A modular approach to the bisbenzylisoquinoline alkaloids tetrandrine and isotetrandrine

Schütz, Ramona; Meixner, Maximilian; Antes, Iris; Bracher, Franz

doi:10.1039/d0ob00078g

Cited by 19 publications

(17 citation statements)

References 65 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Further we replaced the methoxybenzyl residue by a thienylmethyl (target compound RMS5 - 6 ) and by a non-aromatic butylidene unit ( RMS9 - 10 ). The synthesis of these tetrandrine analogues is based on our recently published racemic total synthesis of tetrandrine and isotetrandrine [ 44 ] following the therein described synthetic protocol of “Route 1b”. The intermediate 11 (no.…”

Section: Resultsmentioning

confidence: 99%

“…19 in Ref. [ 44 ]) of the (iso)tetrandrine synthesis served as a valuable starting material, since it already comprises one tetrahydrobenzylisoquinoline unit (rings A′-C′) and ring A of the second half of the bisbenzylisoquinoline scaffold (see Fig. 1 ).…”

Section: Resultsmentioning

confidence: 99%

“…To circumvent this problem, the carbamate groups were first removed by treatment with methyl lithium and the resulting secondary amino groups were subsequently N-methylated via reductive alkylation using formaldehyde/NaBH 3 CN. Since the N -acyl Pictet-Spengler condensations expectedly proceeded with no or only rather poor diastereoselectivity [ 44 ] (with a tendency for the formation of the R , R / S , S isomers), we obtained racemic mixtures of diastereomers in every case. Luckily we were able to separate the open-chain diastereomers obtained in the N -acyl Pictet-Spengler reactions by flash column chromatography to provide, in the end, each tetrandrine analogue eventually as racemic compound with the relative stereoconfiguration of either tetrandrine ( 1 ) or isotetrandrine ( 2 ) ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Side effects might therefore be reduced by lowering the required therapeutic dose and, therefore, our study strongly suggests their investigation using in vivo models. Moreover, based on these encouraging data and facilitated by our recent work on effective total synthesis of the bisbenzylisoquinoline alkaloids tetrandrine and isotetrandrine [ 44 ], further investigations regarding structure-activity relationships in this chemical class should be part of future medicinal chemistry projects.…”

Section: Discussionmentioning

confidence: 99%

See 3 more Smart Citations

Synthesis, biological evaluation and toxicity of novel tetrandrine analogues

Schütz

Müller

Geisslinger

et al. 2020

European Journal of Medicinal Chemistry

Self Cite

View full text Add to dashboard Cite

In this work, we present the design and synthesis of novel fully synthetic analogues of the bisbenzylisoquinoline tetrandrine, a molecule with numerous pharmacological properties and the potential to treat life-threatening diseases, such as viral infections and cancer. Its toxicity to liver and lungs and the underlying mechanisms, however, are controversially discussed. Along this line, novel tetrandrine analogues were synthesized and biologically evaluated for their hepatotoxicity, as well as their antiproliferative and chemoresistance reversing activity on cancer cells. Previous studies suggesting CYP-mediated toxification of tetrandrine prompted us to amend/replace the suspected metabolically instable 12-methoxy group. Of note, employing several in vitro models showed that the proposed CYP3A4-driven metabolism of tetrandrine and analogues is not the major cause of hepatotoxicity. Biological characterization revealed that some of the novel tetrandrine analogues sensitized drug-resistant leukemia cells by inhibition of the P-glycoprotein. Interestingly, direct anticancer effects improved in comparison to tetrandrine, as several compounds displayed a markedly enhanced ability to reduce proliferation of drug-resistant leukemia cells and to induce cell death of liver cancer cells. Those enhanced anticancer properties were linked to influences on activation of the kinase Akt and mitochondrial events. In sum, our study clarifies the role of CYP3A4-mediated toxicity of the bisbenzylisoquinoline alkaloid tetrandrine and provides the basis for the exploitation of novel synthetic analogues for their antitumoral potential.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Synthesis, biological evaluation and toxicity of novel tetrandrine analogues

Schütz

Müller

Geisslinger

et al. 2020

European Journal of Medicinal Chemistry

Self Cite

View full text Add to dashboard Cite

show abstract

“…Tetrandrine is a bisbenzylisoquinoline that can be extracted from the perennial vine plant Stephania tetrandra S. Moore (Chinese patent WO2004009106A1, 2002), which has been used in traditional Chinese medicine ( [1], [2] and references therein). It can also be synthesised chemically (US Patent 10,023,584 B2, 2018, [3]) .…”

Section: Introductionmentioning

confidence: 99%

Tetrandrine as a Therapeutic Agent for COVID-19

Heister

Poston

Authorea

View full text Add to dashboard Cite

More than one million patients worldwide have been diagnosed with coronavirus disease 19 (COVID-19) to date (WHO situation report, 8th April 2020). There is neither a vaccine to prevent infection with the causative organism, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), nor a cure. In the struggle to devise potentially useful therapeutics in record time, the repurposing of existing drugs is a key route of action. In this review we argue that the bisbenzylisoquinoline and calcium channel blocker tetrandrine, originally extracted from the plant Stephania tetrandra and utilised in traditional Chinese medicine, could be repurposed to treat COVID-19. We collate and review evidence for tetrandrine's putative mechanism of action in viral infection, specifically its recently discovered antagonism of the two-pore channel 2 (TPC2). Consideration of its pharmacodynamics and pharmacokinetics suggests that oral tetrandrine at doses currently used in clinical practice could be an effective agent for the treatment of SARS-CoV-2 infection in humans.

show abstract

Racemic total synthesis and evaluation of the biological activities of the isoquinoline–benzylisoquinoline alkaloid muraricine

Schütz

Müller

Gerndt

et al. 2020

Archiv der Pharmazie

View full text Add to dashboard Cite

The first racemic total synthesis of the isoquinoline–benzylisoquinoline alkaloid muraricine is reported herein. Pharmacological characterization identified muraricine as a moderate inhibitor of P‐glycoprotein, a crucial factor of multidrug resistance in cancer. When combined with vincristine, muraricine partly reversed the chemoresistance of vincristine‐resistant leukemia cells at a nontoxic concentration. Furthermore, no cytotoxic effects on noncancerous human cells in therapeutically relevant concentrations were observed.

show abstract

A modular approach to the bisbenzylisoquinoline alkaloids tetrandrine and isotetrandrine

Abstract: A modular short-step synthesis of the bisbenzylisoquinoline alkaloids tetrandrine and isotetrandrine was developed employing N-acyl-Pictet–Spengler reaction and Ullman diaryl ether synthesis as central steps.

Cited by 19 publications

References 65 publications

Synthesis, biological evaluation and toxicity of novel tetrandrine analogues

Synthesis, biological evaluation and toxicity of novel tetrandrine analogues

Tetrandrine as a Therapeutic Agent for COVID-19

Racemic total synthesis and evaluation of the biological activities of the isoquinoline–benzylisoquinoline alkaloid muraricine

Contact Info

Product

Resources

About