2035-75-8Relevant academic research and scientific papers
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
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
, p. 452 - 459 (2010)
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.
Preparation method 6 -hydroxy caproic acid
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Paragraph 0056-0060; 0093; 0095-0098; 0107; 0109-0112, (2021/11/10)
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.
Unified Synthesis of Polycyclic Alkaloids by Complementary Carbonyl Activation**
Christmann, Mathias,He, Guoli,List, Benjamin
supporting information, p. 13591 - 13596 (2021/05/07)
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.
Evodiamine prodrug containing indole quinone unit as well as preparation method and application thereof
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Paragraph 0026, (2021/10/30)
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.
Synthesis, Antiproliferative Activity, and Effect on Carcinoma A549 Cell Microtubules of New Tubuloclustin Analogs
Zefirov,Evteeva, Yu. A.,Fatkulin,Schulz,Kuznetsov,Zefirova
, p. 423 - 428 (2019/09/16)
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.
Oxidation of KA oil to caprolactone with molecular oxygen using N-hydroxyphthalimide-mediated Ce(NH4)2(NO3)6 catalyst
Du, Renfeng,Yuan, Haoran,Yao, Jia,Li, Haoran
, p. 24 - 29 (2019/02/03)
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.
Selective C(sp3)?H Aerobic Oxidation Enabled by Decatungstate Photocatalysis in Flow
Laudadio, Gabriele,Govaerts, Sebastian,Wang, Ying,Ravelli, Davide,Koolman, Hannes F.,Fagnoni, Maurizio,Djuric, Stevan W.,No?l, Timothy
supporting information, p. 4078 - 4082 (2018/03/21)
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.
Room-temperature synthesis of pharmaceutically important carboxylic acids bearing the 1,2,4-oxadiazole moiety
Tarasenko, Marina,Duderin, Nikolay,Sharonova, Tatyana,Baykov, Sergey,Shetnev, Anton,Smirnov, Alexey V.
supporting information, p. 3672 - 3677 (2017/08/23)
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.
Synthesis of AgWCNx Nanocomposites for the One-Step Conversion of Cyclohexene to Adipic Acid and Its Mechanistic Studies
Goyal, Reena,Sameer, Siddharth,Sarkar, Bipul,Bag, Arijit,Singhal, Nikita,Bordoloi, Ankur
, p. 16555 - 16565 (2017/11/10)
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.
Kinetics of the liquid-phase oxidation of 2-hydroxycyclohexanone
Akimov,Puchkov,Nepomnyashchikh,Perkel'
, p. 270 - 278 (2013/07/26)
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.
