ArticleChemical science2017
Total synthesis of a key series of vinblastines modified at C4 that define the importance and surprising trends in activity.
Article in Chemical science, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed, 22 citations in OpenAlex.
- One-Pot Access to Functionalised Malamides via Organocatalytic Enantioselective Formation of Spirocyclic β-Lactone-Oxindoles and Double Ring-Opening.Molecules (Basel, Switzerland) · 2024Article
- Orthogonal Catalysis for an Enantioselective Domino Inverse-Electron Demand Diels-Alder/Substitution Reaction.Chemistry (Weinheim an der Bergstrasse, Germany) · 2022Article
- Total synthesis of (-)-4-desacetoxy-1-oxovindoline: Single atom exchange of an embedded core heteroatom in vindoline.Tetrahedron · 2021Article
- Inverse Electron Demand Diels-Alder Reactions of Heterocyclic Azadienes, 1-Aza-1,3-Butadienes, Cyclopropenone Ketals, and Related Systems. A Retrospective.The Journal of organic chemistry · 2019Review
- Ultra-potent vinblastine analogues improve on-target activity of the parent microtubulin-targeting compound.Bioorganic & medicinal chemistry letters · 2019Article
- High expression of class III β-tubulin has no impact on functional cancer cell growth inhibition of a series of key vinblastine analogs.Bioorganic & medicinal chemistry letters · 2018Article
- The Difference a Single Atom Can Make: Synthesis and Design at the Chemistry-Biology Interface.The Journal of organic chemistry · 2017Article
- Vinblastine 20' Amides: Synthetic Analogues That Maintain or Improve Potency and Simultaneously Overcome Pgp-Derived Efflux and Resistance.Journal of medicinal chemistry · 2017Article
- Key analogs of a uniquely potent synthetic vinblastine that contain modifications of the C20' ethyl substituent.Bioorganic & medicinal chemistry letters · 2017Article
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Authors and funding
8 authors at 1 institution in 1 country.
Funding
Abstract
The total synthesis and evaluation of a key systematic series of vinblastines that incorporate the first deep-seated changes to the substituent at C4 are detailed. The synthetic approach features an expanded and redefined scope of a 1,3,4-oxadiazole [4 + 2]/[3 + 2] cycloaddition cascade in which electronically mismatched electron-deficient trisubstituted alkenes and unactivated trisubstituted alkenes were found to productively initiate the cycloaddition cascade with tethered electron-deficient 1,3,4-oxadiazoles. Such cycloaddition cascades were used to directly introduce altered C4 substituents, providing the basis for concise total syntheses of a series of C4 modified vindolines and their subsequent single-step incorporation into the corresponding synthetic vinblastines in routes as short as 8-12 steps. Evaluation of the synthetic vinblastines revealed a surprisingly large impact and role of the C4 substituent on activity even though it was previously not thought to intimately interact with the biological target tubulin. Only the introduction of a C4 methyl ester, a constitutional isomer of vinblastine in which the carbonyl carbon and ester oxygen of the C4 acetate are transposed, provided a synthetic vinblastine that matched the potency of the natural product. In contrast, even introduction of a C4 acetamide or
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.