Synthesis and evaluation of 8,9-amido analogs of geldanamycin

Andrus, Merritt B.; Wong, Yong; Liu, Jing; Beebe, Kristin; Neckers, Leonard Μ.

doi:10.1016/j.tetlet.2009.09.091

Cited by 10 publications

(9 citation statements)

References 34 publications

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“…Unfortunately, both new geldanamycin derivatives have lost their ability to promote HER2 degradation in SK-Br3 cells (ED 50 > 20 mM, compared to geldanamycin with an ED 50 of 5 nM). 91 5.3 Semisynthetic approaches 5.3.1 Semisynthetic alterations at the quinone/hydroquinone moiety. Semisynthesis is a widely employed technique to access new derivatives of complex natural products.…”

Section: Total Synthesis Approaches To Geldanamycin and Derivativesmentioning

confidence: 99%

Targeting heat-shock-protein 90 (Hsp90) by natural products: geldanamycin, a show case in cancer therapy

et al. 2013

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In this review recent progress in the development of heat shock proteins (Hsp90) in oncogenesis is illuminated. Particular emphasis is put on inhibitors such as geldanamycin and analogues that serve as a natural product show case. Hsp90 has emerged as an important target in cancer therapy and/or against pathogenic cells which elicit abnormal Hsp patterns. Competition for ATP by geldanamycin and related compounds abrogate the chaperone function of Hsp90. In this context, this account pursues three topics in detail: a) Hsp90 and its biochemistry, b) Hsp90 and its role in oncogenesis and c) strategies to create compound libraries of structurally complex inhibitors like geldanamycin on which SAR studies and the development of drugs that are currently in different stages of clinical testing rely.

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Section: Total Synthesis Approaches To Geldanamycin and Derivativesmentioning

confidence: 99%

Targeting heat-shock-protein 90 (Hsp90) by natural products: geldanamycin, a show case in cancer therapy

et al. 2013

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“…Subsequently, Andrus and co-workers completed the first total synthesis of geldanamycin with their work demonstrating the difficultly in accessing the final C-17 methoxy benzoquinone moiety. , A number of different protecting groups were investigated by Andrus, as well as the Panek group, to reliably achieve the final deprotection to yield the desired p -benzoquinone. , Panek and co-workers were able to extend their synthetic route to access other ansamycin natural products, with a particular focus on non-benzoquinone analogs such as reblastatin and autolytimycin . Despite these robust efforts, a facile method to access geldanamycin analogs has thus far eluded the field, with only a handful of synthetic analogs reported …”

Section: Case Studies In Improving Natural Productsmentioning

confidence: 99%

“…79 Despite these robust efforts, a facile method to access geldanamycin analogs has thus far eluded the field, with only a handful of synthetic analogs reported. 80 Semisynthetic methods, however, have demonstrated significant utility for the derivatization of geldanamycin. The α,β-unsaturated quinone was immediately recognized as a redox liability of the core structure but also as a potentially powerful site of reactivity.…”

Section: ■ Introductionmentioning

confidence: 99%

Fixing the Unfixable: The Art of Optimizing Natural Products for Human Medicine

Yñigez-Gutierrez

Bachmann

2019

J. Med. Chem.

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Molecules isolated from natural sources including bacteria, fungi, and plants are a long-standing source of therapeutics that continue to add to our medicinal arsenal today. Despite their potency and prominence in the clinic, complex natural products often exhibit a number of liabilities that hinder their development as therapeutics, which may be partially responsible for the current trend away from natural product discovery, research, and development. However, advances in synthetic biology and organic synthesis have inspired a new generation of natural product chemists to tackle powerful undeveloped scaffolds. In this Perspective, we will present case studies demonstrating the historical and current focus on making targeted, but significant, changes to natural product scaffolds via biosynthetic gene cluster manipulation, total synthesis, semisynthesis, or a combination of these methods, with a focus on increasing activity, decreasing toxicity, or improving chemical and pharmacological properties.

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“…58 Table 7 documents the syn-selectivity of boron-mediated aldol additions of three glycolic acid esters derived from norephedrine. [62][63][64][65] Many aldehydes gave excellent diastereoselectivities but there were exceptions (CH=CMe 2 : entries 6 and 14; C≡CPh: entry 11). The norephedrine-appendage was removed from the aldol syn-61 (entry 13; PG = PMB, R = CH=CH 2 ) with LiOH (not shown) to give the syn-configured (2R,3S)-3-hydroxy-2-(4-methoxybenzyloxy)pent-4enoic acid (footnote b of Table 7 must not be overlooked for interpreting this stereostructure correctly) in 87% yield.…”

Section: Review Syn Thesismentioning

confidence: 99%

Stereoselective Aldol Additions of Glycolic Acid and Its Derivatives

Engesser¹,

Brückner²

2019

Synthesis

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This review gives a comprehensive overview of aldol additions of glycolic acid derivatives to achiral aldehydes and acetals affording α,β-dihydroxycarboxylic acids or derivatives thereof. The focus is on simple diastereoselectivity. A selection of related aldol additions is also presented: aldol additions of glycolic acid derivatives to ketones with two different substituents and aldol additions of α-substituted glycolic acid derivatives.1 Introduction1.1 Organization of this Review1.2 Outside the Scope of this Review: Aldol Additions Giving α,β-Dihydroxyaldehydes and α,β-Dihydroxyketones Diastereoselectively1.3 Non-Aldol Routes to Diastereomerically Pure α,β-Dihydroxycarboxylic Acid Derivatives2 Aldol Additions of Glycolic Acid (Derivative) Enolates to Aldehydes2.1 Aldol Additions of Glycolate Enolates (‘Glycolic Acid Dianions’)2.2 Aldol Additions of Glycolic Ester Enolates2.3 Aldol Additions of Glycolic Thioester Enolates2.4 Aldol Additions of Glycolimide Enolates2.5 Aldol Additions of Glycolamide Enolates2.6 Mukaiyama Aldol Additions of Silyl Ketene Acetals of Glycolic Esters and Thioesters2.7 Aldol Additions of Glycoloyl Chlorides via Acyl Ammonium Enolates3 Aldol-Providing Substitutions of Glycolimide Enolates in Acetals4 Additions Related to Aldol Additions of Glycolic Acid Derivative Enolates to Aldehydes4.1 Selected Simply Diastereoselective Aldol Additions of Enolates of Glycolic Acid Derivatives to Ketones with Two Different Substituents4.2 Simply Diastereoselective Aldol Additions of Enolates of Glycolic Acid Derivatives with a Methyl Substituent at C-α (Lactic Acid Derivatives)5 Conclusion

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Synthesis and evaluation of 8,9-amido analogs of geldanamycin

Cited by 10 publications

References 34 publications

Targeting heat-shock-protein 90 (Hsp90) by natural products: geldanamycin, a show case in cancer therapy

Targeting heat-shock-protein 90 (Hsp90) by natural products: geldanamycin, a show case in cancer therapy

Fixing the Unfixable: The Art of Optimizing Natural Products for Human Medicine

Stereoselective Aldol Additions of Glycolic Acid and Its Derivatives

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