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

Kornienko, Alexander; Clair, James J. La

doi:10.1039/c7np00024c

Cited by 45 publications

(34 citation statements)

References 65 publications

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“…37 The predominant product was a novel dicatechol pyrrole lysine (DCPL) adduct, formed by the addition of two DOPAL molecules to a single lysine sidechain amine and the creation of a carbon-carbon bond between their aldehyde-adjacent carbons to give a pyrrole ring (Figure 1A). The Paal-Knorr reaction pathway provides a likely mechanism for DCPL pyrrole ring formation, 41 with a DOPAL quinone methide acting as a critical intermediate. 37 We noted previously that DCPL is unstable, 37 and we expected that this instability results from oxidation of its two catechol rings.…”

Section: Resultsmentioning

confidence: 99%

Isoindole Linkages Provide a Pathway for DOPAL-Mediated Cross-Linking of α-Synuclein

et al. 2018

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3,4-dihydroxyphenylacetaldehyde (DOPAL) is a toxic and reactive product of dopamine catabolism. In the catecholaldehyde hypothesis for Parkinson’s disease, it is a critical driver of the selective loss of dopaminergic neurons that characterizes the disease. DOPAL also crosslinks α-synuclein, the main component of Lewy bodies, which are a pathological hallmark of the disease. We previously described the initial adduct formed in reactions between DOPAL and α-synuclein, a dicatechol pyrrole lysine (DCPL). Here, we examine the chemical basis for DOPAL-based crosslinking. We find that autoxidation of DCPL’s catechol rings spurs its decomposition, yielding an intermediate dicatechol isoindole lysine (DCIL) product formed by an intramolecular reaction of the two catechol rings to give an unstable tetracyclic structure. DCIL then reacts with a second DCIL to give a dimeric, di-DCIL. This product is formed by an intermolecular carbon-carbon bond between the isoindole rings of the two DCILs that generates two structurally nonequivalent and separable atropisomers. Using α-synuclein, we demonstrate that the DOPAL-catalyzed formation of oligomers can be separated into two steps. The initial adduct formation occurs robustly within an hour, with DCPL as the main product, and the second step crosslinks α-synuclein molecules. Exploiting this two-stage reaction, we use an isotopic labeling approach to show the predominant crosslinking mechanism is an inter-adduct reaction. Finally, we confirm that a mass consistent with a di-DCIL linkage can be observed in dimeric α-synuclein by mass spectrometry. Our work elucidates previously unknown pathways of catechol-based oxidative protein damage and will facilitate efforts to detect DOPAL-based crosslinks in disease-state neurons.

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Section: Resultsmentioning

confidence: 99%

Isoindole Linkages Provide a Pathway for DOPAL-Mediated Cross-Linking of α-Synuclein

et al. 2018

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“…Specifically, α,βunsaturated aldehydes such as the endogenous ligand (4-hydroxynonenal), the main odiferous compound in cinnamon (cinnamaldehyde), and the irritant compound acrolein, activate the TRPA1 channel by covalent modification of N-terminal cysteine residues [49][50][51][52] . Sesquiterpenes with a α,β-unsaturated 1,4-dialdehyde moiety, on the other hand, have been shown to undergo Paal-Knorr condensation reactions with lysine residues 30,34,53 . Since there have been no studies showing the reaction of CDIAL with thiol or amine residues, the reaction of L-cysteine methyl ester with CDIAL was used as a model system to study the reaction of 1 with a biological substrate which may in principle react by either thiol or amine addition.…”

Section: Model Study On the Nucleophilic Addition Of Thiol Or Amino Rmentioning

confidence: 99%

Semi-synthetic Cinnamodial Analogues: Structural Insights into the Insecticidal and Antifeedant Activities of Drimane Sesquiterpenes Against the Mosquito Aedes aegypti

Manwill

Kalsi

et al. 2019

Preprint

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The Aedes aegypti mosquito serves as a major vector for viral diseases, such as dengue, chikungunya, and Zika, which are spreading across the globe and threatening public health. In addition to increased vector transmission, the prevalence of insecticideresistant mosquitoes is also on the rise, thus solidifying the need for new, safe and effective insecticides to control mosquito populations. We recently discovered that cinnamodial, a unique drimane sesquiterpene dialdehyde of the Malagasy medicinal plant Cinnamosma fragrans, exhibited significant larval and adult toxicity to Ae. aegypti and was more efficacious than DEET -the gold standard for insect repellents -at repelling adult female Ae. aegypti from blood feeding. In this study several semisynthetic analogues of cinnamodial were prepared to probe the structure-activity relationship (SAR) for larvicidal, adulticidal and antifeedant activity against Ae. aegypti. Initial efforts were focused on modification of the dialdehyde functionality to produce more stable active analogues and to understand the importance of the 1,4-dialdehyde and the α,ßunsaturated carbonyl in the observed bioactivity of cinnamodial against mosquitoes. This study represents the first investigation into the SAR of cinnamodial as an insecticide and repellent against the medically important Ae. aegypti mosquito. Scheme 1. Derivatization of 1 into structural analogues. Reagents and conditions: (a) NaClO 2 , NaH 2 PO 4 •H 2 O, H 2 O 2 , MeCN, H 2 O, r.t., 24 h; (b) TMS-CHN 2 , MeOH:Et 2 O, 0 o C, 30 min;( c) H 2 N-NH 2 , CH 2 Cl 2 :EtOH, 2 h; (d) MeOH, r.t.; (e) HOCH 2 CH 2 OH, p-TsOH, benzene, reflux, 24 h. Scheme 2. Synthesis of lactols 8 and 9, and formation of 10 from lactol 9. Reagents and conditions: (a) 1 eq. MeMgBr, THF, 78 o C, 2 h; (b) CDCl 3 , 22 d. Scheme 3. Synthesis of 1,4-dione 13. Reagents and conditions: (a) 5 eq. MeMgBr, THF, 78 o C, 2 h; (b) 3.3 eq. PCC, DCM, 0 o C → r.t., 2h. Scheme 4. Reaction mechanism of the reaction of 1 with L-cysteine methyl ester via a cationic azomethine (A) to form the pyrrolidine (16).

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“…The fused and bridged dioxabicyclooctanone moieties degrade in the presence of primary amine functionalities to form pyrrole products via putative 1,4‐dialdehyde intermediates. This mode of conjugation is suggested to be important for the Golgi phenotype of these natural products …”

Section: Figurementioning

confidence: 99%

Enantioselective Total Synthesis of Macfarlandin C, a Spongian Diterpenoid Harboring a Concave‐Substituted cis‐Dioxabicyclo[3.3.0]octanone Fragment

et al. 2020

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The enantioselective total synthesis of the rearranged spongian diterpenoid (−)‐macfarlandin C is reported. This is the first synthesis of a rearranged spongian diterpenoid in which the bulky hydrocarbon fragment is joined via a quaternary carbon to the highly hindered concave face of the cis‐2,8‐dioxabicyclo[3.3.0]octan‐3‐one moiety. The strategy involves a late‐stage fragment coupling between a tertiary carbon radical and an electrophilic butenolide resulting in the stereoselective formation of vicinal quaternary and tertiary stereocenters. A stereoselective Mukaiyama hydration that orients a pendant carboxymethyl side chain cis to the bulky octahydronapthalene substituent was pivotal in fashioning the challenging concave‐substituted cis‐dioxabicyclo[3.3.0]octanone fragment.

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

Cited by 45 publications

References 65 publications

Isoindole Linkages Provide a Pathway for DOPAL-Mediated Cross-Linking of α-Synuclein

Isoindole Linkages Provide a Pathway for DOPAL-Mediated Cross-Linking of α-Synuclein

Semi-synthetic Cinnamodial Analogues: Structural Insights into the Insecticidal and Antifeedant Activities of Drimane Sesquiterpenes Against the Mosquito Aedes aegypti

Enantioselective Total Synthesis of Macfarlandin C, a Spongian Diterpenoid Harboring a Concave‐Substituted cis‐Dioxabicyclo[3.3.0]octanone Fragment

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