hu, Wei-Xiao
p. 332 - 334
(2007/10/03)

Self-condensation of activated malonic acid half esters: A model for the decarboxylative Claisen condensation in polyketide biosynthesis
The reaction of a malonic acid half oxyester with a N-hydroxysuccinimidyl ester-forming reagent resulted in self-condensation to provide the corresponding 1,3-acetonedicarboxylic acid diester. This new method does not require a divalent metal chelator or a coordinating solvent for successful condensation.
Ryu, Youngha,Scott, A. Ian
p. 7499 - 7502
(2007/10/03)

Synthesis of amphiphilic fullerene derivatives and their incorporation in Langmuir and Langmuir-Blodgett films
Various amphiphilic fullerene derivatives were prepared by functionalization of [5,6]fullerene-C60-Ih (C60) with malonate or bis-malonate derivatives obtained by esterification of the malonic acid mono-esters 5-7. Cyclopropafullerene 10 was obtained by protection of the carboxylic acid function of 6 as a tert-butyl ester, followed by Bingel addition to C60 and a deprotection step (Scheme 2). The preparation of 10 was also attempted directly from the malonic acid mono-ester 6 under Bingel conditions. Surprisingly, the corresponding 3'-iodo-3'H-cyclopropa[1,9][5,6]fullerene-C60-Ih-3'- carboxylate 11 was formed instead of 10 (Scheme 3). The general character of this new reaction was confirmed by the preparation of 15 and 16 from the malonic acid mono-esters 13 and 14, respectively (Scheme 4). All the other amphiphilic fullerene derivatives were prepared by taking advantage of the versatile regioselective reaction developed by Diederich and co-workers which led to macrocyclic bis-adducts of C60 by a cyclization reaction at the C-sphere with bis-malonate derivatives in a double Bingel cyclopropanation. The bis-adducts 37-39 with a carboxylic acid polar head group and four pendant long alkyl chains of different length were prepared from diol 22 and acids 5-7, respectively (Scheme 9). In addition, the amphiphilic fullerene derivatives 45, 46, 49, 54, and 55 bearing different polar head groups and compound 19 with no polar head group were synthesized (Schemes 11 - 13, 15, and 5, resp.). The ability of all these compounds to form Langmuir monolayers at the air-water interface was investigated in a systematic study. The films at the water surface were characterized by their surface pressure vs. molecular area isotherms, compression and expansion cycles, and Brewster-angle microscopy. The spreading behavior of compound 10 was not good, the two long alkyl chains in 10 being insufficient to prevent aggregation resulting from the strong fullerene-fullerene interactions. While no films could be obtained from compound 19 with no polar head group, all the corresponding amphiphilic fullerene bis-adducts showed good spreading characteristics and reversible behavior upon successive compression/expansion cycles. The encapsulation of the fullerene in a cyclic addend surrounded by four long alkyl chains is, therefore, an efficient strategy to prevent the irreversible aggregation resulting from strong fullerene-fullerene interactions usually observed for amphiphilic C60 derivatives at the air-water interface. The balance of hydrophobicity to hydrophilicity was modulated by changing the length of the surrounding alkyl chains or the nature of the polar head group. The best results in terms of film formation and stability were obtained with the compounds having the largest polar head group, i. e. 45 and 46, and dodecyl chains. Finally. the Langmuir films obtained from the amphiphilic fullerene bis-adducts were transferred onto solid substrates, yielding high-quality Langmuir-Blodgett films.
Felder, Delphine,Nava, Manuel Gutierrez,Del Pilar Carreon, Maria,Eckert, Jean-Francois,Luccisano, Michael,Schall, Corinne,Masson, Patrick,Gallani, Jean-Louis,Heinrich, Benoit,Guillon, Daniel,Nierengarten, Jean-Francois
p. 288 - 319
(2007/10/03)

Process for preparation of dicarboxylic acid monoesters
A process for producing a dicarboxylic acid monoester which comprises subjecting a dicarboxylic acid monoester or an alkali metal salt of a dicarboxylic acid monoester and a metal alkoxide to transesterification in the presence of an organic solvent, or a process for producing a dicarboxylic acid monoester which comprises subjecting a dicarboxylic acid monoester or an alkali metal salt of a dicarboxylic acid monoester and an alcohol to transesterification in the presence of a metal alkoxide.
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(2008/06/13)

New trisubstituted cyclopentadienyl ligands: Synthesis, characterisation and catalytic properties of mono and dinuclear cobalt, rhodium, iron and ruthenium complexes
The synthesis of a set of dialkyl 4-alkoxycarbonylcyclopenta-1,3-diene-1,2-diacetates (1a-e) is described. Their coordinating abilities as anions have been investigated in relation to the formation of new sandwich, half-sandwich and dinuclear complexes and their structural features. We report here the preparation and characterisation of some complexes such as a mononuclear half-sandwich cobalt(1,5-COD) complex which has shown to be a very efficient catalyst for the cyclocotrimerisation reaction of alkynes and nitriles to pyridines. Half-sandwich rhodiumdicarbonyl complexes containing trisubstituted cyclopentadienyl ligands with ester chains of different length have been employed successfully as catalysts for hydroformylation of styrene. Finally ligands 1a-e have been used for the synthesis of ferrocenes and dinuclear carbonyl complexes of iron and ruthenium. The structures of the complexes 1,5-cycloctadiene[1-methoxycarbonyl-3,4-di(methoxycarbonylmethylene) cyclopentadienyl]cobalt [Co(MDMCp)COD] (9), dicarbonyl[1-methoxycarbonyl-3,4-di(methoxycarbonylmethylene)cyclopentadienyl] rhodium [Rh(MDMCp)(CO)2] (2a) and of a new ferrocene complex [Fe(MDMCp)2] (15a) have been determined by X-ray diffraction methods.
Costa, Mirco,Dalcanale, Enrico,Dias, Francisco Santos,Graiff, Claudia,Tiripicchio, Antonio,Bigliardi, Lorenzo
p. 179 - 193
(2007/10/03)

Replacement of glycine with dicarbonyl and related moieties in analogues of the C-terminal pentapeptide of cholecystokinin: CCK2 agonists displaying a novel binding mode
Recent advances in the field of cholecystokinin have indicated the possible occurrence of multiple affinity states of the CCK2 receptor. Besides, numerous pharmacological experiments performed 'in vitro' and 'in vivo' support the eventuality of different pharmacological profiles associated to CCK2 ligands. Indeed, some agonists are essentially anxiogenic and uneffective in memory tests, whereas others are not anxiogenic and appear as able to reinforce memory. The reference compound for the latter profile is the CCK-8 analogue BC 264 (Boc-Tyr(SO3H)-gNle-mGly-Trp-(NMe)Nle-Asp-Phe-NH2). However, although tetrapeptide ligands based on CCK-4 (Trp-Met-Asp-Phe-NH2) are known to possess sufficient structural features for CCK2 recognition, none shares the properties of BC 264. Hence we have developed new short peptidic or pseud-opeptidic derivatives containing the C-terminal tetrapeptide of BC 264. Our results indicate that some compounds characterized by the presence of two carbonyl groups at the N-terminus, as in 2b (HO2C-CH2-CONH-Trp-(NMe)Nle-Asp-Phe-NH2), are likely to show a BC 264-like profile, bind to the CCK2 receptor in a specific way, and display remarkable affinities (2b: 0.28 nM on guinea-pig cortex membrane preparations). This original binding mode is discussed and further enlightened by NMR and molecular modeling studies.
Bellier,Million,DaNascimento,Meudal,Kellou,Maigret,Garbay
p. 3614 - 3623
(2007/10/03)

THERAPEUTIC AGENT FOR DIABETES
A therapeutic agent for diabetes, which comprises a compound of the formula [I] wherein Xis a group of the formula wherein R4and R5are the same or different and each is a hydrogen atom, an optionally substituted alkyl having 1 to 5 carbon atoms and the like, and R6is a hydrogen atom or an amino-protecting group; R1is an optionally substituted alkyl having 1 to 5 carbon atoms, an optionally substituted alkenyl having 2 to 6 carbon atoms and the like, R2is a hydrogen atom, an optionally substituted alkyl having 1 to 5 carbon atoms and the like, R2' is a hydrogen atom, and R3is an optionally substituted alkyl having 1 to 5 carbon atoms and the like, a prodrug thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof and a solvate thereof. The compound of the present invention shows superior blood sugar decreasing action on the state of hyperglycemia, but does not affect the blood sugar when it is in the normal range or in the hypoglycemic state, which means that it is free of serious side effects such as hypoglycemia. Therefore, the compound of the present invention is useful as a therapeutic drug for diabetes and also useful as a preventive of the chronic complications of diabetes.
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(2008/06/13)

Cyclopropanation of C60 with malonic acid mono-esters
Reaction of C69 with malonic acid mono-esters in the presence of iodine and diazabicyclo[5.4.0]undec-7-ene (DBU) provides the corresponding 61-iodo- 1,2-methano[60]fullerene-61-carboxylates. This cyclopropanation of C60 seems to occur via a carbenoid intermediate.
Nierengarten, Jean-Francois,Nicoud, Jean-Francois
p. 7737 - 7740
(2007/10/03)

Hydroxamic acid-based bisubstrate analog inhibitors of Ras farnesyl protein transferase
The rational design, synthesis, and activity of novel, hydroxamic acid- based, collective bisubstrate analog inhibitors of farnesyl protein transferase (FPT) is described. This class of compounds differ structurally from the conventional FPT inhibitors by
Patel, Dinesh V.,Young, Marian G.,Robinson, Simon P.,Hunihan, Lisa,Dean, Brenda J.,Gordon, Eric M.
p. 4197 - 4210
(2007/10/03)

γ-turn peptidomimetics as fibrinogen antagonists
This invention relates to a method of inhibiting platelet aggregation, and compounds which are mimics of the peptide sequence Arg-Gly-Asp.
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(2008/06/13)

Metabolism of the Insecticide Phoxim in Plants and Cell Suspension Cultures of Soybean
The metabolism of phoxim (Z-α-imino>phenylacetonitrile), Volaton, was investigated using heterotrophic cell suspension cultures of soybean (Glycine max L.) and isolated organs (roots, stems, cotyledons, and leaves) of aseptically grown soybean plants.In both systems phoxim was first hydrolyzed to the corresponding oxime, which was then reduced to a primary nitrile amine.The primary amino group was N-malonylated as the terminal step of the catabolic sequence.The structure of this terminal metabolite was elucidated by spectroscopic (UV, IR, NMR, and MS) methods and chemical synthesis.In the plant no organ-specific differences in phoxim metabolism were observed.In the cell culture system phoxim was quantitatively converted to the N-malonate within 18-20 h, whereas in plant organs such extensive conversion could not be observed even within incubation times of about 5 days.The N-malonate was found to be excreted from the cultured cells into the medium; this effect could not be shown for the plant tissues.Keywords: Organothiophosphate metabolism; soybean plants and cell suspension cultures; conjugation reactions; N-malonylation; O-glucoside formation
Hoehl, Hans-Ulrich,Barz, Wolfgang
p. 1052 - 1056
(2007/10/02)

ALKYLATION OF AMBIDENT NUCLEOPHILIC HYDROXAMATES WITH 4-SUBSTITUTED 2-AZETIDINONES: FORMATION OF BICYCLIC β-LACTAM INTERMEDIATES
Silver salts of various O-alkylhydroxamic acids react with 4-substituted 2-azetidinones (7) to produce novel substituted β-lactams.N- or O-alkylation of the hydroxamate silver salts can be controlled by reaction conditions, variation of the leaving group (OAc or SEt) of the 4-substituted 2-azetidinone, and the mode of formation of the silver salt itself.Elaboration of the products to azapenems and oxapenams may produce novel β-lactam derivatives for biological evaluation.
Stauber, Margaret J.,Debiak-Krook, Therese,Miller, Marvin J.
p. 1205 - 1235
(2007/10/02)

The use of γ-turn mimetics to define peptide secondary structure
A novel γ-turn mimetic 2 has been prepared based on retro amide peptide design. Incorporation of this mimetic into linear peptide fibrinogen receptor antagonist 7 (GPIIb/IIIa receptor) affords the opportunity to test models of antagonist pharmacophore.
Callahan,Newlander,Burgess,Eggleston,Nichols,Wong,Huffman
p. 3479 - 3488
(2007/10/02)

Process for preparing malonic monoester
A malonic monoester is prepared in a good yield by a single step reaction by reacting malonic acid with an alcohol in the presence of a base and an activator of malonic acid selected from the group consisting of an acyl halide or halocarbonate and an acid anhydride or dicarbonate.
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(2008/06/13)

SELECTIVE MONOETHERIFICATION AND MONOESTERIFICATION OF DIOLS AND DIACIDS UNDER PHASE-TRANSFER CONDITIONS
Research on the selectivity of etherification reactions of diols and esterification reactions of diacids by alkyl halides under phase-transfer catalysis has shown that under such conditions, selectivity of monoetherification increases in the order prim sec tert diols, though overall yield of monoether decreases from sec to tert diols.Monoesterification of diacids was accomplished with a high degree of selectivity.Optimal extraction of diols and diacids was found to correspond in general to chain lengths of around 5 carbons.This could mean that the complex formed between the catalyst and the anion to react is stabilized for certain carbon lengths by inner solvation in virtue of its spatial conformation.
Zerda, Jaime de la,Barak, Gabriela,Sasson, Yoel
p. 1533 - 1536
(2007/10/02)

REACTION OF TRIMETHYLSILYL DERIVATIVES WITH MELDRUM'S ACID : A NEW AND EASY MONOFUNCTIONALIZATION OF MALONIC ACID
Treament of Meldrum's acid with silylated derivatives (amines, lactams or alcohols) yields very easily monofunctionalized malonic silyl esters.Hydrolysis of these silyl esters leads to the corresponding monoacids with a very good yield.
Rigo, B.,Fasseur, D.,Cauliez, P.,Couturier, D.
p. 3073 - 3076
(2007/10/02)

Chemistry of Pyrrolic Compounds. XLVI Benzyl β-Keto Propionate Porphyrins: A New Synthesis of Deoxyophylloerythroaetioporphyrin and Harderoporphyrin
Porphyrins with benzyl β-keto propionate side chains have been prepared by condensation of the appriopriate porphyrin acid chloride with the magnesium chelate of the enolate form of benzyl hydrogen malonate.Intermediates of this class have been used in th
Chaudhry, Irshad A.,Clezy, Peter S.,Mirza, Aminul H.
p. 1095 - 1104
(2007/10/02)