Total Synthesis as a Resource in the Discovery of Potentially Valuable Antitumor Agents: Cycloproparadicicol

Yamamoto, Kana; Garbaccio, R. M.; Stachel, Shawn J.; Solit, David B.; Chiosis, Gabriela; Rosen, Neal

doi:10.1002/ange.200390300

Cited by 30 publications

(43 citation statements)

References 30 publications

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“…This renewed interest in radicicol prompted further work on its total synthesis notably by the Lett group [13,14] and the Danishefsky group [15] as well as studies to define the structure-activity relationship of this potential therapeutic. [16][17][18][19][20] Pearl and co-workers showed that despite the lack of structural similarity between radicicol and ATP, radicicol was a competitive ligand for the ATP binding site of HSP90. [21] More recently, a third natural product, novobiocin (3, Figure 1), has also been shown to inhibit HSP90, though through a different binding site.…”

Section: Introductionmentioning

confidence: 99%

Solution‐ and Solid‐Phase Synthesis of Radicicol (Monorden) and Pochonin C

Barluenga

Moulin

López

et al. 2005

Chemistry A European J

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A modular synthesis for pochonin C and radicicol is reported. The two natural products were prepared in seven and eight steps, respectively, from three readily available fragments. Alternative syntheses of these compounds were achieved using a combination of polymer-bound reagents and solid phase reactions. The conformation of the two natural products was studied and compared by using 2D NMR spectroscopy.

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Section: Introductionmentioning

confidence: 99%

Solution‐ and Solid‐Phase Synthesis of Radicicol (Monorden) and Pochonin C

Barluenga

Moulin

López

et al. 2005

Chemistry A European J

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“…15,[51][52][53][54][55] The reported potencies for geldanamycin against eukaryotic cell lines range between 20 nM and 5 mM, 19,45,51,56 and the observed variability has been shown to be both methodology-dependent as well as cell line dependent. 57 Geldanamycin-based analogues compete with ATP/ADP for binding to the ATP-binding pocket of Hsp90. 58 The binding affinity (K d ) of geldanamycin (1) for the N-terminal domain of yeast Hsp90 is 1.2 mM, 59 and the crystal structure of geldanamycin bound to its N-terminal Hsp90 binding pocket has highlighted unique structural changes that occur at the binding interface.…”

Section: Geldanamycinmentioning

confidence: 99%

“…Indeed, Danishefsky has shown that merely inversion of the epoxide stereochemistry leads to a 40-fold drop in the activity of the compound. 57 Replacement of the epoxide with a cyclopropyl ring as in cycloproparadicicol, 11, induced a lower penalty than inverting the stereochemistry of the epoxide, dropping the IC 50 B8-fold (20 nM vs. 160 nM) (Figure 2.9, 11). The inclusion of a cyclopropyl ring was a significant improvement as it provided a potent yet stable inhibitor.…”

Section: Direct Analogues Of Radicicolmentioning

confidence: 99%

“…Similar to the epoxide analogues, inversion of the cyclopropyl group stereochemistry also gave a drop in activity. 57 Additionally, removal of the epoxide altogether, 104 or its replacement with rings such as a thiirane and cyclic carbonate 109 or other H-bonding moieties 110 gave much lower activity than radicicol itself, proposed to be due to the adoption of an alternative macrocycle conformation. 110 (1) and (c) radicicol (10) co-crystallised with yeast Hsp90.…”

Section: Direct Analogues Of Radicicolmentioning

confidence: 99%

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Recent Advances in Macrocyclic Hsp90 Inhibitors

Ramsey

Kitson

Levin

et al. 2014

Macrocycles in Drug Discovery

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Natural products were the first compounds to confirm the advantages of cyclised structures, where the ring conformation provides structural stability and chemical potency. Successful clinical applications of macrocyclic compounds in oncology have produced powerful incentives within the medicinal chemistry community to explore macrocyclic drug candidates that target novel oncogenic pathways. Numerous receptors, signalling molecules, and enzymes involved in oncogenesis require the chaperone activity of heat shock protein 90 (Hsp90), an ATPase-driven dimer whose chief molecular roles involve protein folding and stabilisation. Herein we describe four classes of macrocyclic Hsp90 inhibitors. Class I macrocyclic anticancer agents, currently in clinical trials, target the ATP-binding pocket of Hsp90 and include synthetic derivatives of the ansamycin antibiotic geldanamycin (17-AAG or tanespimycin, 17-DMAG or alvespimycin, IPI-504 or retaspimycin). Class II inhibitors (radicicol, radanamycin), which also target the ATP-binding pocket of Hsp90, demonstrate greater potency than Class I inhibitors in preclinical studies, and recent improvements incorporated into synthetic derivatives and chimeras have led to greater structural stability than class I without loss of potency. Class III features synthetic derivatives targeting Hsp90's ATPase activity (o-aminobenzamides and aminopyrimidines), with promising clinical data pointing to these scaffolds as the next generation of therapeutic Hsp90 inhibitors. Class IV compounds are allosteric inhibitors that bind to the N-middle domain of Hsp90 and block access to proteins that bind the C-terminus of Hsp90 (SM122 and SM145). This final class is unique as it does not target the ATP binding site of Hsp90, thereby avoiding induction of the heat shock response. Development of compounds that modulate Hsp90's C-terminus may prove to be an effective method of avoiding the rescue response mounted when blocking the ATP-ase activity of Hsp90.

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“…Um dieses Problem zu lösen, entwarfen wir das Analogon Cycloproparadicicol, das anstelle des Epoxids eine stabilere Cyclopropyleinheit enthält. [24] Ein interessanter Schritt in der Synthese von Cycloproparadicicol ist die Ringschlussmetathese-Sequenz zum Aufbau von C5 (Schema 6).…”

Section: Radicicoleunclassified

Zum Wirkungsbereich der chemischen Synthese: Aufbau einer Minipipeline in einem akademischen Labor

Wilson

2010

Angewandte Chemie

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In dieser Retrospektive erinnern wir an einige ausgewählte Beispiele für die Synergie zwischen der sehr anspruchsvollen chemischen Synthese und der Identifizierung von neuen vielversprechenden Wirkstoff‐Kandidaten als potenzielle Pharmazeutika. Die Weiterentwicklung von oft niedermolekularen Zielverbindungen zu solchen, deren Größe normalerweise mit biologischen Wirkstoffen assoziiert ist, wird ebenfalls dargelegt.

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Total Synthesis as a Resource in the Discovery of Potentially Valuable Antitumor Agents: Cycloproparadicicol

Cited by 30 publications

References 30 publications

Solution‐ and Solid‐Phase Synthesis of Radicicol (Monorden) and Pochonin C

Solution‐ and Solid‐Phase Synthesis of Radicicol (Monorden) and Pochonin C

Recent Advances in Macrocyclic Hsp90 Inhibitors

Zum Wirkungsbereich der chemischen Synthese: Aufbau einer Minipipeline in einem akademischen Labor

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