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Hyperforin analogs, methods of synthesis, and uses thereof

A halogen and compound technology, applied in the field of preparing hyperforin analogues described herein, can solve problems such as difficult synthesis of hyperforin analogues, inapplicability of hyperforin, etc.

Inactive Publication Date: 2014-04-16
PRESIDENT & FELLOWS OF HARVARD COLLEGE
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Various syntheses of the less complex bicyclic polyprenylated acylphloroglucinols have been achieved, but to date none of these methods have been applicable to the more complex hypericin (see, e.g., Nuhant et al., Org. Lett. (2007) 9: 287-289; Qi et al., J. Am. Chem. Soc. (2007) 129: 12682-12683; Rodeschini et al., Org. Lett. (2006) 8: 5283-5285; Siegel and Danishefsky, J. Am. Chem. Soc. (2006) 128:1048-1049)
Shibasaki's enantioselective synthesis of hyperforin is a milestone achievement, but it is not easy to synthesize hyperforin analogues according to his method

Method used

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  • Hyperforin analogs, methods of synthesis, and uses thereof
  • Hyperforin analogs, methods of synthesis, and uses thereof
  • Hyperforin analogs, methods of synthesis, and uses thereof

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Embodiment

[0493] In order that the invention described herein may be more fully understood, the following examples are set forth. It should be understood that these examples are for illustrative purposes only and do not limit the invention in any way.

[0494] Synthesis of Hypericin

[0495] The criteria for the development of an enantioselective synthesis of hyperforin were that it must be very simple (about 10-15 steps), involve minimal changes in oxidation state, be modular, and be derived from starting materials that are readily available . By satisfying these criteria, we can easily obtain many hyperforin analogs for biological research. The retrosynthesis of hypericin is shown in figure 1 . The first simplification is the derivation of hyperforin from an intermediate in which the key C2 and C5 quaternary atomic centers are set. We envisage that this intermediate will be derived from the Lewis acid-catalyzed 6-endo-tet cyclization of enol ethers to trisubstituted epoxides. W...

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Abstract

The present invention provides a novel 11-step enantioselective approach to the natural product hyperforin, which enables access to a wide variety of hyperforin analogs. The present invention also provides pharmaceutical compositions comprising inventive hyperforin analogs. Hyperforin analogs synthesized using the present synthetic method are envisionsed useful in the treatment of various conditions, including, but not limited to, depression and conditions characterized by depression, inflammatory skin conditions, diabetes, asthma, chronic obstructive pulmonary disease (COPD), kidney disorders, and ischemic brain damage.

Description

[0001] related application [0002] This application claims priority under 35 U.S.C. §119(e) to U.S. Provisional Patent Application U.S.S.N. 61 / 493,250, filed June 3, 2011, which is incorporated herein by reference. Background technique [0003] Hypericin is thought to be the constituent of Hypericum nigra to be responsible for its antidepressant activity (see, eg, Chatterjee et al., Life Sci. (1998) 63:499-510). Hypericin is the only known selective agonist of the TRPC6 (standard transient receptor potential) ion channel, which leads to Ca +2 and Na + Ion influx into neurons and neuronal axonal sprouts (see, eg, Leuner et al., FASEB J. (2007) 21:4101-4111). Unlike synthetic SSRI antidepressants, hyperforin induces increases in synaptic serotonin and norepinephrine levels, possibly through antagonism of TRPC6. Therefore, TRPC6 may be a new antidepressant target. Because only a few small molecules are known to selectively activate TRPC channel proteins, and these proteins a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C49/733C07C49/743
CPCC07F7/1836C07C45/29C07F7/0818C07D493/08C07C49/753C07C49/733C07F7/0834C07C49/743C07C2602/46C07F7/1804A61P11/06A61P11/08A61P13/12A61P17/00A61P25/00A61P25/14A61P25/16A61P25/20A61P25/24A61P25/28A61P29/00A61P9/10A61P3/10C07F7/081
Inventor M.D.谢尔B.A.斯帕林格D.莫比尤斯
Owner PRESIDENT & FELLOWS OF HARVARD COLLEGE
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