2. Academic Validation
  3. Ligand-Enabled Pd-Catalyzed sp3 C‒H Macrocyclization: Synthesis and Evaluation of Macrocyclic Sulfonamide for the Treatment of Parkinson's Disease

Ligand-Enabled Pd-Catalyzed sp3 C‒H Macrocyclization: Synthesis and Evaluation of Macrocyclic Sulfonamide for the Treatment of Parkinson's Disease

  • Angew Chem Int Ed Engl. 2024 Jul 30:e202412296. doi: 10.1002/anie.202412296.
Tongyu Bi 1,  Yunxia Cui 2,  Shuai Liu 3,  Haiyue Yu 1,  Weirong Qiu 1,  Ke-Qiang Hou 1,  Jiaqi Zou 4,  Zhipeng Yu 4,  Feili Zhang 1,  Zhongliang Xu 1,  Jian Zhang 5,  Xiaojun Xu 6,  Weibo Yang 7
Affiliations

Affiliations

  • 1 Shanghai Institute of Materia Medica Chinese Academy of Sciences, Medicinal chemistry, CHINA.
  • 2 Shanghai Jiaotong University, School of Medicine, CHINA.
  • 3 Zhejiang University, Medicinal chemistry, CHINA.
  • 4 Nanjing University of Chinese Medicine, Medicinal chemistry, CHINA.
  • 5 Shanghai Jiaotong University, Pharmacology, CHINA.
  • 6 Zhejiang University, Pharmacology, CHINA.
  • 7 Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, State Key Laboratory of Drug Research, 555 Zuchongzhi Road, Shanghai 201203, China, 201203, Shanghai, CHINA.
PMID: 39078406 DOI: 10.1002/anie.202412296
Abstract

The development of simplified synthetic strategy to create structurally and functionally diverse pseudo-natural macrocyclic molecules is highly appealing but poses a marked challenge. Inspired by natural scaffolds, herein, we describe a practical and concise ligand-enabled Pd(II)-catalysed sp3 C‒H alkylation, olefination and arylation macrocyclization, which could offer a novel set of pseudo-natural macrocyclic sulfonamides. Interestingly, the potential of ligand acceleration in C‒H activation is also demonstrated by an unprecedented enantioselective sp3 C‒H alkylation macrocyclization. Moreover, a combination of in silico screening and biological evaluation led to the identification of a novel spiro-grafted macrocyclic sulfonamide 2a, which showed a promising efficacy for the treatment of Parkinson's disease (PD) in a mouse model through the activation of silent information regulator Sirtuin 3 (SIRT3).

Keywords

C-H activation, ligand-mediated macrocyclization, Pd catalysis, SIRT3, PD treatment.

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