- The synthesis of corticosteroid-carborane esters for the treatment of rheumatoid arthritis via boron neutron capture synovectomy
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Two corticosteroid-carborane esters were synthesized through the use of a BOP-Cl promoted esterification. The steroid-carborane conjugates are designed to selectively deliver boron to arthritic tissue for boron neutron capture synovectomy, a new therapeut
- Valliant, John F.,Schaffer, Paul,Britten, James F.,Davison, Alan,Jones, Alun G.,Yanch, Jacquelyn C.
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Read Online
- Diethylzinc-Mediated Radical 1,2-Addition of Alkenes and Alkynes
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A novel diethylzinc-mediated radical 1,2-addition of perfluoroalkyl iodides to unactivated alkenes and alkynes is presented, which demonstrates a novel way to generate an ethyl difluoroacetate radical. This method is highly efficient and gives full conversions of the substrates, high yields of the products, and negligible byproducts and requires no column chromatography purifications. The mild conditions enable this protocol to exhibit excellent functional group compatibility.
- Li, Xin,He, Songtao,Song, Qiuling
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supporting information
p. 2994 - 2999
(2021/05/04)
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- NOVEL LYSOPHOSPHATIDIC ACID DERIVATIVE
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PROBLEM TO BE SOLVED: To provide a compound that specifically activates an LPA4 receptor, and a pharmaceutical composition containing the same. SOLUTION: This invention relates to a novel lysophosphatidic acid derivative that has an agonistic action on an LPA4 receptor and is useful for the prevention and/or treatment of a disease with angiodysplasia caused by the LPA4 receptor, or a disease associated with angiopathy, or symptoms associated therewith. This invention also relates to a pharmaceutical composition containing the lysophosphatidic acid derivative. SELECTED DRAWING: None COPYRIGHT: (C)2021,JPOandINPIT
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Paragraph 0519-0521
(2021/05/28)
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- Original synthesis of radiolabeling precursors for batch and on resin one-step/late-stage radiofluorination of peptides
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Radiolabeling of peptides with fluorine-18 is hurdled by their chemical sensitivity and complicated processes. Original triflyl-pyridine intermediates afforded ammonium precursors that were radiolabeled at low temperature. From that study, a generic tag h
- Richard, Mylène,Specklin, Simon,Roche, Mélanie,Hinnen, Fran?oise,Kuhnast, Bertrand
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supporting information
p. 2507 - 2510
(2020/03/06)
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- GOLD (I)-PHOSPHINE 1,2,3-TRIAZOLE DERIVATIVES WITH ANTIOBIOTIC PROPERTIES
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The present invention relates to gold (l)-phosphine 1,2,3-triazole compounds, and their use in a human or animal medicine. The present invention also relates to using such compounds for the prevention and/or treatment of an infection, i.e. inhibitors of growth of Gram-positive and/or Gram-negative bacteria. On another aspect the invention relates to the synthesis of the gold (l)-phosphine compounds of the invention and to their synthesis intermediates. The present invention finds applications in the medical, veterinary and/or chemical fields.
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Page/Page column 35-36
(2020/01/11)
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- An Atom-Economic and Stereospecific Access to Trisubstituted Olefins through Enyne Cross Metathesis Followed by 1,4-Hydrogenation
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The combination of intermolecular enyne cross metathesis and subsequent 1,4-hydrogenation opens a stereocontrolled and atom-economic access to trisubstituted olefins. By investigating different combinations of functionalized alkyne and alkene substrates, we found that the outcome (yield, E / Z ratio) of the Grubbs II-catalyzed enyne cross-metathesis step depends on the substrate's structure, the amount of the alkene (used in excess), and the (optional) presence of ethylene. In any case, the 1,4-hydrogenation, catalyzed by 1,2-dimethoxybenzene-Cr(CO) 3, proceeds stereospecifically to yield exclusively the E -products from both the E- and Z- 1,3-diene intermediates obtained by metathesis. A rather broad scope and functional group compatibility of the method is demonstrated by means of 15 examples.
- Ratsch, Friederike,Schmalz, Hans-Günther
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supporting information
p. 785 - 792
(2018/01/27)
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- Remote Nucleophilic Allylation by Allylrhodium Chain Walking
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Metal migration through a carbon chain is a versatile method for achieving remote functionalization. However, almost all known examples involve the overall net migration of alkylmetal species. Here, we report that allylrhodium species obtained from hydrorhodation of 1,3-dienes undergo chain walking toward esters, amides, or (hetero)arenes over distances of up to eight methylene units. The final, more highly conjugated allylrhodium species undergo nucleophilic allylation with aldehydes and with an imine to give Z-homoallylic alcohols and amines, respectively.
- Groves, Alistair,Martínez, Jose I.,Smith, Joshua J.,Lam, Hon Wai
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supporting information
p. 13432 - 13436
(2018/09/21)
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- Remote Cooperative Group Strategy Enables Ligands for Accelerative Asymmetric Gold Catalysis
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An accelerative asymmetric gold catalysis is achieved for the first time via chiral ligand metal cooperation. An asymmetrically positioned remote amide group in the designed chiral binaphthyl-based ligand plays the essential role of a general base catalyst and selectively accelerates the cyclizations of 4-allen-1-ols into one prochiral allene face. The reactions are mostly highly enantioselective with achiral substrates, and due to the accelerated nature of the catalysis catalyst loadings as low as 100 ppm are allowed. With a pre-existing chiral center at any of the backbone sp3-carbons, the reaction remained highly efficient and most importantly maintained excellent allene facial selectivities regardless of the substrate stereochemistry. By using different combinations of ligand and substrate enantiomers, it is now possible to access all four stereoisomers of versatile 2-vinyltetrahydrofurans with exceedingly high selectivity. The underpinning design of this chemistry reveals a novel and conceptually distinctive strategy to tackle challenging asymmetric gold catalysis, which to date has relied on decelerative asymmetric steric hindrance approaches.
- Wang, Zhixun,Nicolini, Corrado,Hervieu, Cedric,Wong, Yuk-Fai,Zanoni, Giuseppe,Zhang, Liming
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supporting information
p. 16064 - 16067
(2017/11/22)
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- New Colchicine-Derived Triazoles and Their Influence on Cytotoxicity and Microtubule Morphology
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A series of new colchicinoids with a variable triazole unit at C-7 was synthesized through Cu(I)-catalyzed 1,3-dipolar cycloaddition (click-chemistry) of a colchicine-derived azide with various alkynes and the cytotoxicity against THP-1 and Jurkat cancer cell lines was used for structural optimization. Three particularly active compounds (IC50 ≤ 5 nM) were additionally investigated with respect to their efficacy against relevant solid tumor cell lines (HeLa, A549, and SK MES 1). Besides distorting the microtubule morphology by tubulin depolymerization, one compound also exhibited a pronounced centrosome declustering effect in triple negative breast cancer cells (MDA-MB-231) and nonsmall cell lung cancer cells (H1975).
- Thomopoulou, Persefoni,Sachs, Julia,Teusch, Nicole,Mariappan, Aruljothi,Gopalakrishnan, Jay,Schmalz, Hans-Günther
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supporting information
p. 188 - 191
(2016/03/01)
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- Total synthesis of azumamide A and azumamide E, evaluation as histone deacetylase inhibitors, and design of a more potent analogue
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(Chemical Equation Presented) The unprecedented diastereoselective Mannich reaction of a Z-allylsulfoximine was a key step in the total synthesis of the marine natural products azumamide A and E, and an unnatural analogue. Their relative potency as histone deacetylase inhibitors was evaluated and found to correlate with predicted zinc-binding affinity.
- Wen, Shijun,Carey, Krystle L.,Nakao, Yoichi,Fusetani, Nobuhiro,Packham, Graham,Ganesan
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p. 1105 - 1108
(2007/10/03)
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- VLA-4 INHIBITOR
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A compound which selectively inhibits bonding between a ligand and α4β1 integrin (VLA-4); a process for producing the compound; and a medicine containing the compound. The compound is one represented by, e.g., the formula (I) or a salt thereof. Also provided is a preventive and/or therapeutic agent which contains the compound or salt as a major component and is effective against diseases attributable to cell adhesion, such as, e.g., inflammatory reaction, autoimmune disease, cancer metastasis, bronchial asthma, nasal obstruction, diabetes, arthritis, psoriasis, multiple sclerosis, inflammatory intestinal disease, and rejection reaction in transplantation. (In the formula, Y1 represents arylene, etc.; V1 represents aryl, etc.; and R11 to R14 each represents H, OH, halogeno, etc.)
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Page/Page column 84-85
(2010/02/15)
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- Design, synthesis, and antifolate activity of new analogues of piritrexim and other diaminopyrimidine dihydrofolate reductase inhibitors with ω-carboxyalkoxy or ω-carboxy-1-alkynyl substitution in the side chain
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As part of a search for dihydrofolate reductase (DHFR) inhibitors combining the high potency of piritrexim (PTX) with the high antiparasitic vs mammalian selectivity of trimethoprim (TMP), the heretofore undescribed 2,4-diamino-6-(2′,5′-disubstituted benzyl)pyrido[2,3-d]pyrimidines 6-14 with O-(ω-carboxyalkyl) or ω-carboxy-1-alkynyl groups on the benzyl moiety were synthesized and tested against Pneumocystis carinii, Toxoplasma gondii, and Mycobacterium avium DHFR vs rat DHFR. Three N-(2,4-diaminopteridin-6-yl)methyl)-2′-(ω-carboxy-1-alkynyl) -dibenz[b,f]azepines (19-21) were also synthesized and tested. The pyridopyrimidine with the best combination of potency and selectivity was 2,4-diamino-5-methyl-6-[2′-(5-carboxy-1-butynyl)-5′-methoxy]benzyl] pyrimidine (13), with an IC50 value of 0.65 nM against P. carinii DHFR, 0.57 nM against M. avium DHFR, and 55 nM against rat DHFR. The potency of 13 against P. carinii DHFR was 20-fold greater than that of PTX (IC50 = 13 nM), and its selectivity index (SI) relative to rat DHFR was 85, whereas PTX was nonselective. The activity of 13 against P. carinii DHFR was 20 000 times greater than that of TMP, with an SI of 96, whereas that of TMP was only 14. However 13 was no more potent than PTX against M. avium DHFR, and its SI was no better than that of TMP. Molecular modeling dynamics studies using compounds 10 and 13 indicated a slight binding preference for the latter, in qualitative agreement with the IC50 data. Among the pteridines, the most potent against P. carinii DHFR and M. avium DHFR was the 2′-(5-carboxy-1-butynyl) dibenz[b,f]azepinyl derivative 20 (IC50 = 2.9 nM), whereas the most selective was the 2′-(5-carboxy-1-pentynyl) analogue 21, with SI values of > 100 against both P. carinii and M. avium DHFR relative to rat DHFR. The final compound, 2,4-diamino-5-[3′-(4-carboxy-1-butynyl)-4′-bromo- 5′-methoxybenzyl]pyrimidine (22), was both potent and selective against M. avium DHFR (IC50 = 0.47 nM, SI = 1300) but was not potent or selective against either P. carinii or T. gondii DHFR.
- Chan, David C. M.,Fu, Hongning,Forsch, Ronald A.,Queener, Sherry F.,Rosowsky, Andre
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p. 4420 - 4431
(2007/10/03)
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- Sulfonamides having antiangiogenic and anticancer activity
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Compounds having methionine aminopeptidase-2 inhibitory (MetAP2) are described. Also described are pharmaceutical compositions comprising the compounds, methods of treatment using the compounds, methods of inhibiting angiogenesis, and methods of treating cancer.
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- Sulfonamides having antiangiogenic and anticancer activity
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Compounds having methionine aminopeptidase-2 inhibitory (MetAP2) are described. Also described are pharmaceutical compositions comprising the compounds, methods of treatment using the compounds, methods of inhibiting angiogenesis, and methods of treating cancer.
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- Further studies on 2,4-diamino-5-(2′,5′-disubstituted benzyl)pyrimidines as potent and selective inhibitors of dihydrofolate reductases from three major opportunistic pathogens of AIDS
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As part of an ongoing effort to discover novel small-molecule antifolates combining the enzyme-binding species selectivity of trimethoprim (TMP) with the potency of piritrexim (PTX), 10 previously unreported 2,4-diamino-5-(2′-methoxy-5′-substituted)benzylpyrimidines (2-11) containing a carboxyl group at the distal end of the 5′-substituent were synthesized and tested as inhibitors of dihydrofolate reductase (DHFR) from Pneumocystis carinii (Pc), Toxoplasma gondii (Tg), and Mycobacterium avium (Ma), three of the opportunistic pathogens frequently responsible for life-threatening illness in people with impaired immune systems as a result of HIV infection or immunosuppressive chemotherapy. The selectivity index of DHFR inhibition was evaluated by comparing the potency of each compound against the parasite enzymes with its potency against rat liver DHFR. 2,4-Diamino-5-[5′-(5-carboxy-1-pentynyl)-2′- methoxybenzyl]pyrimidine (3) inhibited Pc DHFR with a selectivity index of 79 and was 430 times more potent than TMP. 2,4-Diamino-5-[5′-(4-carboxy-1-butynyl)-2′-methoxybenzyl] pyrimidine (2), with one less carbon than 3 in the side chain, had a selectivity index of 910 against Ma DHFR and was 43 times more potent than TMP. 2,4-Diamino-5-[5′-(5-carboxypentyl)-2′-methoxybenzyl]pyri midine (6) had a selectivity index of 490 against Tg DHFR and was 320 times more potent than TMP. 2,4-Diamino-5-[5′-(6-carboxy-1-hexynyl)-2′-methoxybenzyl] pyrimidine (4), with one more carbon than 3, was less potent against all three of the parasite enzymes than either 3 or 6 and also had a lower selectivity index than 3 against the Pc enzyme. However, 4 was the only member of the series with a selectivity index of >300 against both Tg and Ma DHFR. Given that PTX is at least 10 times more potent against rat DHFR than against P. carinii or T. gondii DHFR and that the selectivity index of several of the compounds matches or exceeds that of TMP as well as PTX, our results suggest that it may be possible to develop clinically useful nonclassical antifolates that are both potent and selective against the major opportunistic pathogens of AIDS.
- Rosowsky, Andre,Forsch, Ronald A.,Queener, Sherry F.
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p. 1726 - 1736
(2007/10/03)
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- Biphenyl hydroxamate inhibitors of matrix metalloproteinases
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Compounds of formula STR1 or a pharmaceutically acceptable salt thereof inhibit matrix metalloproteinases and TNFα secretion and are useful in the treatment of inflammatory disease states. Also disclosed are matrix metalloproteinases and TNFα secretion inhibiting compositions and a method for inhibiting matrix metalloproteinases and TNFα secretion.
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- Studies on the synthesis of nargenicin A1: Highly stereoselective synthesis of the complete carbon framework via the transannular Diels-Alder reaction of an 18-membered macrolide
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A synthesis of the complete carbon skeleton of the nargenicins, represented by tricyclic lactone 45, is described. The key step of the synthesis of 45 is the Yamaguchi macrolactonization of hydroxy acid 44 which is followed by the facile transannular Diels-Alder reaction of the 18-membered macrolide 22. This sequence provides tricycle 45 in 66% yield, along with a 14% yield of tricycle 46 which is epimeric at C(10). Macrolide 22 was obtained in 38% yield when the macrolactonization was performed at 80°C. The transannular Diels-Alder reaction of 22 at 80°C provided tricycle 45 as the exclusive product (85% yield). In contrast, the intramolecular Diels-Alder reaction of seco ester 43 provided a mixture of trans-fused 47 in 56% yield and the desired cis-fused cycloadduct 48 in only 27% yield. Two independent stereochemical control features determine the success of the transannular Diels-Alder reaction of 22: the C(6)-Br steric directing group that dictates that only one of the two faces of the diene is accessible to the dienophile in transition state 14 and allylic strain considerations involving the C(16)-Me substituent which enable only one face of the dienophile to be accessible to the diene in transition state 14. The latter effect is operational only in the transannular cycloaddition mode as indicated by the results with 43. Az added benefit of this strategy is that the 10-membered lactone is established by a formal ring contraction of the more easily synthesized 18-membered lactone. Attempts to extend this strategy to the transannular Diels-Alder reaction of the C(13)-hydroxyl substituted macrolide 13 have not been successful.
- Roush, William R.,Koyama, Kazuo,Curtin, Michael L.,Moriarty, Kevin J.
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p. 7502 - 7512
(2007/10/03)
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- Palladium-Catalyzed Reaction of Vinyl Triflates and Vinyl/Aryl Halides with 4-Alkynoic Acids: Regio- and Stereoselective Synthesis of (E)-δ-Vinyl/aryl-γ-methylene-γ-butyrolactones
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The pallakdium-catalyzed reaction of vinyl triflates and vinyl/aryl halides with 4-pentynoic acid, 2,2-disubstituted 4-pentynoic acids, and 5-substituted 4-pentynoic acids produced regio- and stereoselectively the corresponding (E)-d-vinyl/aryl-γ-methylen
- Arcadi, Antonio,Burini, Alfredo,Cacchi, Sandro,Delmastro, Monica,Marinelli, Fabio,Pietroni, Bianca Rosa
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p. 976 - 982
(2007/10/02)
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