- Structure–activity relationship and biological evaluation of berberine derivatives as PCSK9 down-regulating agents
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Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a secreted protein and its deficiency markedly enhanced the survival rate of patient with cardiovascular diseases (CVDs). Forty berberine (BBR) derivatives were synthesized and evaluated for their activities on down-regulating the transcription of PCSK9 in HepG2 cells, taking BBR as the lead. Structure–activity relationship (SAR) analysis revealed that 2,3-dimethoxy moiety might be beneficial for activity. Among them, 9k displayed the most potent activity with IC50 value of 9.5 ± 0.5 μM, better than that of BBR. Also, it significantly decreased PCSK9 protein level at cellular level, as well as in the liver and serum of mice in vivo. Furthermore, 9k markedly increased LDLR expression and LDL-C clearance via down-regulating PCSK9 protein. The mechanism of action of 9k is targeting HNF1α and/or Sp1 cluster modulation upstream of PCSK9, a different one from BBR. Therefore, 9k might have the potential to be a novel PCSK9 transcriptional inhibitor for the treatment of atherosclerosis, worthy for further investigation.
- Fan, Tian-Yun,Yang, Yu-Xin,Zeng, Qing-Xuan,Wang, Xue-Lei,Wei, Wei,Guo, Xi-Xi,Zhao, Li-Ping,Song, Dan-Qing,Wang, Yan-Xiang,Wang, Li,Hong, Bin
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- Design and Use of de novo Cascades for the Biosynthesis of New Benzylisoquinoline Alkaloids
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The benzylisoquinoline alkaloids (BIAs) are an important group of secondary metabolites from higher plants and have been reported to show significant biological activities. The production of BIAs through synthetic biology approaches provides a higher-yielding strategy than traditional synthetic methods or isolation from plant material. However, the reconstruction of BIA pathways in microorganisms by combining heterologous enzymes can also give access to BIAs through cascade reactions. Most importantly, non-natural BIAs can be generated through such artificial pathways. In the current study, we describe the use of tyrosinases and decarboxylases and combine these with a transaminase enzyme and norcoclaurine synthase for the efficient synthesis of several BIAs, including six non-natural alkaloids, in cascades from l-tyrosine and analogues.
- Wang, Yu,Tappertzhofen, Nadine,Méndez-Sánchez, Daniel,Bawn, Maria,Lyu, Boyu,Ward, John M.,Hailes, Helen C.
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supporting information
p. 10120 - 10125
(2019/06/27)
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- SEPIAPTERIN REDUCTASE INHIBITORS FOR THE TREATMENT OF PAIN
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Disclosed herein are small molecule heterocyclic inhibitors of sepiapterin reductase (SPR), and pro-drugs and pharmaceutically acceptable salts thereof. The Also featured are pharmaceutical compositions of the compounds and uses of these compounds for the treatment or prevention of pain (e.g., inflammatory pain, nociceptive pain, functional pain, and neuropathic pain)
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- Tetrahydroisoquinoline based sulfonamide hydroxamates as potent matrix metalloproteinase inhibitors
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The synthesis and MMP inhibitory activity of a series of tetrahydroisoquinoline based sulfonamide hydroxamates are described. In nine MMPs tested, most of the compounds display potent inhibition activity except for MMP-7. Some subtle isozyme selectivity is observed by varying the substituents at the 6- and 7-positions and aromatic ring of arylsulfonyl groups.
- Ma, Dawei,Wu, Wengen,Yang, Guoxin,Li, Jingya,Li, Jia,Ye, Qizhuang
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- PPAR compounds
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PPAR alpha activators, pharmaceutical compositions containing such compounds and the use of such compounds to elevate certain plasma lipid levels, including high density lipoprotein-cholesterol and to lower certain other plasma lipid levels, such as LDL-cholesterol and triglycerides and accordingly to treat diseases which are exacerbated by low levels of HDL cholesterol and/or high levels of LDL-cholesterol and triglycerides, such as atherosclerosis and cardiovascular diseases, in mammals, including humans.
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- Compounds and pharmaceutical use thereof
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PCT No. PCT/JP97/00291 Sec. 371 Date Aug. 6, 1998 Sec. 102(e) Date Aug. 6, 1998 PCT Filed Feb. 6, 1997 PCT Pub. No. WO97/29079 PCT Pub. Date Aug. 14, 1997The compounds of the formula (I) wherein each symbol is as defined in the specification, pharmaceutically acceptable salts thereof and pharmaceutical use thereof. The Compound (I) and pharmaceutically acceptable salts thereof of the present invention selectively act on cannabinoid receptors, particularly peripheral receptors, cause less side effects on the central system, and have superior immunoregulating action, antiinflammatory action, antiallergic action and therapeutic effect on nephritis. Therefore, they are useful as cannabinoid receptor, particularly peripheral cannabinoid receptor activators and antagonists, immunoregulators, therapeutic agents for autoimmune diseases, antiinflammatory agents, antiallergic agents and therapeutic agents for nephritis.
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- Process for the preparation of (8As,12AS,13AS)-decahydroisoquino ((2,1-G) (1,6)-naphthyridin-8-one derivatives
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The invention provides a process for preparing single enantiomers of compounds represented by the formula: STR1 and chiral acid addition salts thereof; wherein: X and Y are independently hydrogen; lower alkyl; lower alkoxy; or halo; or X and Y taken together is methylenedioxy or ethylene-1,2-dioxy; which includes reduction of a compound represented by the formula: STR2 to give a mixture of stereoisomers represented by the formula: STR3 wherein each wavy line independently represents a bond in either the α or β position; followed by dissolving the mixture of stereoisomers and a chiral resolving acid in a suitable solvent and allowing the solution to crystallize, giving a salt of the desired enantiomer.
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- Synthesis and Murine Antineoplastic Activity of Bis Derivatives of Pyrroloisoquinoline
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The synthesis of 4,5-dihydropyrroloisoquinolines is reported.A key intermediate in the synthesis of 8-methoxy-4,5-dihydropyrroloisoquinolines, 6-hydroxy-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid (6), was prepared by using a regiospeci
- Anderson, Wayne K.,McPherson, Howard L.,New, James S.,Rick, Arvela C.
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p. 1321 - 1325
(2007/10/02)
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