Synthesis and structure–activity relationships of radicicol derivatives and WNT-5A expression inhibitory activity

Shinonaga, Hideki; Noguchi, Toshiya; Ikeda, Akiko; Aoki, Mari; Fujimoto, Natsuko; Kawashima, Akira

doi:10.1016/j.bmc.2009.04.060

Cited by 18 publications

(15 citation statements)

References 33 publications

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“…The planar structure of 5 is identical to semisynthetic epoxide-opened diasteromers of natural radicicol described in both patent 26 and peer-reviewed literature. 27,28 The configuration of position C-2 is proposed to be analogous to that of radicicol ( 1 ), and the anti relative configuration for the 1,2-diol of 5 is assigned based on a vicinal proton coupling constant of J 4,5 = 5.4 Hz, which matched the reported value of the synthetic anti diastereomer (lit. 27 J 4,5 = 6.1 Hz).…”

Section: Resultsmentioning

confidence: 79%

Study of Marine Natural Products Including Resorcyclic Acid Lactones from Humicola fuscoatra That Reactivate Latent HIV-1 Expression in an in Vitro Model of Central Memory CD4+ T Cells

et al. 2014

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An extract of Humicola fuscoatra (UCSC strain no. 108111A) was shown to reactivate latent HIV-1 expression in an in vitro model of central memory CD4+ T cells. We report the bioassay-guided isolation and structure determination of several resorcyclic acid lactones, including four known compounds, radicicol (1, aka. monorden) and pochonins B (2), C (3), and N (4), and three new analogues, radicicols B–D (5–7). Compounds 1–3 and 5 showed moderate activities in the memory T cell model of HIV-1 latency. Radicicol (1) displayed lower potency in reactivating latent HIV-1 (EC50 = 9.1 μM) relative to the HDAC inhibitors apicidin (EC50 = 0.3 μM), romidepsin (EC50 = 0.003 μM), and SAHA (EC50 = 0.6 μM); however, it achieved equivalent maximum efficacy relative to the positive control compounds (98% of SAHA and romidepsin).

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Section: Resultsmentioning

confidence: 79%

Study of Marine Natural Products Including Resorcyclic Acid Lactones from Humicola fuscoatra That Reactivate Latent HIV-1 Expression in an in Vitro Model of Central Memory CD4+ T Cells

et al. 2014

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“…SC0924 was fermented and the resulting cultures were extracted as described previously. 22 The CHCl 3 -soluble extract was separated by silica gel, polyamide, ODS, and Sephadex LH-20 column chromatography (CC), followed by preparative HPLC to furnish the new compounds paecilomycins N–P ( 1 – 3 ), dechloropochonin I ( 4 ), monocillins VI ( 5 ) and VII ( 6 ), 4′-methoxymonocillin IV ( 7 ), and 4′-hydroxymonocillin IV ( 8 ), and the known compounds 2′ α -hydroxymonocillin II ( 9 ), 23 monocillins I–IV ( 10 – 13 ), 24 radicicol ( 14 ), 25 monorden D ( 15 ), 26 lasicicol ( 16 ), 27 and hypothemycin ( 17 ). 28 The known compounds were characterized by comparing their spectroscopic data with the published values.…”

Section: Resultsmentioning

confidence: 99%

Antifungal and Cytotoxic β-Resorcylic Acid Lactones from a Paecilomyces Species

Xue

et al. 2017

J. Nat. Prod.

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Eight new β-resorcylic acid lactones (RALs), including the hypothemycin-type compounds paecilomycins N–P (1–3) and the radicicol-type metabolites dechloropochonin I (4), monocillins VI (5) and VII (6), 4′-hydroxymonocillin IV (7), and 4′-methoxymonocillin IV (8), along with nine known RALs (9–17), were isolated from the cultures of Paecilomyces sp. SC0924. Compounds 1 and 2 feature a novel 6/11/5 ring system and 3 is the first 5′-keto RAL. The structures of 1–8 were elucidated on the basis of extensive spectroscopic analysis, X-ray diffraction analysis, and theoretical calculations of ECD spectra. Compounds 3, 5, and 6 exhibit cytotoxicity against MCF-7, A549, and HeLa cells, and compounds 5 and 7 display antifungal activity against Peronophythora litchii.

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“…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: 97%

“…110 (1) and (c) radicicol (10) co-crystallised with yeast Hsp90. Images from the article by Pearl et al 59 Moody and Shinonaga have developed synthetic radicicol analogues in which the dienone moiety has been removed (12 and 13, Figure 2.9), 104,109,110 while Danishefsky has replaced the dienone of cycloproparadicicol with a triazole (14). 112 Moody has also incorporated a triazole into the macrocycle to give compound 15 in order to investigate the benefits of additional H-bonding potential.…”

Section: Direct Analogues Of Radicicolmentioning

confidence: 97%

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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Synthesis and structure–activity relationships of radicicol derivatives and WNT-5A expression inhibitory activity

Cited by 18 publications

References 33 publications

Study of Marine Natural Products Including Resorcyclic Acid Lactones from Humicola fuscoatra That Reactivate Latent HIV-1 Expression in an in Vitro Model of Central Memory CD4+ T Cells

Study of Marine Natural Products Including Resorcyclic Acid Lactones from Humicola fuscoatra That Reactivate Latent HIV-1 Expression in an in Vitro Model of Central Memory CD4+ T Cells

Antifungal and Cytotoxic β-Resorcylic Acid Lactones from a Paecilomyces Species

Recent Advances in Macrocyclic Hsp90 Inhibitors

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