Synthetic ansamycins prepared by a ring-expanding Claisen rearrangement. Synthesis and biological evaluation of ring and conformational analogues of the Hsp90 molecular chaperone inhibitor geldanamycin

McErlean, Christopher S. P.; Proisy, Nicolas; Davis, Christopher J.; Boland, Nicola A.; Sharp, Swee Y.; Boxall, Kathy; Slawin, Alexandra M. Z.; Workman, Paul; Moody, Christopher J.

doi:10.1039/b615378j

Cited by 21 publications

(12 citation statements)

References 100 publications

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“…The NMR spectra are in agreement with those reported in the literature. 6 1 H NMR (300 MHz, CDCl 3 ): δ 11.04 (s, 1H, OH), 8.03 (d, J=8.1 Hz, 1H, H-3), 6.54 (d, J=2.7 Hz, 1H, H-6), 6.52 (dd, J=8.1, 2.7 Hz, 1H, H-4), 3.88 (s, 3H, OCH 3 ); 13 C NMR (75 MHz, CDCl 3 ): δ 167.0 (C), 157.9 (C), 127.7 (C) 126.9 (CH), 109.4 (CH), 101.3 (CH), 56.1 (OCH 3 ); IR (KBr):  cm -1 (OH), 3094 cm -1 (ArH), 2989, 2950, 2920 cm -1 (CH 3 ), 1622 cm -1 (C=C), 1509, 1334 cm -1 (NO 2 ), 1253, 1176, 1094 cm -1 (C-O).…”

Section: -Nitro-4-phenylphenol (2a)mentioning

confidence: 99%

Improved Protocol for Mononitration of Phenols with Bismuth(III) and Iron(III) Nitrates

Wasinska

Korczewska

Giurg

et al. 2014

Synthetic Communications

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Melting points were determined on a digital melting-point apparatus, using standard open capillary method. NMR spectra were recorded in CDCl 3 or DMSO-d 6 on a FT NMR spectrometer (300.1 for 1 H and 75.4 for 13 C or 600.6 for 1 H and 151.0 for 13 C) at 22 °C. The chemical shifts values  are given in parts per million (ppm) downfield relative to TMS, and coupling constants J are in Hertz (Hz). Multiplicity (s=singlet, d=doublet, t=triplet, dd=doublet of doublets, m=multiplet, br=broad). Residual solvent central peaks were measured; CDCl 3  1 H 7.26, 13 C 77.00; DMSO-d 6  1 H 2.50, 13 C 39.43. Infrared spectra were recorded on a FT-IR instrument in KBr pellets or as thin films, and wave number were expressed in cm -1 . The progress of the reaction was monitored by thin layer chromatography on silica gel coated plates (Merck 60F 254 ), and visualization was accomplished with UV light and/or on iodine vapour. Chromatographic purification was performed using silica gel column chromatography (Merck 60, particle size 70-230 mesh). Yields refer to isolated compounds, estimated to be >98% pure as determined by 1 H NMR.Bi(NO 3 ) 3 •5H 2 O, Fe(NO 3 ) 3 •9H 2 O, (NH 4 ) 2 Ce(NO 3 ) 6, substituted phenols, silica gel 60 (70-230 mesh), acetone and other solvents were purchased from commercial suppliers.

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Section: -Nitro-4-phenylphenol (2a)mentioning

confidence: 99%

Improved Protocol for Mononitration of Phenols with Bismuth(III) and Iron(III) Nitrates

Wasinska

Korczewska

Giurg

et al. 2014

Synthetic Communications

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“…In a different study on the SAR of GA, McErlean et al synthesized derivatives where only a few substituents were present on GA’s backbone [36]. Thus, derivatives containing only the C-2, C-14 methyl, C-17 methoxy, or C-17 carbamate were made (Fig.…”

Section: Natural Product Macrocycle Hsp Inhibitorsmentioning

confidence: 99%

“…This can be attributed to the lack of hydrogen bonding networks between the amino acids within the N-terminal ATP binding pocket and the substituents on GA’s macrocycle. It is interesting to note that these basic stripped down derivatives exhibited micromolar potency in the drug-resistant HCT-116 colon cancer cell line, however this is attributed to the compounds acting via a different mechanism other than through modulating Hsp90’s activity [36]. …”

Section: Natural Product Macrocycle Hsp Inhibitorsmentioning

confidence: 99%

Macrocyclic Inhibitors of Hsp90

Johnson¹,

Singh²,

Nazarova³

et al. 2010

CTMC

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Heat shock proteins (HSP) are a family of highly conserved proteins, whose expression increases in response to stresses that may threaten cell survival. Over the past decade, heat shock protein 90 (Hsp90) has emerged as a potential therapeutic target for cancer as it plays a vital role in normal cell maturation and acts as a molecular chaperone for proper folding, assembly, and stabilization of many oncogenic proteins. To date, a majority of Hsp90 inhibitors that have been discovered are macrocycles. The relatively rigid conformation provided by the macrocyclic scaffold allows for a selective interaction with a biological target such as Hsp90. This review highlights the discovery and development of nine macro-cycles that inhibit the function of Hsp90, detailing their potency and the client proteins affected by Hsp90 inhibition.

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“…[12][13][14] As a result, significant research efforts have been devoted to discovering and synthesising potent small molecule inhibitors of Hsp90, a topic which has been the focus of many reviews. 2,9,10,[15][16][17][18][19][20][21][22] Seminal research in this area was centred on the natural products geldanamycin 1, 23,24 a benzoquinone ansamycin polyketide, which has been the subject of previously published research from our group, [25][26][27] and radicicol 2, a resorcylic acid lactone (RAL) first isolated in 1953, 28 which is the most potent in vitro Hsp90 inhibitor found to date (IC 50 = 20 -23 nM). [29][30][31] Unfortunately, radicicol exhibits no in vivo activity, which may be due to the highly sensitive functionality present in the molecule, including an epoxide and a conjugated dienone, both of which are readily metabolised.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of macrolactam analogues of radicicol and their binding to heat shock protein Hsp90

et al. 2014

Self Cite

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Macrolactam analogues of the natural lactone radicicol bind to Hsp90. AbstractA series of macrolactam analogues of the naturally occurring resorcylic acid lactone radicicol have been synthesised from methyl orsellinate in 7 steps, involving chlorination, protection of the two phenolic groups, and hydrolysis to the benzoic acid.Formation of the dianion and quenching with a Weinreb amide results in acylation of the toluene methyl group that is followed by amide formation and ring closing metathesis to form the macrocyclic lactam. Final deprotection of the phenolic groups gives the desired macrolactams whose binding to the N-terminal domain of yeast *

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Synthetic ansamycins prepared by a ring-expanding Claisen rearrangement. Synthesis and biological evaluation of ring and conformational analogues of the Hsp90 molecular chaperone inhibitor geldanamycin

Cited by 21 publications

References 100 publications

Improved Protocol for Mononitration of Phenols with Bismuth(III) and Iron(III) Nitrates

Improved Protocol for Mononitration of Phenols with Bismuth(III) and Iron(III) Nitrates

Macrocyclic Inhibitors of Hsp90

Synthesis of macrolactam analogues of radicicol and their binding to heat shock protein Hsp90

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