Recent syntheses and biological profiling of quassinoids

Pazur, Ethan J; Wipf, Peter

doi:10.1039/d2ob00490a

Cited by 10 publications

(7 citation statements)

References 58 publications

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“…They are complex molecules which are difficult to synthesise. Nonetheless, innovative synthesis approaches for this class of compounds have been reported in several studies [ 24 – 28 ] and concisely reviewed by others [ 29 , 30 ]. Biologically, quassinoids have demonstrated exceptional potency across different disease areas including cancer, HIV and, as noted in this study, malaria [ 22 , 23 ].…”

Section: Results Discussion and Conclusionmentioning

confidence: 99%

Prioritised identification of structural classes of natural products from higher plants in the expedition of antimalarial drug discovery

Moyo,

Invernizzi,

Mianda

et al. 2023

Nat. Prod. Bioprospect.

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The emergence and spread of drug-recalcitrant Plasmodium falciparum parasites threaten to reverse the gains made in the fight against malaria. Urgent measures need to be taken to curb this impending challenge. The higher plant-derived sesquiterpene, quinoline alkaloids, and naphthoquinone natural product classes of compounds have previously served as phenomenal chemical scaffolds from which integral antimalarial drugs were developed. Historical successes serve as an inspiration for the continued investigation of plant-derived natural products compounds in search of novel molecular templates from which new antimalarial drugs could be developed. The aim of this study was to identify potential chemical scaffolds for malaria drug discovery following analysis of historical data on phytochemicals screened in vitro against P. falciparum. To identify these novel scaffolds, we queried an in-house manually curated database of plant-derived natural product compounds and their in vitro biological data. Natural products were assigned to different structural classes using NPClassifier. To identify the most promising chemical scaffolds, we then correlated natural compound class with bioactivity and other data, namely (i) potency, (ii) resistance index, (iii) selectivity index and (iv) physicochemical properties. We used an unbiased scoring system to rank the different natural product classes based on the assessment of their bioactivity data. From this analysis we identified the top-ranked natural product pathway as the alkaloids. The top three ranked super classes identified were (i) pseudoalkaloids, (ii) naphthalenes and (iii) tyrosine alkaloids and the top five ranked classes (i) quassinoids (of super class triterpenoids), (ii) steroidal alkaloids (of super class pseudoalkaloids) (iii) cycloeudesmane sesquiterpenoids (of super class triterpenoids) (iv) isoquinoline alkaloids (of super class tyrosine alkaloids) and (v) naphthoquinones (of super class naphthalenes). Launched chemical space of these identified classes of compounds was, by and large, distinct from that of ‘legacy’ antimalarial drugs. Our study was able to identify chemical scaffolds with acceptable biological properties that are structurally different from current and previously used antimalarial drugs. These molecules have the potential to be developed into new antimalarial drugs.

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Section: Results Discussion and Conclusionmentioning

confidence: 99%

Prioritised identification of structural classes of natural products from higher plants in the expedition of antimalarial drug discovery

Moyo,

Invernizzi,

Mianda

et al. 2023

Nat. Prod. Bioprospect.

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“…Triterpenoids are of great interest to natural product chemists, organic chemists, and medicinal chemists alike due to their complex structures and a wide array of bioactivities. , The regio- and stereoselective synthesis or modification of such polycyclic and often densely functionalized molecules remains an outstanding challenge and severely hinders drug development of such compounds. − As an alternative to synthesis, many organisms, particularly plants, possess elaborate biochemical machinery to produce diverse triterpenoids with high selectivity. The biosynthesis of plant triterpenoids is generally divided into two phases (Figure A): (1) First, the underlying carbon skeleton is generated by an oxidosqualene cyclase (OSC), based on epoxide-mediated rearrangements; (2) then, tailoring enzymes such as cytochrome P450 monooxygenases (P450s) and glycosyltransferases (GTs) introduce specific functionalizations and decorations, e.g., oxidations or glycosylations, but leave the carbon skeleton unaltered. − An enzymatic way to modify the skeletons of already functionalized triterpenoids would be highly desirable to rapidly expand their chemical space.…”

Section: Introductionmentioning

confidence: 99%

Post-Cyclization Skeletal Rearrangements in Plant Triterpenoid Biosynthesis by a Pair of Branchpoint Isomerases

2023

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Triterpenoids possess potent biological activities, but their polycyclic skeletons are challenging to synthesize. The skeletal diversity of triterpenoids in plants is generated by oxidosqualene cyclases based on epoxide-triggered cationic rearrangement cascades. Normally, triterpenoid skeletons then remain unaltered during subsequent tailoring steps. In contrast, the highly modified triterpenoids found in Sapindales plants imply the existence of post-cyclization skeletal rearrangement enzymes that have not yet been found. We report here a biosynthetic pathway in Sapindales plants for the modification of already cyclized tirucallane triterpenoids, controlling the pathway bifurcation between different plant triterpenoid classes. Using a combination of bioinformatics, heterologous expression in plants and chemical analyses, we identified a cytochrome P450 monooxygenase and two isomerases which harness the epoxidation-rearrangement biosynthetic logic of triterpene cyclizations for modifying the tirucallane scaffold. The two isomerases share the same epoxide substrate made by the cytochrome P450 monooxygenase CYP88A154, but generate two different rearrangement products, one containing a cyclopropane ring. Our findings reveal a process for skeletal rearrangements of triterpenoids in nature that expands their scaffold diversity after the initial cyclization. In addition, the enzymes described here are crucial for the biotechnological production of limonoid, quassinoid, apoprotolimonoid, and glabretane triterpenoids.

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“…[1,2] The regio-and stereoselective synthesis or modification of such polycyclic and often densely functionalised molecules remains an outstanding challenge and severely hinders drug development of such compounds. [3][4][5] As an alternative to synthesis, many organisms, particularly plants, possess elaborated biochemical machineries to produce diverse triterpenoids with high selectivity. The biosynthesis of plant triterpenoids is generally divided into two phases: (1) The underlying polycyclic carbon skeleton is generated by an oxidosqualene cyclase; (2) tailoring enzymes introduce specific functionalisations and decorations, e.g.…”

Section: Introductionmentioning

confidence: 99%

Post-Cyclase Skeletal Rearrangements in Plant Triterpenoid Biosynthesis by a Pair of Branchpoint Isomerases

Chuang

Liu

Franke

2022

Preprint

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Triterpenoids possess potent biological activities, but their polycyclic skeletons are challenging to synthesise. In biochemistry, the skeletal diversity of plant triterpenoids is normally generated by oxidosqualene cyclases and remains unaltered during subsequent tailoring steps. In contrast, we report here enzyme-mediated skeletal rearrangements after the initial cyclisation, controlling the pathway bifurcation between different plant triterpenoid classes. Using a combination of bioinformatics, heterologous expression in plants and chemical analyses, we identified a cytochrome P450 monooxygenase and two isomerases for this process. The two isomerases share one epoxide substrate but generate two different rearrangement products, one containing a cyclopropane ring. Our findings reveal a new strategy how triterpenoid skeletal diversity is generated in Nature and are crucial for the biotechnological production of limonoid, quassinoid, isoprotolimonoid and glabretane triterpenoids.

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Recent syntheses and biological profiling of quassinoids

Abstract: Quassinoids exhibit diverse biological properties and pose synthetically challenging targets. Focusing on accomplishments over the past 15 years, we discuss strategies and tactics of total syntheses as well as SAR and biological functions.

Cited by 10 publications

References 58 publications

Prioritised identification of structural classes of natural products from higher plants in the expedition of antimalarial drug discovery

Prioritised identification of structural classes of natural products from higher plants in the expedition of antimalarial drug discovery

Post-Cyclization Skeletal Rearrangements in Plant Triterpenoid Biosynthesis by a Pair of Branchpoint Isomerases

Post-Cyclase Skeletal Rearrangements in Plant Triterpenoid Biosynthesis by a Pair of Branchpoint Isomerases

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