Chemistry and Biology of the Zaragozic Acids (Squalestatins)

Nadin, Alan; Nicolaou, K. C.

doi:10.1002/anie.199616221

Cited by 109 publications

(35 citation statements)

References 134 publications

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“…[405] Thus, farnesyl diphosphate is for example a critical downstream intermediate in the cholesterol pathway, needed for the farnesylation of numerous proteins. It constitutes an essential building block for the biosynthesis of ubiquinone and geranylgeranyl diphosphate along with their secondary products, e.g.…”

Section: Discussionmentioning

confidence: 99%

Pharmaceuticals

Schaefer

2014

Natural Products in the Chemical Industry

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A boy who is born in Germany today has a probable life expectancy of around 77 years, and a girl one of 82 years -twice as long as in the year 1880. This increase is a consequence of both, better living circumstances -working conditions, food, clothing, housing -, and also a result of more comprehensive medical care. Thus, a whole range of infectious diseases has been wiped out, or brought at least under control, and the mortality rate for civilisation-and age-related diseases has dropped. Vaccinations and drugs play a key role in this outcome. The 20th century is characterised especially by the worldwide blossoming of the pharmaceutical industry. More and more, the targeted search for and development of new drugs have replaced serendipitous discoveries (Fig. 5.1). Pharmaceuticals of the last century.

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Section: Discussionmentioning

confidence: 99%

Pharmaceuticals

Schaefer

2014

Natural Products in the Chemical Industry

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“…The same substructure is the core of the natural product zaragozic acid, which showed interesting biological activity [16]. Would the potential rearrangement always be noticed?…”

Section: Molecules That Cannot Be Madementioning

confidence: 98%

Computational assessment of synthetic procedures

Goodman

Socorro

2007

J Comput Aided Mol Des

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Synthetic chemistry is hard because some reasonable looking molecules cannot be made, because there are errors in the chemical literature, because it is easy to miss reaction possibilities and because even the shape of molecules is very difficult to determine. We propose an approach to the computational analysis of reactions that tries to circumvent these difficulties, by restricting the analysis to simple rules for reactivity that can generate a large number of competing pathways. This huge ensemble is filtered using computational methods to pick out the most likely pathways, and to suggest possible products.

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“…7 zaragozic acid A and B, were only submicromolar inhibitors of SQS in vitro even though they have alkyl chains corresponding to those of the zaragozic acids [83]. A nice review on the chemistry and biology of this "fascinating" class of molecules, as described therein, is given by Nadin and Nicolaou [84].…”

Section: Zaragozic Acids (Squalestatins)mentioning

confidence: 99%

Squalene Synthase Inhibitors: An Update on the Search for New Antihyperlipidemic and Antiatherosclerotic Agents

Kourounakis

Katselou²,

Matralis³

et al. 2011

CMC

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Atherosclerosis and related heart disease is strongly associated with elevated blood levels of total (and LDL) cholesterol. Due to the widespread incidence as well as severity of this pathological condition, major efforts have been made for the discovery and development of hypocholesteroleamic agents. In the past few decades, HMG-CoA reductase inhibitors (statins) are being extensively used as lipid lowering drugs. These agents act predominantly by inhibiting the enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) that is the rate limiting step of cholesterol biosynthesis. Both the success as well as drawbacks of HMGRIs, have led to the investigation and design of inhibitors of other (downstream) enzymes involved in the multistep cholesterol biosynthetic pathway. One such class of agents consists of the squalene sythase inhibitors which act at the first and solely committed step towards the biosynthesis of the cholesterol nucleus. This target is considered not to interfere with the biosynthesis of other biologically important molecules and thus a better side-effect profile is expected for these inhibitors. Several classes of squalene synthase inhibitors (SQSIs), such as substrate or transition-state analogues, zaragozic acids or 2,8- dioxabicyclo[3.2.1]octane derivatives, dicarboxylic acid and quinuclidine derivatives, 4,1-benzoxazepine as well as substituted morpholine derivatives, have been studied as potent inhibitors of squalene synthase. So far only one benzoxazepine derivative (TAK-475) has been evaluated in advanced clinical trials. In this article we review the up to date research and literature on the therapeutic potential of this relatively new class of compounds, the drug discovery efforts towards the development of active squalene synthase inhibitors, their activity profile and effectiveness, as well as their structure-activity relationships.

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Chemistry and Biology of the Zaragozic Acids (Squalestatins)

Cited by 109 publications

References 134 publications

Pharmaceuticals

Pharmaceuticals

Computational assessment of synthetic procedures

Squalene Synthase Inhibitors: An Update on the Search for New Antihyperlipidemic and Antiatherosclerotic Agents

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