Synthesis of Bioactive 2‐Aza‐Analogues of Ipecac and Alangium Alkaloids

Kölzer, Michael; Weitzel, Kerstin; Göringer, H. Ulrich; Thines, Eckhard; Opatz, Till

doi:10.1002/cmdc.201000230

Cited by 9 publications

(4 citation statements)

References 41 publications

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“…For the most highly inhibited category of drugs, we searched the literature to see if they had previously been characterized as anti-trypanosomal. Berberine, ipecac syrup, disulfiram, methylene blue hydrate, promethazine hydrochloride, perphenazine, promazine hydrochloride, and triflupromazine have all previously been reported to inhibit growth in T. brucei and our results agree with those previously published reports [25][26][27][28][29] (S1 Table, S2 Table). Several other drugs, including nitrofurazone, aminacrine, clemastine fumarate, bepridil hydrochloride, amiodarone hydrochloride, prochlorperazine dimaleate, protriptyline hydrochloride, fluoxetine hydrochloride, apomorphine hydrochloride, and proadifen hydrochloride have been shown to inhibit growth in T. cruzi [27,[30][31][32][33][34][35][36][37][38].…”

Section: Identification Of In Vitro Inhibitors For T Brucei Growthsupporting

confidence: 93%

Identification of clinically approved small molecules that inhibit growth and affect transcript levels of developmentally regulated genes in the African trypanosome

et al. 2020

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Trypanosoma brucei are unicellular parasites endemic to Sub-Saharan Africa that cause fatal disease in humans and animals. Infection with these parasites is caused by the bite of the tsetse fly vector, and parasites living extracellularly in the blood of infected animals evade the host immune system through antigenic variation. Existing drugs for Human and Animal African Trypanosomiasis are difficult to administer and can have serious side effects. Resistance to some drugs is also increasing, creating an urgent need for alternative trypanosomiasis therapeutics. We screened a library of 1,585 U.S. or foreign-approved drugs and identified 154 compounds that inhibit trypanosome growth. As all of these compounds have already undergone testing for human toxicity, they represent good candidates for repurposing as trypanosome therapeutics. In addition to identifying drugs that inhibit trypanosome growth, we wished to identify small molecules that can induce bloodstream form parasites to differentiate into forms adapted for the insect vector. These insect stage parasites lack the immune evasion mechanisms prevalent in bloodstream forms, making them vulnerable to the host immune system. To identify drugs that increase transcript levels of an invariant, insect-stage specific surface protein called procyclin, we engineered bloodstream reporter parasites that express Green Fluorescent Protein (GFP) following induction or stabilization of the procyclin transcript. Using these bloodstream reporter strains in combination with automated flow cytometry, we identified eflornithine, spironolactone, and phenothiazine as small molecules that increase abundance of procyclin transcript. Both eflornithine and spironolactone also affect transcript levels for a subset of differentiation associated genes. While we failed to identify compounds that increase levels of procyclin protein on the cell surface, this study is proof of principle that these fluorescent reporter parasites represent a useful tool for future small molecule or genetic screens aimed at identifying molecules or processes that initiate remodeling of the parasite surface during life cycle stage transitions.

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Section: Identification Of In Vitro Inhibitors For T Brucei Growthsupporting

confidence: 93%

Identification of clinically approved small molecules that inhibit growth and affect transcript levels of developmentally regulated genes in the African trypanosome

et al. 2020

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“…36 A similar strategy based on the generation of an N-acyliminium intermediate was employed by Opatz et al in 2010 for their remarkable preparation of bioactive 2-aza-analogues of Ipecac and Alangium alkaloids (Scheme 9). 38 Such compounds are known for their potent eukaryotic cytotoxicity, 39 which has led to their use for the treatment of a range of protozoal infections, 40 and are invariably characterized by a pyrido[2,1-a]isoquinoline scaffold. However such compounds have serious limitations, such as severe side effects and a small therapeutic window, which prompted the authors to investigate the preparation of pyrazino[2,1-a]isoquinoline analogues, hoping to improve their properties.…”

Section: Short Review Syn Thesismentioning

confidence: 99%

“…showed an improved potency/toxicity ratio compared to emetine, which could encourage further studies towards the development of more potent analogues. 38 In concluding this section, it should be mentioned that the same cyclization approach was employed for the solidphase synthesis of pyrazinoisoquinoline derivatives. In 2006, Todd and co-workers reported a solid-phase synthesis of praziquantel (1) based on a traceless linker strategy, whereby the growing precursor was attached to a hydroxymethyl polystyrene resin via an acetal.…”

Section: Short Review Syn Thesismentioning

confidence: 99%

Preparation of Reduced Pyrazino[2,1-a]isoquinoline Derivatives: Important Heterocycles in the Field of Bioactive Compounds

et al. 2016

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Partially hydrogenated pyrazino[2,1-a]isoquinoline derivatives, such as praziquantel, have been the subject of significant research efforts in the field of medicinal chemistry, thanks to their antihelmintic, antiprotozoal, and antifungal activities. Nevertheless, methods for their efficient synthesis (and especially for their stereoselective preparation) can be traced back to just a few general procedures. In this short review we will summarize the approaches developed so far to access pyrazino[2,1-a]isoquinolines, with a particular focus on bioactive derivatives, and will highlight their features and weaknesses, aiming to stimulate further investigations in the preparation of this important class of heterocyclic compounds. 1 Introduction 2 Different Approaches to the Synthesis of Pyrazino[2,1-a]isoquinolines 2.1 1-(Aminomethyl)tetrahydroisoquinoline Ring Closure 2.2 Diketopiperazine Reduction/Cyclization 2.3 N-Acyliminium Ion Cyclizations 2.4 Radical Cyclizations 2.5 Multicomponent Reactions 2.6 Miscellaneous Routes 3 Access to Enantiomerically Pure Praziquantel 4 Conclusions

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“…For instance, a multistep synthesis of enantiomerically enriched bioactive 2-aza-analogs of Ipecac and Alangium alkaloids has been recently reported starting from a chiral amino acid and using a complete diastereoselective Speckamp cyclization as a key step to obtain an oxo-piperazine which is eventually reduced. Here we describe our approach to the tetrahydropyrazinoisoquinoline skeleton which is based on the intramolecular radical cyclization of suitably protected 2-substituted 3,4-dihydropyrazines 8 (Scheme ).…”

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confidence: 99%

Stereoselective Synthesis of 3-Substituted Tetrahydropyrazinoisoquinolines via Intramolecular Cyclization of Enantiomerically Enriched Dihydro-2H-pyrazines

et al. 2015

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The preparation of 3-substituted tetrahydropyrazinoisoquinolines using the tributyltin hydride mediated intramolecular radical cyclization of suitably protected 2-substituted 3,4-dihydropyrazines is reported. The compounds are obtained as single enantiomers, as the relative configuration of the new generated stereogenic center is driven by the stereochemistry of the 2-substituted carbon in the starting materials, which is in turn derived from naturally occurring amino acids.

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Synthesis of Bioactive 2‐Aza‐Analogues of Ipecac and Alangium Alkaloids

Cited by 9 publications

References 41 publications

Identification of clinically approved small molecules that inhibit growth and affect transcript levels of developmentally regulated genes in the African trypanosome

Identification of clinically approved small molecules that inhibit growth and affect transcript levels of developmentally regulated genes in the African trypanosome

Preparation of Reduced Pyrazino[2,1-a]isoquinoline Derivatives: Important Heterocycles in the Field of Bioactive Compounds

Stereoselective Synthesis of 3-Substituted Tetrahydropyrazinoisoquinolines via Intramolecular Cyclization of Enantiomerically Enriched Dihydro-2H-pyrazines

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