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

и другие.

Angewandte Chemie, Год журнала: 2024, Номер 136(45)

Опубликована: Июль 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).

Язык: Английский

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

Christian Brudy,

Carlo Walz,

Moritz Spiske

и другие.

Journal of Medicinal Chemistry, Год журнала: 2024, Номер 67(17), С. 14768 - 14785

Опубликована: Авг. 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.

Язык: Английский

Процитировано

13
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

и другие.

Angewandte Chemie International Edition, Год журнала: 2024, Номер 63(45)

Опубликована: Июль 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).

Язык: Английский

Процитировано

3
Allylic C–H oxygenation of unactivated internal olefins by the Cu/azodiformate catalyst system DOI Creative Commons
Le Wang,

Yuan She,

Jie Xiao

и другие.

Nature Communications, Год журнала: 2025, Номер 16(1)

Опубликована: Янв. 20, 2025

Язык: Английский

Процитировано

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

Eunbee Baek,

Jonghoon Kim

и другие.

Pharmaceuticals, Год журнала: 2025, Номер 18(5), С. 617 - 617

Опубликована: Апрель 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.

Язык: Английский

Процитировано

0
Macrocyclization via remote meta-selective C–H olefination using a practical indolyl template DOI Creative Commons
Pengfei Zhang, Zhiwei Jiang, Zhoulong Fan

и другие.

Chemical Science, Год журнала: 2023, Номер 14(31), С. 8279 - 8287

Опубликована: Янв. 1, 2023

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

Язык: Английский

Процитировано

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

Bichao Song,

Ke‐Qiang Hou, Weibo Yang

и другие.

Elsevier eBooks, Год журнала: 2024, Номер unknown, С. 65 - 84

Опубликована: Ноя. 1, 2024

Язык: Английский

Процитировано

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

Zhongwen Luo

и другие.

Organic Letters, Год журнала: 2024, Номер 26(7), С. 1463 - 1467

Опубликована: Фев. 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.

Язык: Английский

Процитировано

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

и другие.

Angewandte Chemie, Год журнала: 2024, Номер 136(45)

Опубликована: Июль 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).

Язык: Английский

Процитировано

0