- Hybrid inhibitors of phosphatidylinositol 3-kinase (PI3K) and the mammalian target of rapamycin (mTOR): Design, synthesis, and superior antitumor activity of novel wortmannin-rapamycin conjugates
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Hyperactivation of the PI3K/AKT/mTOR signaling pathway is common in cancer, and PI3K and mTOR act synergistically in promoting tumor growth, survival, and resistance to chemotherapy. Thus, combined targeting of PI3K and mTOR presents an opportunity for robust and synergistic anticancer efficacy. 17-Hydroxywortmannin (2a) analogues conjugated to rapamycin (3a) analogues via a prodrug linker are uniquely positioned for this approach. Our efforts led to the discovery of diester-linked conjugates that, upon in vivo hydrolysis, released two highly potent inhibitors. Conjugate 7c provided enhanced solubility relative to 3a and to an equivalent mixture of 3a and 9a and demonstrated profound activity in U87MG mouse xenografts, achieving an MED of 1.5 mg/kg, following weekly intravenous dosing. At 15 mg/kg, 7c completely inhibited the growth of HT29 tumors, whereas an equivalent mixture of the inhibitors was poorly tolerated. In the A498 renal tumor model, 7c exhibited superior efficacy over 3a or 9a when administered as a single agent or in combination with bevacizumab. Thus,we have uncovered a novel approach to target both PI3K and mTOR via hybrid inhibitors, leading to a broader and more robust anticancer efficacy. 2009 American Chemical Society.
- Ayral-Kaloustian, Semiramis,Gu, Jianxin,Lucas, Judy,Cinque, Michael,Gaydos, Christine,Zask, Arie,Chaudhary, Inder,Wang, Jianyao,Di, Li,Young, Mairead,Ruppen, Mark,Mansour, Tarek S.,Gibbons, James J.,Yu, Ker
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Read Online
- Preparation method 6 -hydroxy caproic acid
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The invention provides a preparation method of 6 -hydroxycaproic acid. The method comprises the following steps: 1) subjecting 1 and 6 - adipic acid to intramolecular dehydration to obtain adipic anhydride. 2) The adipic acid anhydride is reacted with fatty alcohol to obtain the adipic acid monoester. 3) The adipic acid monoester was subjected to a reduction reaction under hydrogen pressure to give 6 - hydroxycaproic acid. 1-hydroxycaproic acid is prepared by taking 6 - and 6 - adipic acid cheap and easily available as raw materials through intramolecular dehydration, ring opening esterification, hydrogenation reduction and the like.
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Paragraph 0056-0060; 0093; 0095-0098; 0107; 0109-0112
(2021/11/10)
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- Unified Synthesis of Polycyclic Alkaloids by Complementary Carbonyl Activation**
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A complementary dual carbonyl activation strategy for the synthesis of polycyclic alkaloids has been developed. Successful applications include the synthesis of tetracyclic alkaloids harmalanine and harmalacinine, pentacyclic indoloquinolizidine alkaloid nortetoyobyrine, and octacyclic β-carboline alkaloid peganumine A. The latter synthesis features a protecting-group-free assembly and an asymmetric disulfonimide-catalyzed cyclization. Furthermore, formal syntheses of hirsutine, deplancheine, 10-desbromoarborescidine A, and oxindole alkaloids rhynchophylline and isorhynchophylline have been achieved. Finally, a concise synthesis of berberine alkaloid ilicifoline B was completed.
- Christmann, Mathias,He, Guoli,List, Benjamin
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supporting information
p. 13591 - 13596
(2021/05/07)
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- Evodiamine prodrug containing indole quinone unit as well as preparation method and application thereof
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The invention relates to an evodiamine prodrug containing an indole quinone unit as well as a preparation method and application thereof. The invention synthesizes a series of strong active evodiamine derivatives with indole quinine units, has strong anti-proliferative activity on non-small cell lung cancer (non-small cell lung cancer, NSCLC), and has dosage and time dependence. In-vitro experiments evaluate their biological activity, suggesting that the synthesized compounds have a strong inhibitory activity on lung cancer strains. Through molecular docking analysis, the binding affinity of the ligand to the active site of the target protein is predicted, and the interaction ability of the ligand and the protein is strong.
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Paragraph 0026
(2021/10/30)
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- Oxidation of KA oil to caprolactone with molecular oxygen using N-hydroxyphthalimide-mediated Ce(NH4)2(NO3)6 catalyst
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In traditional Baeyer-Villiger oxidation, peracids or hydrogen peroxide are usually adopted as the oxidants. When molecular oxygen is used as oxidant, the sacrificial agents are always indispensable, such as aldehydes that are transformed into cheap acids after reaction. In this work, KA oil (the industrial raw material, a mixture of cyclohexanol and cyclohexanone) has been oxidized to caprolactone by molecular oxygen using N-hydroxyphthalimide (NHPI) and cerium ammonium nitrate (CAN) as catalyst, in which the sacrificial agent is cyclohexanol, and it is converted into cyclohexanone, then into caprolactone rather than into byproducts. The selectivity of caprolactone was 98% with cyclohexanol conversion of 34% and it was still kept at 90% when the conversion reached to 46%. The mechanism investigation showed a bifunctional role of CAN, which performed both as a radical initiator for cyclohexanol oxidation and a Lewis acid for Baeyer-Villiger reaction. In the Baeyer-Villiger oxidation, a weak interaction between cerium and cyclohexanone was suggested by Fourier Transform Infrared Spectroscopy (FTIR), meanwhile, the active species generated from cerium and hydrogen peroxide was separated and characterized by FTIR. The detailed research also revealed an unusual effect between cerium and the Br?nsted acid generated as a byproduct, which was critical for caprolactone synthesis.
- Du, Renfeng,Yuan, Haoran,Yao, Jia,Li, Haoran
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- Synthesis, Antiproliferative Activity, and Effect on Carcinoma A549 Cell Microtubules of New Tubuloclustin Analogs
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Combretastatin analogs of the antitumor agent tubuloclustin {N-[7-(adamant-2-yloxy)-7-oxoheptanoyl]-Ndeacetylcolchicine} were prepared via esterification of combretastatin by monoesters of pimelic or adipic acid with adamantan-2-ol or (adamantan-1-yl)methanol. These conjugates were stable and cytotoxic to human lung carcinoma A549 cells (EC50 ≈ 50 – 70 nM) and caused depolymerization of microtubules and slight clustering of tubulin. Tubuloclustin analogs with shortened linkers were prepared via amidation by N-deacetylcolchicine of monoesters of adipic or succinic acids with adamantan-1-ol or (adamantan-1-yl)methanol. The conjugate N-[6-(adamantyl)-6-oxohexanoyl]-N-deacetylcolchicine was more active (EC50 ≈ 4 nM) than tubuloclustin and promoted strong tubulin clusterization. All compounds induced apoptosis of A549 cells. Tests in vivo of N-[6-(adamantyl)-6-oxoheaxnoyl]-N-deacetylcolchicine on carcinoma A549 experimental models were concluded to be promising.
- Zefirov,Evteeva, Yu. A.,Fatkulin,Schulz,Kuznetsov,Zefirova
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p. 423 - 428
(2019/09/16)
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- Selective C(sp3)?H Aerobic Oxidation Enabled by Decatungstate Photocatalysis in Flow
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A mild and selective C(sp3)?H aerobic oxidation enabled by decatungstate photocatalysis has been developed. The reaction can be significantly improved in a microflow reactor enabling the safe use of oxygen and enhanced irradiation of the reaction mixture. Our method allows for the oxidation of both activated and unactivated C?H bonds (30 examples). The ability to selectively oxidize natural scaffolds, such as (?)-ambroxide, pregnenolone acetate, (+)-sclareolide, and artemisinin, exemplifies the utility of this new method.
- Laudadio, Gabriele,Govaerts, Sebastian,Wang, Ying,Ravelli, Davide,Koolman, Hannes F.,Fagnoni, Maurizio,Djuric, Stevan W.,No?l, Timothy
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supporting information
p. 4078 - 4082
(2018/03/21)
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- Synthesis of AgWCNx Nanocomposites for the One-Step Conversion of Cyclohexene to Adipic Acid and Its Mechanistic Studies
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A novel catalyst composed of silver nanoparticles grafted on WCNx has been prepared by using a facile pH-adjusted method. The material reported in this study presents a non-mineral acid route for the synthesis of the industrially significant monomer adipic acid through the selective oxidation of cyclohexene. Ag has been stabilized in the hydrophobic matrix during the formation of the mesoporous silica material by using aniline as stabilizing agent. A cyclohexene conversion of 92.2 % with 96.2 % selectivity for adipic acid was observed with the AgWCNx-2 catalyst, therefore, the AgWCNx catalyst was found to be efficient for the direct conversion to adipic acid with respect to their monometallic counterparts. The energy profile diagrams for each reaction path by using the AgWCNx catalyst were studied along with their monometallic counterparts by using the Gaussian 09 package. The reported material can avoid the use of harmful phase-transfer catalysts (PTC) and/or chlorinated additives, which are two among other benefits of the reported work.
- Goyal, Reena,Sameer, Siddharth,Sarkar, Bipul,Bag, Arijit,Singhal, Nikita,Bordoloi, Ankur
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p. 16555 - 16565
(2017/11/10)
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- Room-temperature synthesis of pharmaceutically important carboxylic acids bearing the 1,2,4-oxadiazole moiety
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An efficient and mild one-pot protocol has been developed for the synthesis of 1,2,4-oxadiazoles via the reaction of amidoximes with dicarboxylic acid anhydrides in a NaOH/DMSO medium. The method allows the synthesis of diversely substituted carboxylic acids bearing the 1,2,4-oxadiazole motif, – a popular building block for pharmaceutical research, in moderate to excellent yields. The reaction scope includes aromatic and heteroaromatic amidoximes as well as five-, six- and seven-membered anhydrides. The advantages of this procedure are proven gram-scalability and the use of inexpensive starting materials, which from a process chemistry point of view are essential for future industrial applications.
- Tarasenko, Marina,Duderin, Nikolay,Sharonova, Tatyana,Baykov, Sergey,Shetnev, Anton,Smirnov, Alexey V.
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supporting information
p. 3672 - 3677
(2017/08/23)
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- Kinetics of the liquid-phase oxidation of 2-hydroxycyclohexanone
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The kinetics of oxygen uptake in the azobisisobutyronitrile-initiated oxidation of 2-hydroxycy-clohexanone (RCH(OH)C(O)R) at 323 K has been investigated (chlorobenzene solvent, [RCH(OH)C(O)R] = 0.15-1.30 mol/L, initiation rate of w i = 0.016-0.473 mol L-1 s -1). The effective oxidizability parameter k p, eff(2k t,eff)-0.5 has been determined by solving the inverse kinetic problem using the entire data array obtained while varying [RCH(OH)C(O)R] and w i. The rate constants of chain propagation and termination and the equilibrium constant of the addition of the hydroxyperoxyl radical to the ketoalcohol have been derived from the dependence of the oxidizability parameter on the substrate concentration. The rate constant of bimolecular chain initiation has been calculated to be k 0 = 9.7 × 10-7 L mol-1 s-1. The ratio of the rate constants of quadratic-law peroxyl radical recombination reactions without and with chain termination (k eff′/k t,eff′) increases with increasing [RCH(OH)C(O)R], passes through a maximum at a substrate concentration of 0.8 mol/L, and then falls off. It is demonstrated that this effect is due to the variation of the proportions of the hydroperoxyl and organic (1-hydroxy-2-oxocyclohexylperoxyl or 1,2-dihydroxy-1-cyclo- hexylperoxyl) radicals in the reaction medium.
- Akimov,Puchkov,Nepomnyashchikh,Perkel'
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p. 270 - 278
(2013/07/26)
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- A Ru-Sn-Co/AlO(OH) as a highly efficient catalyst for hydrogenation of dimethyl adipate to 1,6-hexanodiol in aqueous phase
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A Ru-Sn-Co/AlO(OH) catalyst was prepared by co-impregnation, calcination, and hydrothermal reduction. The catalyst was well characterized by BET, XRD, SEM-EDX, XPS, H2-TPR, and M?ssbauer spectroscopy, and then it was applied in the hydrogenation of dimethyl adipate to 1,6-hexanodiol in aqueous phase. It was found that the addition of cobalt could stabilize Sn(IV) and the cooperation between tin and cobalt could promote the reduction of ruthenium oxide. The γ-Al2O3 in the catalyst Ru-Sn-Co/γ-Al2O3 was transformed to AlO(OH) by the hydrothermal reduction. It was suggested that the stabilized Sn(IV) and the interaction between the hydroxyl group on the surface of AlO(OH) and the solvent water played a key role to improve the conversion of dimethyl adipate and the selectivity to 1,6-hexanodiol. The conversion of dimethyl adipate and the selectivity to 1,6-hexanodiol were up to 98% and 95%, respectively, under 5 MPa of H2 and 493 K for 10 h.
- Jiang, Hong-Bin,Jiang, Hai-Jun,Su, Ke,Zhu, De-Ming,Zheng, Xue-Li,Fu, Hai-Yan,Chen, Hua,Li, Rui-Xiang
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p. 164 - 170
(2013/03/13)
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- Structure-activity relationship of a new series of reversible dual monoacylglycerol lipase/fatty acid amide hydrolase inhibitors
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The two endocannabinoids, anandamide (AEA) and 2-arachidonoylglycerol (2-AG), play independent and nonredundant roles in the body. This makes the development of both selective and dual inhibitors of their inactivation an important priority. In this work we report a new series of inhibitors of monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH). Among them, (±)-oxiran-2-ylmethyl 6-(1,1′-biphenyl-4-yl)hexanoate (8) and (2R)-(-)-oxiran-2-ylmethyl(4-benzylphenyl)acetate (30) stand out as potent inhibitors of human recombinant MAGL (IC50 (8) = 4.1 μM; IC 50 (30) = 2.4 μM), rat brain monoacylglycerol hydrolysis (IC 50 (8) = 1.8 μM; IC50 (30) = 0.68 μM), and rat brain FAAH (IC50 (8) = 5.1 μM; IC50 (30) = 0.29 μM). Importantly, and in contrast to the other previously described MAGL inhibitors, these compounds behave as reversible inhibitors either of competitive (8) or noncompetitive nature (30). Hence, they could be useful to explore the therapeutic potential of reversible MAGL inhibitors.
- Cisneros, José A.,Bj?rklund, Emmelie,González-Gil, Inés,Hu, Yanling,Canales, ángeles,Medrano, Francisco J.,Romero, Antonio,Ortega-Gutiérrez, Silvia,Fowler, Christopher J.,López-Rodríguez, María L.
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supporting information; experimental part
p. 824 - 836
(2012/04/10)
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- Simple preparation of symmetrical carboxylic acid anhydrides by means of Na2CO3/SOCl2
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A convenient and general method for the synthesis of symmetrical carboxylic acid anhydrides using sodium carbonate/thionyl chloride is described. Copyright Taylor & Francis Group, LLC.
- Kazemi,Kiasat,Mombaini
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p. 3219 - 3223
(2008/02/12)
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- HISTONE DEACETYLASE INHIBITORS AS THERAPEUTICS FOR NEUROLOGICAL DISEASES
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The invention provides HDAC inhibitors that may be used as therapeutics for the treatment of a neurodegenerative or neuromuscular condition. The invention provides compounds of formula I. The invention also provides pharmaceutical compositions and articles of manufacture that include these compounds, as well as methods of treating and methods of preventing or delaying the onset of a neurodegenerative or neuromuscular condition.
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Page/Page column 38; 39
(2008/06/13)
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- DENTRITIC POLYMERS, CROSSLINKED GELS, AND THEIR USES IN ORTHOPEDIC APPLICATIONS
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The present invention provides compositions, kits, and methods for repairing cartilaginous tissue. Certain methods of the invention utilize dendritic macromolecules formed by treating a dendritic compound with light or a linking compound. In certain instances, the dendritic compounds have a lysine, cysteine, isocysteine residue or other nucleophilic group attached to their peripheries. Addition of a compound containing two or more electrophilic groups, such as aldehydes, activated esters, or acrylates, to the lysine-capped, cysteine-capped, or isocysteine-capped dendrimers produces a polymeric compound that can repair a cartilage defect.
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Page/Page column 238-239
(2010/10/20)
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- DENDRITIC POLYMERS, CROSSLINKED GELS, AND THEIR USES AS OPHTHALMIC SEALANTS AND LENSES
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The present invention provides compositions and methods for sealing a wound and preparing a lens. The methods of the invention utilize dendritic macromolecules formed by treating a dendritic compound with light or a linking compound. In certain instances, the dendritic compounds have a lysine-, cysteine-, isocysteine-residue or other nucleophilic group attached to the periphery of the dendrimer: Addition of a compound containing two or more electrophilic groups such as aldehydes, activated esters, or acrylates to the lysine-, cysteine-, or isocysteine-capped dendrimers produces a polymeric compound that can form a seal or a lens. Another aspect of the invention relates to a method of treating disease using the pharmaceutical compositions of the invention. Other aspects of the invention relate to kits for sealing a wound or preparing a lens, delivery devices, and methods for controlling the polymerization of a hydrogel system.
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Page/Page column 286-287
(2010/10/20)
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- Emulsifier
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The present invention relates to a novel emulsifier which comprises at least one pregelatinized, crosslinked starch selected from a C2-C5 hydroxyalkyl starch and a C2-C18 acyl starch and at least one starch derivative containing a hydrophobic group or both a hydrophilic group and a hydrophic group, which has been degraded by reaction with an exo-enzyme capable of cleaving 1,4-alpha-D-glucosidic linkages from non-reducing ends of starch, but incapable of cleaving 1,6-alpha-D-glucosidic linkages of starch. Such emulsifier achieves stable compositions, which are salt tolerant and do not exhibit tackiness. Further, the emulsifier is ethoxylate-free and may be used in a variety of compositions, including cosmetic compositions.
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Page/Page column 6
(2010/02/14)
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- Ozonolysis of enol ethers. Part 10. Ozonization of enol ethers from 1,2- and 1,3-dicarbonyl compounds: Direct quantitative synthesis of phthalonic acid anhydride
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The results of ozonolyses of enol ethers from 1.2- and 1.3-dicarbonyl compounds presented here strongly indicate that these reactions do not proceed via the established Criegee ozonolysis mechanism for nucleophilic C=C bonds. The quantitative one-step synthesis of phthalonic acid anhydride via ozonolysis of 2-(methoxymethyliden)-1H-inden-1.3(2H)-dione (28a) is described. Furthermore, a revision of the theory of alkene ozonolysis in the presence of tetracyanoethylene (TCNE) is proposed on the basis of a single-electron-transfer (SET) chemistry.
- Schank, Kurt,Beck, Horst,Pistorius, Susanne
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p. 2025 - 2049
(2007/10/03)
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- Production and use of derivatized homoserine lactones
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The present invention provides analogues of autoinducer molecules that are derivatized to allow their attachment to other molecules and surfaces. Libraries of the autoinducer analogues are also contemplated. Also provided are methods for using the compounds of the invention to produce compositions, such as immunoconjugates, antibodies and vaccines, which are useful for treating and preventing disease states in a subject. The compositions of the invention are also useful in various assays, including assessing the autoinducer load in a subject.
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Page column 42-43
(2008/06/13)
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- CEPHEM COMPOUND
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The present invention is concerned with a novel cephem compound, with a process for the production of this compound, which process may contain or consist of fermentative steps, chemical steps, and/or biotransformation steps. A cephem compound according to the present invention characterised by formula (I) or a salt or ester thereof, wherein R is selected from the group consisting of (carboxymethylthio)propionyl (carboxyethylthio)propionyl Y- CH2-CO15 wherein Y is phenyl, phenoxy or tetrazolyl HOOC-X-CO wherein X is defined as (CH2)4 or wherein X is defined as (CH2)P-A-(CH2)q, wherein p and q each individually are 0, 1, 2, 3 or 4, and A is CH=CH, C-=C, CHB, C=O, O, S, NH, the nitrogen optionally being substituted or the sulfur optionally being oxidized, and B is hydrogen, halogen, C1-3 alkoxy, hydroxyl, or optionally substituted methyl, with the proviso that p+q should be 2 or 3, when A is CH=CH or C=-C, or p+q should be 3 or 4, when A is CHB, C=O, 0, S or NH or wherein X is (CH2)m-CH=A-(CH2)n or (CH2)m-C=-C-(CH2)n, wherein m and n each individually are 0, 1, 2 or 3 and m+n = 2 or 3, and A is CH or N, or wherein X is (CH2)p-CH=CH-C H=C-(CH2)q wherein p and q each individually are 0 or 1 and p+q = 0 or 1 and wherein R' is selected from the group consisting of OH O-(alkyl 1-6C) wherein the alkyl can be straight or branched and O-C(alkyl 1-6C)-O-(alkyl 1-6C) wherein the alkyl groups can be straight or branched can inter alia be prepared by fermentative techniques according to the invention and in particular using a suitable microorganism possessing or being transformed with the genes needed for conversion of an appropriate acyl-6-aminopenicillanic acid into the desired compound.
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- Mechanistic insights into the conversion of cyclohexene to adipic acid by H2O2 in the presence of a TAPO-5 catalyst
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The stereochemistry of the 1,2-cyclohexanediol intermediate plays an important role with regard to both the rate and selectivity of the production of adipic acid from cyclohexene in the absence of an organic solvent. A titanium-containing aluminophosphate molecular sieve (TAPO-5) is shown to serve as a good heterogeneous catalyst for this reaction.
- Lee, Sang-Ok,Raja, Robert,Harris, Kenneth D. M.,Thomas, John Meurig,Johnson, Brian F. G.,Sankar, Gopinathan
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p. 1520 - 1523
(2007/10/03)
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- Synthesis and protein binding of (4-carboxybutyl)carbamoyl- substituted taxoids
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(4-Carboxybutyl)carbamates 5 and 6, as well as 10, derived from 10-O-deacetylbaccatin III (1) and paclitaxel (2), respectively, were synthesized by reaction of unprotected 1 and 2′-O-(methoxyacetyl)paclitaxel (8), respectively, with trimethylsilyl 5-isocyanatopentanoate in good yields. The carbamoyl-taxoids were conjugated to bovine-serum albumin and analyzed by MALDI-TOF mass spectrometry.
- Blitzke, Torsten,Baranovsky, Alexander,Schneider, Bernd
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p. 1989 - 1995
(2007/10/03)
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- Synthesis and Stabilisation of Isocyanatoketenes
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The isocyanatocarbonyl chlorides 1a-m were prepared and converted to the corresponding isocyanatoketenes 2a-m by means of hydrogen chloride elimination with triethylamine. (Isocyanatoalkyl)ketenes with less then three carbon atoms between the functional groups yield crosslinked and oligomeric products, respectively, by intermolecular reaction of the different heterocumulene systems. (ω-Isocyanatoalkyl)aldoketenes with three and more carbon atoms between the functional groups (2d-h) stabilize uniformly by -cycloaddition of the ketene groups to yield 3-(ω-isocyanatoalkyl)-4-(ω-isocyanatoalkylidene)-2-oxetanones (3d-h) (diisocyanatodiketenes). (4-Isocyanatophenyl)ketene (2l) and (3-isocyanato-1,5-pentanediyl)ketene (2k) stabilize in analogy to the unsubstituted parent compounds to give 6l and 4k, respectively.
- Mormann, Werner,Hoffmann, Silke,Hoffmann, Walter
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p. 285 - 290
(2007/10/02)
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- OXIDATION OF CYCLOHEXANONE AND 2-HYDROXYCYCLOHEXANONE IN PRESENCE OF CHROMIUM NAPHTHENATE.
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A comparison of the kinetics of accumulation of the products of oxidation of cyclohexanone and 2-hydroxycyclohexanone in presence of chromium and cobalt naphthenates and in absence of catalysts showed that the composition of the reaction products varies considerably with the nature of the catalytic metal. In distinction from polymethylene hydrocarbons, which form carbonyl compounds, cyclohexanone is concerted in presence of chromium salts predominantly through 2-hydrocyclohexanone. Oxidation of cyclohexanone and 2-hydroxycyclohexanone in presence of chromium naphthenate gives lower yields of 1,2-cyclohexanedione than the noncatalytic reaction or the reaction catalyzed by cobalt napthenate.
- Freidin,Perkel',Borodina
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p. 2483 - 2486
(2007/10/02)
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