Chemical modification of paraherquamide. 1. Unusual reactions and absolute stereochemistry

Blizzard, Timothy A.; Marino, Gaye; Mrozik, Helmut; Fisher, Michael H.; Hoogsteen, Karst; Springer, James P.

doi:10.1021/jo00272a039

Cited by 32 publications

(8 citation statements)

References 2 publications

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“…This compound was condensed with the N-para-methoxybenzyl-protected cyclo-Gly-L-Pro diketopiperazine (75) to give the a,b-unsaturated species 76, which was the final product reported in this study. No further work from this laboratory was reported using this approach and attempts to conduct Diels-Alder reactions were not described.…”

Section: )mentioning

confidence: 80%

“…[65][66][67][68][69] The parent and most potent member, paraherquamide A, was isolated from cultures of Penicillium paraherquei as first described by Yamazaki in 1980. 70,71) The simplest member, paraherquamide B, plus five other structurally related paraherquamides C-G were isolated from Penicillium charlesii (fellutanum) (ATCC 20841) in 1990 at Merck & Co. [72][73][74][75][76][77][78] and concomitantly at SmithKline Beecham. 79) Subsequently, three additional related compounds, VM55596, VM55597 and VM55599 were discovered by the same group at SmithKline Beecham from Penicillium strain IMI 332995.…”

Section: The Paraherquamides Marcfortines and Related Alkaloidsmentioning

confidence: 99%

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Total Synthesis and Biosynthesis of the Paraherquamides: An Intriguing Story of the Biological Diels–Alder Construction

Williams

2002

Chem. Pharm. Bull.

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The paraherquamides constitute an unusual family of prenylated indole alkaloids that are secondary metabolites produced by Penicillium sp. and Aspergillus sp. fungi. This review will cover both the biosynthesis as well as the chemical synthesis of this family of natural products. Particular emphasis will be placed on the provocative hypothesis that the core bicyclo[2.2.2]diazaoctan ring system, which is common to this entire family, is formed by a biological DielsAlder reaction.Despite its widespread use in synthetic organic chemistry, the Diels-Alder cycloaddition reaction does not occur frequently in nature. 1,2) There are just a few reports in the literature claiming the identification of an enzyme that catalyzes this most ubiquitous synthetic ring-forming reaction. [3][4][5][6] A possible explanation for this is that, enzymes generally catalyze reactions by stabilizing the structure and charge of the developing transition state. For most reactions subject to this stratagem of catalysis, both the starting substrate and the product differ significantly with respect to structure from the transition state; it is this fundamental difference that allows for turnover; i.e., both the product and the starting substrate must bind to the enzyme less tightly than the transition state structure. In the Diels-Alder reaction, the transition state is highly ordered and closely resembles the structure of the product (see Fig. 1, below). In other words, an enzyme that was designed to stabilize the transition state structure for this reaction would be expected to be inhibited by the product (via tight binding) and turnover (thus catalysis) would be precluded. It is from within the excitement of this fundamental question, that this review will hold as a guiding light.The only examples of protein-catalyzed Diels-Alder reactions are those of catalytic antibodies that have recently been shown to catalyze the intermolecular [4ϩ2] cycloaddition reaction.7-9) In these cases, the initial Diels-Alder adducts were high-energy substances that significantly change their structure or conformation after the initial cyclocondensation and were subsequently released from the antibody CDR (allowing for turnover). In addition, ribozymes have been reported to catalyze the Diels-Alder reaction and findings in this area have been reviewed. 10) The Penicillium sp. that produces the brevianamides/paraherquamides may be a rare, but vitally important example of the existence of DielsAlderases. It is further significant to note in the context of the catalytic antibody stratagem that, the brevianamide DielsAlder adducts (which are proposed to be the brevianamides themselves) are very rigid substances; therefore, a significant change in conformation or structure is either impossible or highly unlikely. Elucidation of the mechanism for turnover in the purported paraherquamide and brevianamide [4ϩ2] cycloaddition reaction should be an extremely interesting and significant finding.In order to do proper justice to the history of the biosynthetic Diels-Alder p...

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Section: )mentioning

confidence: 80%

Section: The Paraherquamides Marcfortines and Related Alkaloidsmentioning

confidence: 99%

Total Synthesis and Biosynthesis of the Paraherquamides: An Intriguing Story of the Biological Diels–Alder Construction

Williams

2002

Chem. Pharm. Bull.

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“…Our work has focused on the families of monoketopiperazines (MKPs) such as the paraherquamides (Phq) [2,3] and malbrancheamides (Mal) [4], and diketopiperazines (DKP) such as the stephacidins [5], notoamides (Not) [6‐8], and brevianamides (Bvn) (Figs 1–3) [9]. These molecules display significant biological activities with potential therapeutic value such as anthelmintics [10‐13], vasodilators [14], and anticancer agents [15]. All bear a similar core scaffold, but vary structurally based on key functionalities including oxidation, halogenation, and additional ring systems.…”

Section: Introduction To Fungal Indole Alkaloidsmentioning

confidence: 99%

Enzyme evolution in fungal indole alkaloid biosynthesis

Fraley

Sherman

2020

The FEBS Journal

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The class of fungal indole alkaloids containing the bicyclo[2.2.2]diazaoctane ring is comprised of diverse molecules that display a range of biological activities. While much interest has been garnered due to their therapeutic potential, this class of molecules also displays unique chemical functionality, making them intriguing synthetic targets. Many elegant and intricate total syntheses have been developed to generate these alkaloids, but the selectivity required to produce them in high yield presents great barriers. Alternatively, if we can understand the molecular mechanisms behind how fungi make these complex molecules, we can leverage the power of nature to perform these chemical transformations. Here, we describe the various studies regarding the evolutionary development of enzymes involved in fungal indole alkaloid biosynthesis.

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“…19 An alternative approach involves a flavin-dependent amine oxidase, which converts fumiquinazoline A (5) to the spiro-hemiaminal fumiquinazoline C (6). 20 For griseofulvin (7), the unique spirocyclic scaffold is critical for its biological activity. The enzyme responsible for this transformation is proposed to be a P450, 21 and the diradical mechanism involved in the spirocenter formation is similar to that in geodin (4) biosynthesis.…”

Section: Introductionmentioning

confidence: 99%

“…The enzyme responsible for this transformation is proposed to be a P450, 21 and the diradical mechanism involved in the spirocenter formation is similar to that in geodin (4) biosynthesis. 19 Alternatively, the enzyme could perform an epoxidation, and subsequent dehydration and cyclization would convert griseophenone B (8) into the final product desmethyl-dehydrogriseofulvin (7). Of the studies detailing spirocycle formation in natural product biosynthesis, work on the spirotryprostatins revealed intricate enzymatic details for this conversion.…”

Section: Introductionmentioning

confidence: 99%

Molecular Basis for Spirocycle Formation in the Paraherquamide Biosynthetic Pathway

Fraley¹,

Haatveit²,

Ye³

et al. 2019

Preprint

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<div> <div> <div> <p>The paraherquamides are potent anthelmintic natural products with complex heptacyclic scaffolds. One key feature of these molecules is the spiro-oxindole moiety that lends a strained three-dimensional architecture to these structures. The flavin monooxygenase PhqK was found to catalyze spirocycle formation through two parallel pathways in the biosynthesis of paraherquamides A and G. Two new paraherquamides (K and L) were isolated from a ΔphqK strain of Penicillium simplicissimum, and subsequent enzymatic reactions with these compounds generated two additional metabolites paraherquamides M and N. Crystal structures of PhqK in complex with various substrates provided a foundation for mechanistic analyses and computational studies. While it is evident that PhqK can react with various substrates, reaction kinetics and molecular dynamics simulations indicated that the dioxepin-containing paraherquamide L was the favored substrate. Through this effort, we have elucidated a key step in the biosynthesis of the paraherquamides, and provided a rationale for the selective spirocyclization of these powerful anthelmintic agents. </p></div></div><div><div> </div> </div> </div>

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Chemical modification of paraherquamide. 1. Unusual reactions and absolute stereochemistry

Cited by 32 publications

References 2 publications

Total Synthesis and Biosynthesis of the Paraherquamides: An Intriguing Story of the Biological Diels–Alder Construction

Total Synthesis and Biosynthesis of the Paraherquamides: An Intriguing Story of the Biological Diels–Alder Construction

Enzyme evolution in fungal indole alkaloid biosynthesis

Molecular Basis for Spirocycle Formation in the Paraherquamide Biosynthetic Pathway

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Chemical modification of paraherquamide. 1. Unusual reactions and absolute stereochemistry

Cited by 32 publications

References 2 publications

Total Synthesis and Biosynthesis of the Paraherquamides: An Intriguing Story of the Biological Diels&ndash;Alder Construction

Total Synthesis and Biosynthesis of the Paraherquamides: An Intriguing Story of the Biological Diels&ndash;Alder Construction

Enzyme evolution in fungal indole alkaloid biosynthesis

Molecular Basis for Spirocycle Formation in the Paraherquamide Biosynthetic Pathway

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Product

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Total Synthesis and Biosynthesis of the Paraherquamides: An Intriguing Story of the Biological Diels–Alder Construction

Total Synthesis and Biosynthesis of the Paraherquamides: An Intriguing Story of the Biological Diels–Alder Construction