Macrocycles Are Great Cycles: Applications, Opportunities, and Challenges of Synthetic Macrocycles in Drug Discovery

Marsault, Éric; Peterson, Mark L.

doi:10.1021/jm1012374

Cited by 748 publications

(716 citation statements)

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“…To achieve all three of these goals without compromising synthetic efficiency or relevance to complex natural products, we were attracted to cyclodepsipeptides, in which biological activity is quite diverse (18)(19)(20)(21)(22)(23). Herein, we report rapid access to size-diverse collections of cyclooligodepsipeptides using a controlled oligomerization/macrocyclization sequence.…”

mentioning

confidence: 99%

Rapid synthesis of cyclic oligomeric depsipeptides with positional, stereochemical, and macrocycle size distribution control

Batiste

Johnston

2016

Proc. Natl. Acad. Sci. U.S.A.

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Macrocyclic small molecules are attractive tools in the development of sensors, new materials, and therapeutics. Within early-stage drug discovery, they are increasingly sought for their potential to interact with broad surfaces of peptidic receptors rather than within their narrow folds and pockets. Cyclization of linear small molecule precursors is a straightforward strategy to constrain conformationally mobile motifs, but forging a macrocycle bond typically becomes more difficult at larger ring sizes. We report the development of a general approach to discrete collections of oligomeric macrocyclic depsipeptides using an oligomerization/macrocyclization process governed by a series of Mitsunobu reactions of hydroxy acid monomers. Ring sizes of 18, 24, 30, and 36 are formed in a single reaction from a didepsipeptide, whereas sizes of 24, 36, and 60 result from a tetradepsipeptide. The ring-size selectivity inherent to the approach can be modulated by salt additives that enhance the formation of specific ring sizes. Use of chemical synthesis to prepare the monomers suggests broad access to functionally and stereochemically diverse collections of natural product-like oligodepsipeptide macrocycles. Two cyclodepsipeptide natural products were prepared along with numerous unnatural oligomeric congeners to provide rapid access to discrete collections of complex macrocyclic small molecules from medium (18) to large (60) ring sizes.Mitsunobu | total synthesis | collective | macrocycle | oligomerization I nterest in the preparation and use of small molecules exhibiting macrocyclic rings is growing at a tremendous pace, driving the development of new approaches, new chemical reactions, and the underlying chemistry and tools (catalysts) to support them. Historically, studies of macrocyclization reactions have been guided by natural products bearing unusually large carbocycles or mediumand large-ring lactones, amides, and ethers. Fragmentation reactions of polycyclic molecules have long played a role in access to medium-sized macrocycles, whereas macrocyclizations to lactones and amides are often accomplished from linear precursors at high dilution. Insofar as these efforts were typically driven by the goal to prepare a specific macrocycle, often in the form relevant to a natural product synthesis or an engineered constraint to a peptide, absent from the field is an approach that provides rapid access to collections (1) of natural product-like macrocycles, particularly from stereochemically complex, functionally rich, linear precursors (2-6).Pioneers in this area have recorded some success (Fig. 1). Esterification reactions of activated hydroxy acids have led predominantly to diolides, (7-10) and in a single case, oligolides (11). Amidation reactions of activated polypeptides were central to the preparations of macrocyclic peptides by Rothe and Kreiss (12,13) and Wipf and coworkers (14, 15), but they were low yielding and size nonselective. Burke and coworkers (16,17) have shown that the efficiency of an 18-membered oligol...

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confidence: 99%

Rapid synthesis of cyclic oligomeric depsipeptides with positional, stereochemical, and macrocycle size distribution control

Batiste

Johnston

2016

Proc. Natl. Acad. Sci. U.S.A.

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“…[1][2][3][4] The role of macrocycles in medicinal chemistry has been highlighted in many recent reviews. [5][6][7][8][9][10] The efforts are now being focused on functionalization of easily approachable macrocyclic scaffolds with established pharmacophoric groups in search of new drugs for increasingly challenging targets.…”

Section: S P E C I a L I S S U E A R T I C L E Functionalized Calix[4mentioning

confidence: 99%

“…[21][22][23] They can easily be synthesized by the reaction of p-tert-butyl phenol and formaldehyde in the presence of a base. [24] Among several calix[n]arenes, calix [4] arene has been found to be of special interest due to its easy access, unique conformational features and easy postmacrocyclic modifications both at lower and upper rims. This has been manifested by its applications in the area of host-guest chemistry, [25] ion and molecular recognition, [26][27][28][29][30] enzyme mimics, [20] catalysis, [31] interaction with biomolecules, [32,33] ion extraction, [34] and selective ion transport.…”

Section: S P E C I a L I S S U E A R T I C L E Functionalized Calix[4mentioning

confidence: 99%

Functionalized calix[4]arenes as potential therapeutic agents

2017

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Calixarenes, composed of phenolic units linked by methylene bridges at the 2,6-positions, represent a versatile class of macrocyclic compounds in supramolecular chemistry that can host small molecules or ions in their well-defined hydrophobic cavities. In recent years, it has been recognized that this class of compounds has the potential to serve as platform for the design of biological active compounds. Therefore, the calixarenes functionalized with different pharmacophoric groups have been synthesized as target structure by many researchers and were further evaluated for their biological activities. Owing to their promising biological activities such as antiviral, antibacterial, antifungal, and anticancer, the functionalized calixarenes are recently receiving increased attention from pharmaceutical/medicinal chemistry community. In this review, we summarize and discuss the synthetic approaches and the biological potential of functionalized calixarenes, mainly focusing on the selected recent studies for a comprehensive and target-oriented information, which could help in the design and synthesis of new therapeutic agents leading to the development of clinically viable drugs based on these macrocyles. K E Y W O R D Sbiological activity, calixarenes, cone conformation, functionalization, upper/lower rim/annulus

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“…These compounds are found in natural products such as macrolides, that consist of a large macrocyclic lactone ring to which one or more deoxy sugars may be attached, which have antibiotic or antifungal activities and are used as pharmaceutical drugs [3]. Due to their unique properties [4,5], such as of their ability in achieving protein-protein inhibition [6,7] and cell permeability [8], this class of compounds has gained an increased interest in drug development. As a consequence, many macrocycles are currently in clinical development [4], supporting the development of macrocycle-based pharmaceutical companies (Cyclenium pharma, Circle pharma).…”

Section: Introductionmentioning

confidence: 99%

ConfBuster: Open-Source Tools for Macrocycle Conformational Search and Analysis

Barbeau¹,

Vincent²,

Lagüe

2018

JORS

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Macrocycles are cyclic macromolecules that have gained an increased interest in drug development. To our knowledge, the current bioinformatics tools that are available to investigate and predict macrocycles 3D conformations are limited in their availability. In this paper, we introduce ConfBuster, a suite of tools written in Python with the goal of sampling the lower energy conformations of macrocycles. The suite also includes tools for the analysis and visualisation of the conformational search results. Coordinate sets of single molecules in MOL2 or PDB format are required as input, and a set of lower energy conformation coordinates is returned as output, as well as PyMOL script and graphics for results analysis. In addition to Python and the optional R programming languages with freely available packages, the tools require Open Babel and PyMOL to work properly. For several examples, ConfBuster found macrocycle conformations that are within few tenths of Å of the experimental structures in minutes. To our knowledge, this is the only open-source tools for macrocycle conformational search available to the scientific community.

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Macrocycles Are Great Cycles: Applications, Opportunities, and Challenges of Synthetic Macrocycles in Drug Discovery

Abstract: Journal of Medicinal Chemistry PERSPECTIVE drug discovery are discussed. Finally, a perspective on the future of synthetic macrocycles in medicinal chemistry is offered.

Cited by 748 publications

References 325 publications

Rapid synthesis of cyclic oligomeric depsipeptides with positional, stereochemical, and macrocycle size distribution control

Rapid synthesis of cyclic oligomeric depsipeptides with positional, stereochemical, and macrocycle size distribution control

Functionalized calix[4]arenes as potential therapeutic agents

ConfBuster: Open-Source Tools for Macrocycle Conformational Search and Analysis

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