Design, Synthesis, and Biological Evaluation of New Territrem B Analogues

Jiang, Xiangrui; Ao, Lei; Zhou, Chang‐Xin; Yang, Leixiang; Zhang, Qi‐Jun; Li, Haibo; Sun, Lianli; Wu, Xiumei; Bai, Hua; Zhao, Yu

doi:10.1002/cbdv.200590036

Cited by 11 publications

(5 citation statements)

References 22 publications

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“…Despite difficulties in the synthesis of TB, there are reported SAR studies involving TB, its naturally occurring close analogues, and their synthetic derivatives. Important contributions of the A-ring enone, D-ring pyran-2-one, and aromatic E-ring in binding have been noted, − and these observations are consistent with the various protein–ligand interactions seen in the structure. Docking studies involving TB have not been successful in predicting the correct mode of binding .…”

supporting

confidence: 56%

Structures of Human Acetylcholinesterase Bound to Dihydrotanshinone I and Territrem B Show Peripheral Site Flexibility

Cheung

Gary

Shiomi

et al. 2013

ACS Med. Chem. Lett.

232

146

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Acetylcholinesterase is a critical enzyme that regulates neurotransmission by degrading the neurotransmitter acetylcholine in synapses of the nervous system. It is an important target for both therapeutic drugs that treat Alzheimer's disease and chemical warfare agents that cripple the nervous system and cause death through paralysis. The enzyme has both catalytic and peripheral sites to which inhibitors may bind. Structures of recombinant human acetylcholinesterase in complex with the natural product inhibitors dihydrotanshinone I and territrem B reveal dihydrotanshinone I binding that is specific to only the peripheral site and territrem B binding that spans both sites and distorts the protein backbone in the peripheral site. These inhibitors may function as important molecular templates for therapeutics used for treatment of disease and protection against nerve agents.

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supporting

confidence: 56%

Structures of Human Acetylcholinesterase Bound to Dihydrotanshinone I and Territrem B Show Peripheral Site Flexibility

Cheung

Gary

Shiomi

et al. 2013

ACS Med. Chem. Lett.

232

146

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“…The substantial and innovatory activity of territrem B encouraged the search for new territrem B derivatives. Preliminary structure–activity investigations suggested that the 2‐en‐1‐one moiety and the planar conformation were essential for the AChE inhibitory activity . No BuChE inhibition has been observed with territrem B …”

Section: Othersmentioning

confidence: 99%

Nature as a source of metabolites with cholinesterase-inhibitory activity: an approach to Alzheimer's disease treatment

Pinho

Ferreres

Valentão

et al. 2013

Journal of Pharmacy and Pharmacology

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Objectives Alzheimer's disease (AD) is the most common cause of dementia, being responsible for high healthcare costs and familial hardships. Despite the efforts of researchers, no treatment able to delay or stop AD progress exists. Currently, the available treatments are only symptomatic, cholinesterase inhibitors being the most widely used drugs. Here we describe several natural compounds with anticholinesterase (acetylcholinesterase and butyrylcholinesterase) activity and also some synthetic compounds whose structures are based on those of natural compounds. Key findings Galantamine and rivastigmine are two cholinesterase inhibitors used in therapeutics: galantamine is a natural alkaloid that was extracted for the first time from Galanthus nivalis L., while rivastigmine is a synthetic alkaloid, the structure of which is modelled on that of natural physostigmine. Alkaloids include a high number of compounds with anticholinesterases activity at the submicromolar range. Quinones and stilbenes are less well studied regarding cholinesterase inhibition, although some of them, such as sargaquinoic acid or (+)-a-viniferin, show promising activity. Among flavonoids, flavones and isoflavones are the most potent compounds. Xanthones and monoterpenes are generally weak cholinesterase inhibitors. Summary Nature is an almost endless source of bioactive compounds. Several natural compounds have anticholinesterase activity and others can be used as leader compounds for the synthesis of new drugs.

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“…A definitive hypothesis on the development of AD, which may unify the enormous number of neuropathological and neurochemical findings, has not been established. Although acetylcholine degradation was evidenced to be related to AD syndrome, wherein AChE inhibition continues to be an efficient therapeutic modality for AD treatment, 3,4 increasing studies suggest that excessive reactive oxygen species (ROS) produces oxidative stress and has been implicated in the pathogenesis of neurodegenerative diseases including AD and PD. [5][6][7] Clonal pheochromocytoma PC12 cells provide a convenient and well-studied model system for investigation of neuronal injury in vitro.…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis, and Examination of Neuron Protective Properties of Alkenylated and Amidated Dehydro-Silybin Derivatives

Yang

Cong

et al. 2009

J. Med. Chem.

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A series of C7-O- and C20-O-amidated 2,3-dehydrosilybin (DHS) derivatives ((+/-)-1a-f and (+/-)-2), as well as a set of alkenylated DHS analogues ((+/-)-4a-f), were designed and de novo synthesized. A diesteric derivative of DHS ((+/-)-3) and two C23 esterified DHS analogues ((+/-)-5a and (+/-)-5b) were also prepared for comparison. The cell viability of PC12 cells, Fe(2+) chelation, lipid peroxidation (LPO), free radical scavenging, and xanthine oxidase inhibition models were utilized to evaluate their antioxidative and neuron protective properties. The study revealed that the diether at C7-OH and C20-OH as well as the monoether at C7-OH, which possess aliphatic substituted acetamides, demonstrated more potent LPO inhibition and Fe(2+) chelation compared to DHS and quercetin. Conversely, the diallyl ether at C7-OH and C20-OH was more potent in protection of PC12 cells against H(2)O(2)-induced injury than DHS and quercetin. Overall, the more lipophilic alkenylated DHS analogues were better performing neuroprotective agents than the acetamidated derivatives. The results in this study would be beneficial for optimizing the therapeutic potential of lignoflavonoids, especially in neurodegenerative disorders such as Alzheimer's and Parkinson's disease.

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Design, Synthesis, and Biological Evaluation of New Territrem B Analogues

Cited by 11 publications

References 22 publications

Structures of Human Acetylcholinesterase Bound to Dihydrotanshinone I and Territrem B Show Peripheral Site Flexibility

Structures of Human Acetylcholinesterase Bound to Dihydrotanshinone I and Territrem B Show Peripheral Site Flexibility

Nature as a source of metabolites with cholinesterase-inhibitory activity: an approach to Alzheimer's disease treatment

Design, Synthesis, and Examination of Neuron Protective Properties of Alkenylated and Amidated Dehydro-Silybin Derivatives

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