29973-91-9Relevant academic research and scientific papers
Structural simplification of natural product 4-O-methyl saucerneol of lignans, and preparation method, pharmaceutical composition and application thereof
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Paragraph 0117-0120, (2019/07/04)
The invention discloses a structural simplification of a natural product 4-O-methyl saucerneol of lignans, and a preparation method, a pharmaceutical composition and application thereof. The inventionspecifically relates to a compound as shown in a formula (I) or an isomer thereof and a pharmaceutically acceptable salt thereof, and a preparation meathod of the compounds. The novel pharmaceuticalcomposition comprises an effective dose of the compound as shown in the formula (I) and a pharmaceutically acceptable carrier. The invention also discloses application of the compounds to prepare a medicament for the preparation, prevention and/or treatment of tumors, wherein the tumors includes neural glioblastoma, melanoma, gastric cancer, lung cancer, breast cancer, kidney cancer, liver cancer,oral epidermal cancer, cervical cancer, ovarian cancer, pancreatic cancer, prostatic cancer, colon cancer and rectal adenocarcinoma.
Preparation method for ivabradine impurities
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Paragraph 0056; 0071; 0073, (2018/09/11)
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.
Synthesis and Evaluation of Orexin-1 Receptor Antagonists with Improved Solubility and CNS Permeability
Perrey, David A.,Decker, Ann M.,Zhang, Yanan
, p. 587 - 602 (2018/03/27)
Orexins are hypothalamic neuropeptides playing important roles in many functions including the motivation of addictive behaviors. Blockade of the orexin-1 receptor has been suggested as a potential strategy for the treatment of drug addiction. We have previously reported OX1 receptor antagonists based on the tetrahydroisoquinoline scaffold with excellent OX1 potency and selectivity; however, these compounds had high lipophilicity (clogP > 5) and low to moderate solubility. In an effort to improve their properties, we have designed and synthesized a series of analogues where the 7-position substituents known to favor OX1 potency and selectivity were retained, and groups of different nature were introduced at the 1-position where substitution was generally tolerated as demonstrated in previous studies. Compound 44 with lower lipophilicity (clogP = 3.07) displayed excellent OX1 potency (Ke = 5.7 nM) and selectivity (>1,760-fold over OX2) in calcium mobilization assays. In preliminary ADME studies, 44 showed excellent kinetic solubility (>200 μM), good CNS permeability (Papp = 14.7 × 10-6 cm/sec in MDCK assay), and low drug efflux (efflux ratio = 3.3).
Functional reversal of (?)-Stepholidine analogues by replacement of benzazepine substructure using the ring-expansion strategy
Li, Wei,Zhang, Li,Xu, Lili,Yuan, Congmin,Du, Peng,Chen, Jiaojiao,Zhen, Xuechu,Fu, Wei
, p. 599 - 607 (2016/10/06)
(?)-Stepholidine is an active ingredient of the Chinese herb Stephania and naturally occurring tetrahydroprotoberberine alkaloid with mixed dopamine receptor D1 agonistic and dopamine receptor D2 antagonistic activities. In this work, a series of novel hexahydrobenzo[4,5]azepino [2,1-a]isoquinolines were designed and synthesized as ring-expanded analogues of (?)-Stepholidine. Initial pharmacological assays demonstrated that a benzazepine replacement was associated with significant increase in selectivity and functional reversal at dopamine receptor D1. Compound-(?)-15e (Ki?=?5.32?±?0.01?nm) is more potent than (?)-Stepholidine (Ki?=?13?nm) and was identified as a selective dopamine receptor D1 antagonist (IC50?=?0.14?μm). Moreover, molecular modeling suggested that (?)-15e might exert its dopamine receptor D1 antagonistic activities through interacting with the transmembrane helix 7 of dopamine receptor D1.
Designing new analogs for streamlining the structure of cytotoxic lamellarin natural products
Tangdenpaisal, Kassrin,Worayuthakarn, Rattana,Karnkla, Supatra,Ploypradith, Poonsakdi,Intachote, Pakamas,Sengsai, Suchada,Saimanee, Busakorn,Ruchirawat, Somsak,Chittchang, Montakarn
, p. 925 - 937 (2015/03/31)
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.
Facile and Divergent Synthesis of Lamellarins and Lactam-Containing Derivatives with Improved Drug Likeness and Biological Activities
Theppawong, Atiruj,Ploypradith, Poonsakdi,Chuawong, Pitak,Ruchirawat, Somsak,Chittchang, Montakarn
, p. 2631 - 2650 (2016/02/09)
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.
Total synthesis of natural and unnatural lamellarins with saturated and unsaturated D-rings
Ploypradith, Poonsakdi,Petchmanee, Thaninee,Sahakitpichan, Poolsak,Litvinas, Nichole D.,Ruchirawat, Somsak
, p. 9440 - 9448 (2007/10/03)
(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.
TETRACYCLIC SPIROBENZAZEPINE DOPAMINE ANTAGONISTS
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, (2008/06/13)
Novel tetracyclic spirobenzazepine compounds of the formula STR1 or a pharmaceutically-acceptable salt, amide or ester thereof, which are dopamine D-1 receptor antagonists useful for treating dopamine-related neurological and psychological disorders, cogn
Expedient Synthesis of Polyhydroxyisoflavones
Waehaelae, Kristiina,Hase, Tapio A.
, p. 3005 - 3008 (2007/10/02)
A general and direct synthesis of polyhydroxy isoflavones (3-phenyl-4H-1-benzopyran-4-ones) starting from the corresponding unprotected phenols and arylacetic acids is described.The aryl rings may carry additional alkyl, methoxy and/or halogeno groups.Intermediate polyhydroxydeoxybenzoins (1,2-diphenylethanones) can also be isolated in good yields.
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
Fujii, Tozo,Ohba, Masashi,Sakaguchi, Jun
, p. 3628 - 3640 (2007/10/02)
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
