Two-Step Synthesis of Complex Artificial Macrocyclic Compounds

Rudrakshula Madhavachary; Eman M.M. Abdelraheem; Arianna Rossetti; Aleksandra Twarda-Clapa; Bogdan Musielak; Katarzyna Kurpiewska; Justyna Kalinowska-Tłuścik; Tad A. Holak; Alexander Dömling

doi:10.1002/anie.201704426

Two-Step Synthesis of Complex Artificial Macrocyclic Compounds

Rudrakshula Madhavachary, Eman M.M. Abdelraheem, Arianna Rossetti, Aleksandra Twarda-Clapa, Bogdan Musielak, Katarzyna Kurpiewska, Justyna Kalinowska-Tłuścik, Tad A. Holak, Alexander Dömling^*

^*Corresponding author for this work

School of Chemistry

Research output: Contribution to journal › Article (Academic Journal) › peer-review

40 Citations (Scopus)

Abstract

The design and synthesis of head-to-tail linked artificial macrocycles using the Ugi-reaction has been developed. This synthetic approach of just two steps is unprecedented, short, efficient and works over a wide range of medium (8–11) and macrocyclic (≥12) loop sizes. The substrate scope and functional group tolerance is exceptional. Using this approach, we have synthesized 39 novel macrocycles by two or even one single synthetic operation. The properties of our macrocycles are discussed with respect to their potential to bind to biological targets that are not druggable by conventional, drug-like compounds. As an application of these artificial macrocycles we highlight potent p53–MDM2 antagonism.

Original language	English
Pages (from-to)	10725-10729
Number of pages	5
Journal	Angewandte Chemie - International Edition
Volume	56
Issue number	36
Early online date	10 Jul 2017
DOIs	https://doi.org/10.1002/anie.201704426
Publication status	Published - 23 Aug 2017

Keywords

drug discovery
macrocycles
protein–protein interactions
synthetic methods
Ugi reaction

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title = "Two-Step Synthesis of Complex Artificial Macrocyclic Compounds",

abstract = "The design and synthesis of head-to-tail linked artificial macrocycles using the Ugi-reaction has been developed. This synthetic approach of just two steps is unprecedented, short, efficient and works over a wide range of medium (8–11) and macrocyclic (≥12) loop sizes. The substrate scope and functional group tolerance is exceptional. Using this approach, we have synthesized 39 novel macrocycles by two or even one single synthetic operation. The properties of our macrocycles are discussed with respect to their potential to bind to biological targets that are not druggable by conventional, drug-like compounds. As an application of these artificial macrocycles we highlight potent p53–MDM2 antagonism.",

keywords = "drug discovery, macrocycles, protein–protein interactions, synthetic methods, Ugi reaction",

author = "Rudrakshula Madhavachary and Abdelraheem, \{Eman M.M.\} and Arianna Rossetti and Aleksandra Twarda-Clapa and Bogdan Musielak and Katarzyna Kurpiewska and Justyna Kalinowska-T{\l}u{\'s}cik and Holak, \{Tad A.\} and Alexander D{\"o}mling",

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doi = "10.1002/anie.201704426",

language = "English",

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journal = "Angewandte Chemie - International Edition",

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publisher = "John Wiley \& Sons, Ltd.",

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T1 - Two-Step Synthesis of Complex Artificial Macrocyclic Compounds

AU - Madhavachary, Rudrakshula

AU - Abdelraheem, Eman M.M.

AU - Rossetti, Arianna

AU - Twarda-Clapa, Aleksandra

AU - Musielak, Bogdan

AU - Kurpiewska, Katarzyna

AU - Kalinowska-Tłuścik, Justyna

AU - Holak, Tad A.

AU - Dömling, Alexander

PY - 2017/8/23

Y1 - 2017/8/23

N2 - The design and synthesis of head-to-tail linked artificial macrocycles using the Ugi-reaction has been developed. This synthetic approach of just two steps is unprecedented, short, efficient and works over a wide range of medium (8–11) and macrocyclic (≥12) loop sizes. The substrate scope and functional group tolerance is exceptional. Using this approach, we have synthesized 39 novel macrocycles by two or even one single synthetic operation. The properties of our macrocycles are discussed with respect to their potential to bind to biological targets that are not druggable by conventional, drug-like compounds. As an application of these artificial macrocycles we highlight potent p53–MDM2 antagonism.

AB - The design and synthesis of head-to-tail linked artificial macrocycles using the Ugi-reaction has been developed. This synthetic approach of just two steps is unprecedented, short, efficient and works over a wide range of medium (8–11) and macrocyclic (≥12) loop sizes. The substrate scope and functional group tolerance is exceptional. Using this approach, we have synthesized 39 novel macrocycles by two or even one single synthetic operation. The properties of our macrocycles are discussed with respect to their potential to bind to biological targets that are not druggable by conventional, drug-like compounds. As an application of these artificial macrocycles we highlight potent p53–MDM2 antagonism.

KW - drug discovery

KW - macrocycles

KW - protein–protein interactions

KW - synthetic methods

KW - Ugi reaction

UR - https://www.scopus.com/pages/publications/85026504641

U2 - 10.1002/anie.201704426

DO - 10.1002/anie.201704426

M3 - Article (Academic Journal)

C2 - 28691783

AN - SCOPUS:85026504641

SN - 1433-7851

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JO - Angewandte Chemie - International Edition

JF - Angewandte Chemie - International Edition

IS - 36

ER -

Two-Step Synthesis of Complex Artificial Macrocyclic Compounds

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Keywords

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