- Full-synthetic method of racemic tetrandrine
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The invention discloses a full-synthetic method of racemic tetrandrine, and belongs to the technical field of drug synthesis. The full-synthetic method of the racemic tetrandrine comprises the steps that a synthetic route adopts a convergence synthesis method, a 5-bromovanillin, namely a compound 1 and 3-hydroxy-4-methoxyphenylacetic acid, namely a compound 5 are taken as starting materials to obtain a compound 4 and a compound 6 respectively, then the compound 4 and the compound 6 are taken as raw materials to synthesize a compound 11, a compound 19 is synthesized from the compound 11, and finally, the compound 11 reacts with the compound 19. The full-synthetic method of the racemic tetrandrine has the advantages that the synthetic efficiency is higher, the yield is higher, and the cost is lower; the reaction conditions are milder, the operation is simple and convenient, the industrial value is higher, and a reference is provided for the full-synthetic method of optical voidness tetrandrine.
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Paragraph 0093
(2019/07/10)
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- Preparation method for ivabradine impurities
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The invention discloses a preparation method for ivabradine impurities. According to the preparation method, 3-hydroxy-4-methoxyphenylacetic acid (as shown in a formula 1a) and 4-hydroxy-3-methoxyphenylacetic acid (as shown in a formula 1b) are respectively used as a starting raw material and subjected to multiple steps of reactions to prepare two impurities of ivabradine. The preparation method of the invention is simple and realizes high-purity preparation; and the prepared impurities can be used for qualitative and quantitative analysis so as to improve the medication safety of ivabradine.
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Paragraph 0045; 0047
(2018/09/11)
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- Designing new analogs for streamlining the structure of cytotoxic lamellarin natural products
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Despite the therapeutic potential of marine-derived lamellarin natural products, their preclinical development has been hampered by their lipophilic nature, causing very poor aqueous solubility. In order to develop more drug-like analogs, their structure was streamlined in this study from both the cytotoxic activity and lipophilicity standpoints. First, a modified total synthetic route was successfully devised to construct a library of 59 systematically designed lamellarin analogs, which were then subjected to cytotoxicity and log P determinations. Along with the 25 first-generation lamellarins previously synthesized in our laboratory, the structure-activity and structure-lipophilicity relationships were extensively evaluated. Our results clearly indicated the additional structural requirements around the lamellarin skeleton which, when combined with those reported previously, can provide invaluable guidance for further modifications to increase the aqueous solubility of these compounds.
- Tangdenpaisal, Kassrin,Worayuthakarn, Rattana,Karnkla, Supatra,Ploypradith, Poonsakdi,Intachote, Pakamas,Sengsai, Suchada,Saimanee, Busakorn,Ruchirawat, Somsak,Chittchang, Montakarn
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p. 925 - 937
(2015/03/31)
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- Facile and Divergent Synthesis of Lamellarins and Lactam-Containing Derivatives with Improved Drug Likeness and Biological Activities
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With the goal to improve the aqueous solubility of lamellarins, the lactone ring in their skeleton was replaced with a lactam moiety in azalamellarins. However, the reported synthetic route produced such derivatives in very low yields. Hence, this study focused on developing an efficient simplified total synthetic scheme that could furnish both azalamellarins and the parent lamellarins from the same pyrrole ester intermediates. Subsequent comparative profiling revealed that the introduced lactone-to-lactam replacement rendered these molecules less lipophilic, whereas their cancer cytotoxicity remained equipotent to that of the parent compounds. Interestingly, their inhibitory activity was significantly enhanced towards the multifaceted GSK-3β enzyme. Our results clearly demonstrate the therapeutic potential of this promising class of marine-derived natural products and justify their further development, especially into anticancer agents.
- Theppawong, Atiruj,Ploypradith, Poonsakdi,Chuawong, Pitak,Ruchirawat, Somsak,Chittchang, Montakarn
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p. 2631 - 2650
(2016/02/09)
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- Synthesis and initial preclinical evaluation of the P2X7 receptor antagonist [11C]A-740003 as a novel tracer of neuroinflammation
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Neuroinflammation, in particular activation of microglia, is thought to play an important role in the progression of neurodegenerative diseases. In activated microglia, the purinergic P2X7 receptor is upregulated. A-740003, a highly affine and
- Janssen, Bieneke,Vugts, Danielle J.,Funke, Uta,Spaans, Arnold,Schuit, Robert C.,Kooijman, Esther,Rongen, Marissa,Perk, Lars R.,Lammertsma, Adriaan A.,Windhorst, Albert D.
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p. 509 - 516
(2014/08/05)
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- Inverting the regioselectivity of the berberine bridge enzyme by employing customized fluorine-containing substrates
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Fluorine is commonly applied in pharmaceuticals to block the degradation of bioactive compounds at a specific site of the molecule. Blocking of the reaction center of the enzyme-catalyzed ring closure of 1,2,3,4- tetrahydrobenzylisoquinolines by a fluoro moiety allowed redirecting the berberine bridge enzyme (BBE)-catalyzed transformation of these compounds to give the formation of an alternative regioisomeric product namely 11-hydroxy-functionalized tetrahydroprotoberberines instead of the commonly formed 9-hydroxy-functionalized products. Alternative strategies to change the regioselectivity of the enzyme, such as protein engineering, were not applicable in this special case due to missing substrate-enzyme interactions. Medium engineering, as another possible strategy, had clear influence on the regioselectivity of the reaction pathway, but did not lead to perfect selectivity. Thus, only substrate tuning by introducing a fluoro moiety at one potential reactive carbon center switched the reaction to the formation of exclusively one regioisomer with perfect enantioselectivity. Custom-made substrates: Employing customized substrates with a fluoro atom at the normally preferred reaction site switched the regioselectivity of the berberine-bridged enzyme. With this strategy, it was possible to get access to (S)-11-hydroxy-functionalized berbines in an asymmetric fashion by using the wild-type enzyme (see scheme). Copyright
- Resch, Verena,Lechner, Horst,Schrittwieser, Joerg H.,Wallner, Silvia,Gruber, Karl,MacHeroux, Peter,Kroutil, Wolfgang
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p. 13173 - 13179
(2013/01/15)
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- Identification, synthesis, and biological evaluation of metabolites of the experimental cancer treatment drugs indotecan (LMP400) and indimitecan (LMP776) and investigation of isomerically hydroxylated indenoisoquinoline analogues as topoisomerase i poisons
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Hydroxylated analogues of the anticancer topoisomerase I (Top1) inhibitors indotecan (LMP400) and indimitecan (LMP776) have been prepared because (1) a variety of potent Top1 poisons are known that contain strategically placed hydroxyl groups, which provides a clear rationale for incorporating them in the present case, and (2) the hydroxylated compounds could conceivably serve as synthetic standards for the identification of metabolites. Indeed, incubating LMP400 and LMP776 with human liver microsomes resulted in two major metabolites of each drug, which had HPLC retention times and mass fragmentation patterns identical to those of the synthetic standards. The hydroxylated indotecan and indimitecan metabolites and analogues were tested as Top1 poisons and for antiproliferative activity in a variety of human cancer cell cultures and in general were found to be very potent. Differences in activity resulting from the placement of the hydroxyl group are explained by molecular modeling analyses.
- Cinelli, Maris A.,Reddy, P. V. Narasimha,Lv, Peng-Cheng,Liang, Jian-Hua,Chen, Lian,Agama, Keli,Pommier, Yves,Van Breemen, Richard B.,Cushman, Mark
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p. 10844 - 10862
(2013/02/25)
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- Biocatalytic organic synthesis of optically pure (S)-scoulerine and berbine and benzylisoquinoline alkaloids
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A chemoenzymatic approach for the asymmetric total synthesis of the title compounds is described that employs an enantioselective oxidative C-C bond formation catalyzed by berberine bridge enzyme (BBE) in the asymmetric key step. This unique reaction yielded enantiomerically pure (R)-benzylisoquinoline derivatives and (S)-berbines such as the natural product (S)-scoulerine, a sedative and muscle relaxing agent. The racemic substrates rac-1 required for the biotransformation were prepared in 4-8 linear steps using either a Bischler-Napieralski cyclization or a C1-Cα alkylation approach. The chemoenzymatic synthesis was applied to the preparation of fourteen enantiomerically pure alkaloids, including the natural products (S)-scoulerine and (R)-reticuline, and gave overall yields of up to 20% over 5-9 linear steps.
- Schrittwieser, Joerg H.,Resch, Verena,Wallner, Silvia,Lienhart, Wolf-Dieter,Sattler, Johann H.,Resch, Jasmin,MacHeroux, Peter,Kroutil, Wolfgang
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p. 6703 - 6714
(2011/10/18)
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- Enantioselective syntheses and X-ray structures of (S)- and (R)-N-norlaudanidine: trace opium constituents
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The enantioselective synthesis of each of the enantiomers of N-norlaudanidine, a minor Papaver somniferum opium benzyltetrahydoisoquinoline alkaloid is described. This was achieved using a chiral auxiliary-mediated Bischler-Napieralski cyclization-sodium borohydride reduction strategy. The X-ray crystal structures of each of these secondary amines are reported.
- Zein, Ahmed L.,Dakhil, Otman O.,Dawe, Louise N.,Georghiou, Paris E.
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scheme or table
p. 177 - 180
(2010/03/04)
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- Enantioselective total synthesis and X-ray structures of the tetrahydroprotoberberine alkaloids (-)-(S)-tetrahydropalmatrubine and (-)-(S)-corytenchine
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Enantioselective total syntheses and X-ray structures of both (S)-tetrahydropalmatrubine (2) and (S)-corytenchine (3) are reported for the first time. They were both derived from (S)-N-norlaudanidine, a benzyltetrahydroisoquinoline that was synthesized with high (>95% ee) enantioselectivity using a chiral auxiliary-assisted Bischler-Napieralski cyclization/reduction approach.
- Zein, Ahmed L.,Dawe, Louise N.,Georghiou, Paris E.
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scheme or table
p. 1427 - 1430
(2010/10/21)
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- Total synthesis of natural and unnatural lamellarins with saturated and unsaturated D-rings
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(Chemical Equation Presented) Twenty-eight natural and unnatural lamellarins with either a saturated or an unsaturated D-ring were synthesized according to our developed synthetic route. The key step involved the Michael addition/ring closure (Mi-RC) of the benzyldihydroisoquinoline and α-nitrocinnamate derivatives, which provided the 2-carboethoxypyrrole intermediates in moderate to good yields (up to 78% yield). Subsequent hydrogenolysis/lactonization furnished lamellarins with a saturated D-ring in excellent yields (up to 93% yield). DDQ oxidation of the saturated lamellarin acetates led directly to the corresponding unsaturated analogues in 54-95% yield. In addition, only two steps in our developed strategy require column chromatography.
- Ploypradith, Poonsakdi,Petchmanee, Thaninee,Sahakitpichan, Poolsak,Litvinas, Nichole D.,Ruchirawat, Somsak
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p. 9440 - 9448
(2007/10/03)
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- Diastereoselective Synthesis of Cularine Alkaloids via Enium Ions and an Easy Entry to Isoquinolines by Aza-Wittig Electrocyclic Ring Closure
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In preliminary communications, we reported the diastereoselective synthesis of cularine and sarcocapnine via the intramolecular ring closure of nitrenium and oxenium ions, a new highly diastereoselective reductive methylation with (+)-8-phenylmenthyl chloroacetate followed by reduction with sodium borohydride, and a facile entry to the isoquinoline precursors by aza-Wittig electrocyclic ring closure. We now report the full details of the syntheses of (+)-O-demethylcularine, (+)-cularine, (+)-sarcocapnidine, (+)-sarcocapnine, and (+)-crassifoline and describe different methods of synthesis of their precursors.
- Rodrigues, J. Augusto R.,Abramovitch, Rudolph A.,De Sousa, Joana D. F.,Leiva, Genaro C.
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p. 2920 - 2928
(2007/10/03)
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- Vanilloid and isovanilloid analogues as inhibitors of methionyl-tRNA and isoleucyl-tRNA synthetases
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As aminoacyl adenylate surrogates, a series of methionyl and isoleucyl phenolic analogues containing bioisosteric linkers mimicking ribose have been investigated. Inhibition of synthesized compounds to the aminoacylation reaction by the corresponding Escherichia coli methionyl-tRNA and isoleucyl-tRNA synthetases indicated that 18 was found to be a potent inhibitor of isoleucyl-tRNA synthetase. A molecular modeling study demonstrated that in 18, isovanillate and hydroxamate served as proper surrogates for adenine and ribose in isoleucyl adenylate, respectively.
- Lee, Jeewoo,Kang, Sang Uk,Kim, Su Yeon,Kim, Sung Eun,Jo, Yeong Joon,Kim, Sunghoon
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p. 965 - 968
(2007/10/03)
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- Design, synthesis, structure-activity relationships, and biological characterization of novel arylalkoxyphenylalkylamine σ ligands as potential antipsychotic drugs
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Receptor antagonists may be effective antipsychotic drugs that do not induce motor side effects caused by ingestion of classical drugs such as haloperidol. We obtained evidence that 1-(2-dipropylaminoethyl)-4-methoxy- 6H-dibenzo[b,d]pyran hydrochloride 2a had selective affinity for σ receptor over dopamine D2 receptor. This compound was designed to eliminate two bonds of apomorphine 1 to produce structural flexibility for the nitrogen atom and to bridge two benzene rings with a -CH2O- bond to maintain the planar structure. In light of the evidence, N,Y-dipropyl-2-(4-methoxy-3- benzyloxylphenyl)ethylamine hydrochloride 10b was designed. Since compound 10b had eliminated a biphenyl bond of 6H-dibenzo[b,d]pyran derivative 2a, it might be more released from the rigid structure of apomorphine 1 than compound 2a. The chemical modification of compound 10b led to the discovery that N,N-dipropyl-2-[4-methoxy-3-(2-phenylethoxyl)phenyl]ethylamine hydrochloride 10g (NE- 100), the best compound among arylalkoxyphenylalkylamine derivatives 3, had a high and selective affinity for σ receptor and had a potent activity in an animal model when the drug was given orally. We report here the design, synthesis, structure-activity relationships, and biological characterization of novel arylalkoxyphenylalkylamine derivatives 3.
- Nakazato, Atsuro,Ohta, Kohmei,Sekiguchi, Yoshinori,Okuyama, Shigeru,Chaki, Shigeyuki,Kawashima, Yutaka,Hatayama, Katsuo
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p. 1076 - 1087
(2007/10/03)
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- Studies on ristocetin A. A synthesis of protected ristomycinic acid using organomanganese chemistry
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Aryl ether formation by reaction of phenoxide nucleophiles with chloroarene-Mn(CO)3 cationic complexes, followed by reaction of the aryloxyarene-Mn(CO)3 complex with chiral glycine enolate equivalents, provides methodology for the synthesis of protected ristomycinic acid derivatives in a state of high optical purity.
- Pearson, Anthony J.,Shin, Hunwoo
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p. 7527 - 7538
(2007/10/02)
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- Quinolizidines. XXII. An Extension of the "3-Acetylpyridine Route" to the Syntheses of 9-Hydroxy-10-methoxy- and 10-Hydroxy-9-methoxybenzoquinolizidine-Type Alangium Alkaloids
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Alternative syntheses of the Alangium alkaloids bearing the 9-hydroxy-10-methoxy- and 10-hydroxy-9-methoxybenzoquinolizidine skeletons (types 3 and 4) have now become feasible through generally applicable routes starting from 3-acetylpyridine.The route
- Fujii, Tozo,Ohba, Masashi,Sakaguchi, Jun
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p. 3628 - 3640
(2007/10/02)
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- A High-Yield Modification of the Pschorr Phenanthrene Synthesis
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A relationship between substituents on the aryl ring undergoing homolytic aromatic substitution and the yield of Pschorr reaction product has been demonstrated.The new variation in which a (phenylsulfonyl)oxy group is present on the acceptor ring has been used to synthesize several highly oxygenated 9-phenanthrenecarboxylic acids in significantly improved yields.
- Duclos, Richard I.,Tung, Jay S.,Rapoport, Henry
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p. 5243 - 5246
(2007/10/02)
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- BIOSYNTHESIS OF TYLOPHORINE AND TYLOPHORININE
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Administration of 3,4-dihydroxyphenyl(2-(14)C)alanine to young Tylophora asthmatica plants revealed that ring B and carbon atoms C9 and C7' of tylophorine and tylophorinine are derived from dopa.Tracer experiments with 6,7-diphenylhe
- Bhakuni, Dewan S.,Mangla, Virendra K.
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p. 401 - 407
(2007/10/02)
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