Divergent Synthesis and Chemical Reactivity of Bicyclic Lactone Fragments of Complex Rearranged Spongian Diterpenes

Schnermann, Martin J.; Beaudry, Christopher M.; Genung, Nathan E.; Canham, Stephen M.; Untiedt, Nicholas L.; Karanikolas, Breanne; Sütterlin, Christine; Overman, Larry E.

doi:10.1021/ja207727h

Cited by 30 publications

(43 citation statements)

References 57 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…32 To our knowledge, the only reported example of lysine pyrrolylation with a 1,4-dicarbonyl-containing natural product involves the lysozyme modification with spongian diterpenes, a reaction proposed to be responsible for Golgi-modifying properties of these marine metabolites. 33 …”

mentioning

confidence: 99%

Fungal metabolite ophiobolin A as a promising anti-glioma agent: In vivo evaluation, structure–activity relationship and unique pyrrolylation of primary amines

Dasari¹,

Masi

Lisy

et al. 2015

Bioorganic & Medicinal Chemistry Letters

View full text Add to dashboard Cite

Glioblastoma, the most common form of malignant primary brain tumor, is characterized by resistance to apoptosis, which is largely responsible for the low effectiveness of the classical chemotherapeutic approaches based on apoptosis induction in cancer cells. Previously, a fungal secondary metabolite ophiobolin A was found to have significant activity against apoptosis-resistant glioblastoma cells through the induction of a non-apoptotic cell death, thus, offering an innovative strategy to combat this type of cancer. The current work describes the results of a preliminary evaluation of ophiobolin A in an in vivo glioblastoma model and its chemical derivatization to establish first synthetically generated structure-activity relationship. The synthetic work has also led to the discovery of a unique reaction of ophiobolin A with primary amines suggesting the possibility of pyrrolylation of lysine residues on its intracellular target protein(s).

show abstract

mentioning

confidence: 99%

Fungal metabolite ophiobolin A as a promising anti-glioma agent: In vivo evaluation, structure–activity relationship and unique pyrrolylation of primary amines

Dasari¹,

Masi

Lisy

et al. 2015

Bioorganic & Medicinal Chemistry Letters

View full text Add to dashboard Cite

show abstract

“…The modified lysozymes were subjected to trypsin digestion followed by MALDI-MS/MS, revealing covalent modification of the most surface-accessible Lys residues, K33 and K97. 36 This investigation provided evidence for the Paal–Knorr modification of an as yet elusive target. They also demonstrated that pro-drug like motifs can be used to trigger Paal–Knorr reactivity and associated cellular activity.…”

Section: Paal–knorr Modifications Of Biological Targets With Naturamentioning

confidence: 72%

“…3) as well as the blockage of protein transport from the Golgi apparatus to plasma membranes. 35,36 This activity was retained by the structurally simplified analogue 30 , indicating that the dioxabicyclic lactone fragment is the key part of the pharmacophore.…”

Section: Paal–knorr Modifications Of Biological Targets With Naturamentioning

confidence: 94%

“…4a). 36 Using ESI-MS analysis, they observed an increase in m / z of 164 in phosphate buffer (pH 7) when treated with 29 , clearly corresponding to the product of a pyrrole-forming reaction of one lysine residue with 29 (Fig. 4c).…”

Section: Paal–knorr Modifications Of Biological Targets With Naturamentioning

confidence: 99%

“…36 Specifically, it was shown that 29 (R = H) produced pyrrole 33 in high yield in its reaction with 5 equivalents of benzylamine in aq. DMSO, while 30 (R = OAc) yielded pyrrole 36 when treated with 2.5 equivalents of perdeutero-benzylamine in THF- d 8 .…”

Section: Paal–knorr Modifications Of Biological Targets With Naturamentioning

confidence: 99%

See 2 more Smart Citations

Covalent modification of biological targets with natural products through Paal–Knorr pyrrole formation

Kornienko

Clair

2017

Nat. Prod. Rep.

View full text Add to dashboard Cite

Natural products and endogenous metabolites engage specific targets within tissues and cells through complex mechanisms. This review examines the extent to which natural systems have adopted the Paal–Knorr reaction to engage nucleophilic amine groups within biological targets. Current understanding of this mode of reactivity is limited by only a few examples of this reaction in a biological context. This highlight is intended to stimulate the scientific community to identify potential research directions and applications of the Paal–Knorr reaction in native and engineered biological systems.

show abstract

Substituent‐Controlled Selective Synthesis of Spirooxindoles and Oxazolyloxindoles via Two Tandem Reactions

et al. 2015

View full text Add to dashboard Cite

Ac ommon synthetic method involving two tandem processes to preparev arieties of oxindole derivatives, which are important bioactive cores that exist widely in natural products andd rugs,f rom similar materials under mild conditions is described. Herein as ubstituent-controlled product-selectives trategy succeeded in synthesizingspirooxindoles and oxazolyloxindoles with excellent diastereoselectivity from methyleneindolinones and a-bromoamides. The synthesis has clear chemoselectivity,w hich relies on differents ubstituent groups at the nitrogen atomso fa-bromoamides.F rom mechanism analysis, the spirooxindoles were constructed via elimination-Michael-Michael addition from N-benzyloxy-a-bromoamides, while oxazolyloxindolesw ere achieved via cyclization-Michael addition from N-benzoyl-a-bromoamides, both of which cleverlyc ombined the nucleophilic component formation and nucleophile-triggered cascade reactions in one pot.Various oxindole derivatives and their analogues are found in many natural products [1] and bioactivec ompounds, [2] including tetrasubstituted carbon stereocenters, [3] spirocyclic [4] or monocyclic structures, [5] and entirely-carbon [6] or heteroatom-containing compounds. [7] They are known for functional diversity, and could be used as crucial intermediates as well as challenging targets in many total syntheses. [8] For example, Spiroquinazoline 1a (Figure 1), [9] which was isolated from av ariety of fungi of the genera Penicillium and Aspergillus,i nhibits substance P( SP) binding to human NK-1 receptor and, therefore, may serve as al ead compound ford eveloping analgesics. Alantrypinone (1c) [10] potently inhibits insect gamma-aminobutyric acid (GABA) receptors but is much less active toward mammalian GABA receptors. Although an umber of syntheses of these compounds were reported, efficient and elegant strategies are still in great demand. Particularly,t here are very few common strategies accesst ov arieties of molecules using same or similar structuralm otifs [11] and conditions. [12] In addition, the control of product formation is often achieved by slight modification of reagents, substrates, or other conditions. [13] Therefore, it is an important and necessary challenge to develop such commons trategies to synthesize relateda nd more sophisticated spirooxindole structures, which have attracted the attention of synthetic chemists. [14] Herein we explored as ynthetics trategy ideally involving two tandemr eactions by combining the nucleophilic component formation and nucleophile-triggeredc ascade reactions in one pot. The method is highly chemoselective (Scheme 1). The key to these conversionsf or controlling the twot andem reactions lies in differents ubstituents at the nitrogen atoms of abromoamides, from which two types of nucleophilic intermedi-Figure 1. Examples of natural and syntheticbioactive compounds.Scheme1.Twot andem reactions. Bn = benzyl;Bz= benzoyl.

show abstract

Divergent Synthesis and Chemical Reactivity of Bicyclic Lactone Fragments of Complex Rearranged Spongian Diterpenes

Cited by 30 publications

References 57 publications

Fungal metabolite ophiobolin A as a promising anti-glioma agent: In vivo evaluation, structure–activity relationship and unique pyrrolylation of primary amines

Fungal metabolite ophiobolin A as a promising anti-glioma agent: In vivo evaluation, structure–activity relationship and unique pyrrolylation of primary amines

Covalent modification of biological targets with natural products through Paal–Knorr pyrrole formation

Substituent‐Controlled Selective Synthesis of Spirooxindoles and Oxazolyloxindoles via Two Tandem Reactions

Contact Info

Product

Resources

About