Paraherquamide A
(Synonyms: 对郝喹酰胺A,PNU-97333) 目录号 : GC44563A mycotoxin anthelmintic
Cas No.:77392-58-6
Sample solution is provided at 25 µL, 10mM.
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Paraherquamide A is a mycotoxin anthelmintic originally isolated from P. paraherquei. It binds to acetylcholine receptors (IC50 = 0.5 nM for head homogenates of M. domestica) and acts as an antagonist. Paraherquamide A is toxic to C. elegans (LD50 = 2.5 µg/ml) and effective against T. colubriformis infection in gerbils when used at doses ranging from 0.39 to 200 mg/kg. It is toxic to mice (LD50 = 14.9 mg/kg).
Cas No. | 77392-58-6 | SDF | |
别名 | 对郝喹酰胺A,PNU-97333 | ||
Canonical SMILES | CC(C=CO1)(C)OC2=C1C(NC([C@]34C[C@](CN(CC[C@]5(O)C)[C@]5(C6=O)C7)(N6C)[C@]7([H])C3(C)C)=O)=C4C=C2 | ||
分子式 | C28H35N3O5 | 分子量 | 493.6 |
溶解度 | DMF: soluble,DMSO: soluble,Ethanol: soluble,Methanol: soluble | 储存条件 | Store at -20°C |
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1 mg | 5 mg | 10 mg | |
1 mM | 2.0259 mL | 10.1297 mL | 20.2593 mL |
5 mM | 0.4052 mL | 2.0259 mL | 4.0519 mL |
10 mM | 0.2026 mL | 1.013 mL | 2.0259 mL |
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2.
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Studies on Paraherquamide Biosynthesis: Synthesis of Deuterium-Labeled 7-Hydroxy-Pre-Paraherquamide, a Putative Precursor of Paraherquamides A, E & F
Tetrahedron 2009 Apr 18;65(16):3246-3260.PMID:20161298DOI:10.1016/j.tet.2008.08.102.
The stereocontrolled, asymmetric synthesis of triply deuterium-labeled 7-hydroxy-pre-paraherquamide (27) was accomplished, employing a diastereoselective intramolecular S(N)2' cyclization strategy. The deuterium-labeled substrate was interrogated in a precursor incorporation experiment in the paraherquamide-producing organism Penicillium fellutanum. The isolated sample of Paraherquamide A revealed incorporation of one of the two geminal deuterons of the CD(2)-group at C-12 exclusively. The lack of signals for the second deuteron of the CD(2)-group at C-12 and for the CH(2)D-group (C-22/C-23) suggests that this substrate suffered an unexpectedly selective catabolic degradation and metabolic re-incorporation of deuterium thus casting doubt on the proposed biosynthetic intermediacy of 27. Consideration of alternative biosynthetic pathways, including oxidation of the indole C-6 position prior to hydroxylation at C-7 or oxidative spiro-contraction of pre-paraherquamide prior to construction of the dioxepin is discussed. The synthesis of 27 also provides for a concise, asymmetric stereocontrolled synthesis of an advanced intermediate that will be potentially useful in the synthesis of paraherquamide E & F.
Marcfortine and paraherquamide class of anthelmintics: discovery of PNU-141962
Curr Top Med Chem 2002 Jul;2(7):779-93.PMID:12052190DOI:10.2174/1568026023393705.
Three distinct chemical classes for the control of gastrointestinal nematodes are available: benzimidazoles, imidazothiazoles, and macrocyclic lactones. The relentless development of drug resistance has severely limited the usefulness of such drugs and the search for a new class of compounds preferably with a different mode of action is an important endeavor. Marcfortine A (1), a metabolite of Penicillium roqueforti, is structurally related to Paraherquamide A (2), originally isolated from Penicillium paraherquei. Chemically the two compounds differ only in one ring; in marcfortine A, ring G is six-membered and carries no substituents, while in Paraherquamide A, ring G is five-membered with methyl and hydroxyl substituents at C14. Paraherquamide A (2) is superior to marcfortine A as a nematocide. 2-Desoxoparaherquamide A (PNU-141962, 53) has excellent nematocidal activity, a superior safely profile, and is the first semi-synthetic member of this totally new class of nematocides that is a legitimate candidate for development. This review describes the chemistry, efficacy and mode of action of PNU-141962.
Determinants of subtype-selectivity of the anthelmintic Paraherquamide A on Caenorhabditis elegans nicotinic acetylcholine receptors
Mol Pharmacol 2023 Mar 22;MOLPHARM-AR-2022-000601.PMID:36948535DOI:10.1124/molpharm.122.000601.
The anthelmintic Paraherquamide A acts selectively on the nematode L-type nicotinic acetylcholine receptors (nAChRs) but the mechanism of its selectivity is unknown. This study targeted the basis of Paraherquamide A selectivity by determining an X-ray crystal structure of the acetylcholine binding protein (AChBP), a surrogate nAChR ligand-binding domain, complexed with the compound and by measuring its actions on wild-type and mutant Caenorhabditis elegans nematodes and functionally expressed C. elegans nAChRs. Paraherquamide A showed a higher efficacy for the levamisole-sensitive (L-type (UNC-38/UNC-29/UNC-63/LEV8/LEV-1)) nAChR than the nicotine-sensitive (N-type (ACR-16)) nAChR, a result consistent with in vivo studies on wild type worms and worms with mutations in subunits of these two classes of receptors. The X-ray crystal structure of the Ls-AChBP-paraherquamide A complex and site-directed amino acid mutation studies showed for the first time that loop C, loop E and loop F of the orthosteric receptor binding site play critical roles in the observed L-type nAChR selective actions of Paraherquamide A. Significance Statement Paraherquamide A, an oxindole alkaloid, has been shown to act selectively on the L-type over N-type nAChRs in nematodes, but the mechanism of selectivity is unknown. We have co-crystallized Paraherquamide A with the acetylcholine binding protein, a surrogate of nAChRs, and found that structural features of loop C, loop E and loop F contribute to the L-type nAChR selectivity of the alkaloid. The results create a new platform for the design of anthelmintic drugs targeting cholinergic neurotransmission in parasitic nematodes.
Studies on the biosynthesis of Paraherquamide A and VM99955. A theoretical study of intramolecular Diels-Alder cycloaddition
J Org Chem 2003 Apr 4;68(7):2895-902.PMID:12662067DOI:10.1021/jo020564g.
Intramolecular Diels-Alder reactions of 2-azadiene models have been studied quantum chemically at the B3LYP/6-31G level in order to elucidate the stereochemical features of the cyclization step involved in the biosynthesis of Paraherquamide A and VM99955. These cycloadditions take place through concerted transition states associated with [4 + 2] processes. Analysis of the energies along the competitive paths reveals that while the cycloadditions of the oxindoles present a large anti selectivity, the indoles show a low syn selectivity for the formation of the C20 stereogenic center that is larger for the reduced tertiary amide form. The presence of the C14 methyl of the beta-methylproline ring produces a low hindrance along the reaction coordinate for the syn approach of the isoprene framework, in agreement with the low facial selectivity found experimentally. An analysis of the electrophilicity and activation parameters for experimental models of the inter- and intramolecular Diels-Alder reactions reveals several significant factors controlling these biosynthetic cyclizations. The results are in reasonable agreement with the available experimental data.
Asymmetric, stereocontrolled total synthesis of Paraherquamide A
J Am Chem Soc 2003 Oct 8;125(40):12172-8.PMID:14519003DOI:10.1021/ja036713+.
The first total synthesis of Paraherquamide A, a potent anthelmintic agent isolated from various Penicillium sp. with promising activity against drug-resistant intestinal parasites, is reported. Key steps in this asymmetric, stereocontrolled total synthesis include a new enantioselective synthesis of alpha-alkylated-beta-hydroxyproline derivatives to access the substituted proline nucleus and a highly diastereoselective intramolecular S(N)2' cyclization to generate the core bicyclo[2.2.2]diazaoctane ring system.