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Peer-reviewedCC BY-NC-NDJACS Au

A Pathway-Economical Synthesis Enabling Systematic Evaluation: Enantiodivergent Access to Aspidosperma Alkaloids Unlocks Divergent Antitumor Mechanisms.

  • Xiang Li1,2,3
  • Simeng Wang3,4
  • Xiang He1,2,3
  • Guoyu Li1,2,3
  • Jiamo Wu1,2,3
  • Jinming Hu1,2,3
  • Lu Yang1,2,3
  • Lihui Wang3,4
  • Maosheng Cheng1,3
  • Yongxiang Liu1,2,3
4 affiliations
  1. 1Key Laboratory of Structure-Based Drug Design and Discovery, (Shenyang Pharmaceutical University), Ministry of Education, Shenyang 110016, China.
  2. 2Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, China.
  3. 3Institute of Drug Research in Medicine Capital of China, Shenyang Pharmaceutical University, Benxi 117000, China.
  4. 4Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang 110016, China.
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Abstract

The difficulty in efficiently accessing to both enantiomers has long hampered the systematic evaluation of how chirality governs the bioactivity of natural products. We report a pathway-economical synthesis that addresses this challenge, unlocking enantiodivergent access to ten Aspidosperma alkaloids. The highlight of our strategy lies in an intermolecular enantioselective cycloaddition/retro-aza-Michael addition/DDQ-mediated skeletal reorganization cascade induced by Evans' auxiliary, which enables access to either enantiomeric series of the tetracyclic core from common starting materials simply by modulating the solvent. This synthesis enabled a comparative biological evaluation, uncovering starkly divergent antitumor mechanisms between enantiomers: (-)-vincadifformine acts through direct cytotoxicity, whereas its (+)-antipode is noncytotoxic but potently reverses T cell exhaustion via an immune-dependent mechanism. This work not only solves a longstanding supply problem of the two enantiomers of Aspidosperma alkaloids, but, by decoupling cytotoxicity from immunostimulation, identifies (+)-vincadifformine as a promising lead for cancer immunotherapy.

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Cite

BibTeXRIS
BibTeX
@article{li2026pathwayeconomical,
  title = {{A Pathway-Economical Synthesis Enabling Systematic Evaluation: Enantiodivergent Access to Aspidosperma Alkaloids Unlocks Divergent Antitumor Mechanisms.}},
  author = {Xiang Li and Simeng Wang and Xiang He and Guoyu Li and Jiamo Wu and Jinming Hu and Lu Yang and Lihui Wang and Maosheng Cheng and Yongxiang Liu},
  journal = {JACS Au},
  year = {2026},
  month = sep,
  doi = {10.1021/jacsau.6c01163},
  url = {https://europepmc.org/article/MED/42953574},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - A Pathway-Economical Synthesis Enabling Systematic Evaluation: Enantiodivergent Access to Aspidosperma Alkaloids Unlocks Divergent Antitumor Mechanisms.
AU  - Xiang Li
AU  - Simeng Wang
AU  - Xiang He
AU  - Guoyu Li
AU  - Jiamo Wu
AU  - Jinming Hu
AU  - Lu Yang
AU  - Lihui Wang
AU  - Maosheng Cheng
AU  - Yongxiang Liu
PY  - 2026
DA  - 2026/09/23
JO  - JACS Au
DO  - 10.1021/jacsau.6c01163
UR  - https://europepmc.org/article/MED/42953574
AB  - The difficulty in efficiently accessing to both enantiomers has long hampered the systematic evaluation of how chirality governs the bioactivity of natural products. We report a pathway-economical synthesis that addresses this challenge, unlocking enantiodivergent access to ten Aspidosperma alkaloids. The highlight of our strategy lies in an intermolecular enantioselective cycloaddition/retro-aza-Michael addition/DDQ-mediated skeletal reorganization cascade induced by Evans' auxiliary, which enables access to either enantiomeric series of the tetracyclic core from common starting materials simply by modulating the solvent. This synthesis enabled a comparative biological evaluation, uncovering starkly divergent antitumor mechanisms between enantiomers: (-)-vincadifformine acts through direct cytotoxicity, whereas its (+)-antipode is noncytotoxic but potently reverses T cell exhaustion via an immune-dependent mechanism. This work not only solves a longstanding supply problem of the two enantiomers of Aspidosperma alkaloids, but, by decoupling cytotoxicity from immunostimulation, identifies (+)-vincadifformine as a promising lead for cancer immunotherapy.
SN  - 2691-3704
ER  -