Assembly of Complex Macrocycles by Incrementally Amalgamating Unprotected Peptides with a Designed Four-Armed Insert

The Journal of Organic Chemistry
Brice H CurtinPatrick G Harran

Abstract

We describe the asymmetric synthesis of a highly substituted ω-octynoic acid derivative and demonstrate its utility for generating complex macrocycles from unprotected peptides. The molecule harbors an isolated quaternary center that displays four uniquely functionalized arms, each of which can be reacted orthogonally in sequence as the molecule is integrated into peptide structure. These processing sequences entail (1) scaffold ligation, (2) macrocyclization via internal aromatic alkylations or catalyzed etherifications, (3) acyliminium ion mediated embedding of condensed heterocycles, and (4) terminal alkyne derivatization or dimerization reactions. Numerous polycycles are prepared and fully characterized in this study. Factors that influence reaction efficiencies and selectivity are also probed. We construct a novel mimic of the second mitochondria derived activator of caspase using these techniques, wherein subtle variations in macrocycle connectivity have a marked impact on performance. In general, the chemistry is an important step toward facile, systematic access to complex peptidomimetics synthesized by directly altering the structure and properties of machine-made oligomers.

References

Jul 1, 1987·International Journal of Peptide and Protein Research·J PorterJ Rivier
Apr 22, 2004·Journal of the American Chemical Society·Xiaoyu LiDavid R Liu
May 22, 2004·The Journal of Organic Chemistry·Thomas E Nielsen, Morten Meldal
Jul 12, 2005·Journal of Combinatorial Chemistry·Thomas E Nielsen, Morten Meldal
Dec 3, 2005·Organic Letters·Donghui Zhang, Joseph M Ready
Dec 14, 2007·Nature·James A Wells, Christopher L McClendon
Apr 5, 2008·Journal of the American Chemical Society·Yonggui ChiSamuel H Gellman
Jul 2, 2008·Nature Reviews. Drug Discovery·Edward M DriggersNicholas K Terrett
Sep 25, 2008·Journal of the American Chemical Society·Hongda ZhaoPatrick G Harran
Oct 30, 2008·Journal of the American Chemical Society·Brian N TseDavid R Liu
Feb 17, 2010·Journal of the American Chemical Society·Ryan HiliAndrei K Yudin
Mar 9, 2011·Proceedings of the National Academy of Sciences of the United States of America·Albert Isidro-LlobetDavid R Spring
Sep 29, 2011·Nature Chemical Biology·Tina R WhiteR Scott Lokey
Jan 9, 2013·Annual Review of Pharmacology and Toxicology·Victor J Hruby, Minying Cai
Jan 23, 2013·Chemical Communications : Chem Comm·Christopher D Spicer, Benjamin G Davis
Jun 4, 2013·Trends in Pharmacological Sciences·Andrei A IvanovHaian Fu
Sep 18, 2013·Proceedings of the National Academy of Sciences of the United States of America·Kenneth V LawsonPatrick G Harran
Nov 22, 2013·Chemistry : a European Journal·Serge ZaretskyAndrei K Yudin
May 21, 2014·Pharmacology & Therapeutics·Longchuan BaiShaomeng Wang
Jul 21, 2014·Nature Chemical Biology·Jason GavenonisJoshua A Kritzer
Sep 26, 2014·European Journal of Medicinal Chemistry·Andrew M Watkins, Paramjit S Arora
Jan 13, 2015·Chemical Communications : Chem Comm·Laura Nevola, Ernest Giralt
Jan 17, 2015·European Journal of Medicinal Chemistry·Natia Tsomaia
Nov 15, 2015·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Simone Fulda
Nov 23, 2016·Nature Chemistry·John R FrostAndrei K Yudin

❮ Previous
Next ❯

Citations

Sep 20, 2020·Proceedings of the National Academy of Sciences of the United States of America·Ishika SahaPatrick G Harran
Dec 7, 2018·Chemical Reviews·Teresa L MakoMindy Levine

❮ Previous
Next ❯

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.

© 2022 Meta ULC. All rights reserved