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

Tongyu Bi,

Yunxia Cui, Shuai Liu

et al.

Angewandte Chemie, Journal Year: 2024, Volume and Issue: 136(45)

Published: July 30, 2024

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 practical concise ligand‐enabled Pd(II)‐catalyzed sp 3 C−H alkylation, olefination arylation macrocyclization, which could offer novel set sulfonamides. Interestingly, the potential ligand acceleration in activation also demonstrated an unprecedented enantioselective alkylation macrocyclization. Moreover, combination silico screening biological evaluation led identification spiro‐grafted sulfonamide 2 , showed promising efficacy for treatment Parkinson's disease (PD) mouse model through silent information regulator sirtuin (SIRT3).

Language: Английский

The Missing Link(er): A Roadmap to Macrocyclization in Drug Discovery DOI

Christian Brudy,

Carlo Walz,

Moritz Spiske

et al.

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 67(17), P. 14768 - 14785

Published: Aug. 22, 2024

Macrocycles are one of nature's preferred choices to generate large but cell-permeable bioactive molecules. Macrocyclization is increasingly prominent in medicinal chemistry beyond natural products, especially for difficult-to-drug targets. However, strategies best exploit the potential macrocycles only beginning emerge. Here we survey drug discovery campaigns from past decade that cumulated advanced macrocyclic drug-like compounds or candidates. Most were conceived by ring closing based on U- C-shaped conformations observed co-crystal structures. We focus key step linear precursors first macrocycle and follow-up optimization resulting scaffold. Conformational control recurrently emerged as a factor properties linkers an opportunity optimization. With challenging targets, expect these trends become more relevant.

Language: Английский

Citations

10
Allylic C–H oxygenation of unactivated internal olefins by the Cu/azodiformate catalyst system DOI Creative Commons
Le Wang,

Yuan She,

Jie Xiao

et al.

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: Jan. 20, 2025

Language: Английский

Citations

0
Exploring Macrocyclic Chemical Space: Strategies and Technologies for Drug Discovery DOI Creative Commons
Taegwan Kim,

Eunbee Baek,

Jonghoon Kim

et al.

Pharmaceuticals, Journal Year: 2025, Volume and Issue: 18(5), P. 617 - 617

Published: April 24, 2025

Macrocycles have emerged as significant therapeutic candidates in drug discovery due to their unique capacity target complex and traditionally inaccessible biological interfaces. Their structurally constrained three-dimensional configurations facilitate high-affinity interactions with challenging targets, notably protein–protein However, despite potential, the synthesis optimization of macrocyclic compounds present considerable challenges related structural complexity, synthetic accessibility, attainment favorable drug-like properties, particularly cell permeability oral bioavailability. Recent advancements methodologies expanded chemical space accessible macrocycles, enabling creation diverse pharmacologically active compounds. Concurrent developments computational strategies further enhanced macrocycle design, providing valuable insights into predicting molecular properties essential for efficacy. Additionally, a deeper understanding macrocycles’ conformational adaptability, especially ability internally shield polar functionalities improve membrane permeability, has significantly informed rational design. This review discusses recent innovations that advanced over past five years. It emphasizes importance integrating these overcome existing challenges, illustrating how synergy expands potential diversity macrocycles. Selected case studies underscore practical impact integrated approaches, highlighting promising applications across biomedical targets.

Language: Английский

Citations

0
Ligand‐Enabled Pd‐Catalyzed sp3 C−H Macrocyclization: Synthesis and Evaluation of Macrocyclic Sulfonamide for the Treatment of Parkinson's Disease DOI Open Access

Tongyu Bi,

Yunxia Cui, Shuai Liu

et al.

Angewandte Chemie International Edition, Journal Year: 2024, Volume and Issue: 63(45)

Published: July 30, 2024

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 practical concise ligand‐enabled Pd(II)‐catalyzed sp 3 C−H alkylation, olefination arylation macrocyclization, which could offer novel set sulfonamides. Interestingly, the potential ligand acceleration in activation also demonstrated an unprecedented enantioselective alkylation macrocyclization. Moreover, combination silico screening biological evaluation led identification spiro‐grafted sulfonamide 2 , showed promising efficacy for treatment Parkinson's disease (PD) mouse model through silent information regulator sirtuin (SIRT3).

Language: Английский

Citations

3
Macrocyclization via remote meta-selective C–H olefination using a practical indolyl template DOI Creative Commons
Pengfei Zhang, Zhiwei Jiang, Zhoulong Fan

et al.

Chemical Science, Journal Year: 2023, Volume and Issue: 14(31), P. 8279 - 8287

Published: Jan. 1, 2023

Macrocyclization via palladium-catalyzed intramolecular meta -selective C–H olefination was achieved through utilizing a readily accessible and cleavable indolyl template.

Language: Английский

Citations

5
Discovery of lead compounds from pseudo-natural macrocycles enabled by modular biomimetic strategy DOI

Bichao Song,

Ke‐Qiang Hou, Weibo Yang

et al.

Elsevier eBooks, Journal Year: 2024, Volume and Issue: unknown, P. 65 - 84

Published: Nov. 1, 2024

Language: Английский

Citations

1
Regioselective Olefination and Arylation of Arene-Tethered Diols Using the Easily Foldable Directing Groups DOI
Fucheng Yin, Yifan Chen,

Zhongwen Luo

et al.

Organic Letters, Journal Year: 2024, Volume and Issue: 26(7), P. 1463 - 1467

Published: Feb. 13, 2024

Arene-tethered diols constitute a valuable class of structural motifs drug and bioactive natural product molecules. In this study, regioselective protocol for olefination arylation arene-tethered 1,2-diols 1,3-diols has been developed using easily foldable acetal structures attaching pyridine nitrile directing groups. The method overcomes the steric hindrance effect short-chain affords products in high yield regioselectivity. This efficient cascaded catalysis successfully utilized syntheses such as peucedanol, decursinol, marmesin.

Language: Английский

Citations

0
Ligand‐Enabled Pd‐Catalyzed sp3 C−H Macrocyclization: Synthesis and Evaluation of Macrocyclic Sulfonamide for the Treatment of Parkinson's Disease DOI

Tongyu Bi,

Yunxia Cui, Shuai Liu

et al.

Angewandte Chemie, Journal Year: 2024, Volume and Issue: 136(45)

Published: July 30, 2024

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 practical concise ligand‐enabled Pd(II)‐catalyzed sp 3 C−H alkylation, olefination arylation macrocyclization, which could offer novel set sulfonamides. Interestingly, the potential ligand acceleration in activation also demonstrated an unprecedented enantioselective alkylation macrocyclization. Moreover, combination silico screening biological evaluation led identification spiro‐grafted sulfonamide 2 , showed promising efficacy for treatment Parkinson's disease (PD) mouse model through silent information regulator sirtuin (SIRT3).

Language: Английский

Citations

0