New paraherquamide antibiotics with anthelmintic activity.

Blanchflower, Simon E.; Banks, R. M.; Everett, Jeremy R.; Manger, Brian R.; Reading, Christopher

doi:10.7164/antibiotics.44.492

Cited by 95 publications

(34 citation statements)

References 14 publications

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“…Plagiospirolides GC-EIMS analysis was carried out on plagiospirolide A (140) to enable the structures of the spiroterpenoids isolated from the Panamanian liverwort Plagiochila moritziana to be determined. Diplophyllolide (141) and fusicoccadiene (142) were detected, possibly resulting from a retro-Diels-Alder reaction, and both substances were isolated from extracts of Plagiochila moritziana. [67] Further isolations of Plagiochila moritziana provided plagiospirolide E (143).…”

Section: Eudesmanolidesmentioning

confidence: 99%

“…Several related compounds, including VM55595 (343), VM55596 (336), VM55597 (337), and VM55599 (344), were also isolated from this strain. [141] VM55599 (344) is the only member of the family that contains an indole ring instead of an oxindole ring. The most recent additions to the paraherquamide family are SB203105 (339) and SB200437 (340), which were isolated in 1998 from an Aspergillus sp.…”

Section: Paraherquamidesmentioning

confidence: 99%

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Chemistry and Biology of Biosynthetic Diels–Alder Reactions

2003

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Nature's repertoire of biosynthetic transformations has recently been recognized to include the Diels-Alder cycloaddition reaction. Evidence now exists that there are enzymes that mediate the Diels-Alder reaction in secondary metabolic biosynthetic pathways. 2002 marked the 100th anniversary of Alder's birth and 75 years since the discovery of the Diels-Alder reaction. It would appear that living systems discovered and made use of this ubiquitously useful ring-forming reaction eons ago for the construction of complex natural products. In this Review an overview is given of all of the known classes of natural products (polyketides, isoprenoids, phenylpropanoids, alkaloids) that have been speculated to arise by a biological Diels-Alder reaction.

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Section: Eudesmanolidesmentioning

confidence: 99%

Section: Paraherquamidesmentioning

confidence: 99%

Chemistry and Biology of Biosynthetic Diels–Alder Reactions

2003

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“…The oxindole group itself gave a signature fragment ion at m/z 244. The 1 H NMR spectrum of PHQ has been published previously (Liesch and Wichmann, 1990;Blanchflower et al, 1991), and only the chemical shifts of the H12 to 17 protons are given here (Table 2).…”

Section: Aloysius Et Almentioning

confidence: 99%

“…M5 could not be isolated in sufficient amounts, and its activity against H. contortus was not tested; however, it was inactive against T. colubriformis in vivo (Liesch and Wichmann, 1990;Blanchflower et al, 1991).…”

Section: Metabolism Of Paraherquamidementioning

confidence: 99%

Comparative Disposition and Metabolism of Paraherquamide in Sheep, Gerbils, and Dogs

Aloysius

Elipe²,

Arison³

et al. 2008

Drug Metab Dispos

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ABSTRACT:The disposition and metabolism of paraherquamide (PHQ), a potent and broad-spectrum anthelminthic, were examined in sheep, dogs, and gerbils. The metabolism of PHQ in these species was extensive and marked by significant species differences both in vitro and in vivo. In sheep and gerbils, PHQ metabolism occurs mainly at the pyrrolidine moiety, generating several metabolites that, for the most part, retained nematodicidal activity in vitro. In dogs, the dioxepene group was also extensively metabolized, ultimately resulting in formation of a catechol and loss of pharmacological activity. After oral administration of [ 3 H]PHQ to intact sheep, gerbils, and dogs, the majority of the administered radioactivity was recovered in feces. Intact PHQ accounted for 0%(dogs) to ϳ30% (sheep and gerbils) of drug-related material in feces. A detailed investigation of the composition of the intestinal content of sheep indicated that a significant amount of the dose was still present in the rumen 24 h after dose and that PHQ underwent significant dehydration in the cecum. The oral pharmacokinetic parameters of PHQ in sheep and dogs suggest that its absorption is rapid in both species but that its apparent elimination rate is significantly higher in the dog (t 1/2 ϳ 1.5 h) than it is in sheep (t 1/2 ϳ 8.5 h). The short elimination half-life and the absence of PHQ or other active components in the dog gastrointestinal tract provide a potential explanation of the lack of efficacy of PHQ in this species.

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“…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. 80) Very recently, a Pfizer group 81) reported the isolation of anthelmintic metabolites VM54159, SB203105, SB200437 along with the non-tryptophan-derived metabolites possessing the common bicyclo[2.2.2] nucleus aspergillimide (identical to asperparaline A, 82,83) Fig.…”

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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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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New paraherquamide antibiotics with anthelmintic activity.

Cited by 95 publications

References 14 publications

Chemistry and Biology of Biosynthetic Diels–Alder Reactions

Chemistry and Biology of Biosynthetic Diels–Alder Reactions

Comparative Disposition and Metabolism of Paraherquamide in Sheep, Gerbils, and Dogs

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

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New paraherquamide antibiotics with anthelmintic activity.

Cited by 95 publications

References 14 publications

Chemistry and Biology of Biosynthetic Diels–Alder Reactions

Chemistry and Biology of Biosynthetic Diels–Alder Reactions

Comparative Disposition and Metabolism of Paraherquamide in Sheep, Gerbils, and Dogs

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

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