Structure-Based Macrocycle Design in Small-Molecule Drug Discovery and Simple Metrics To Identify Opportunities for Macrocyclization of Small-Molecule Ligands

Cummings, Maxwell D.; Sekharan, Sivakumar

doi:10.1021/acs.jmedchem.8b01985

Cited by 81 publications

(61 citation statements)

References 90 publications

(151 reference statements)

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“…16,20,21 Bisucaberin has been shown to have anti-cancer potential through Fe(III) deprivation mechanisms, 17 which provides impetus to exploring methods beyond total synthesis to improve access to these types of molecules and to allow increased structural diversity. This is in accord with the broader potential of macrocycles as useful drug leads and inhibitors of protein-protein interactions, [23][24][25][26][27][28] which underpins developments in macrocycle synthesis.…”

Section: Introductionmentioning

confidence: 68%

endo-Hydroxamic Acid Monomers for the Assembly of a Suite of Non-native Dimeric Macrocyclic Siderophores Using Metal-Templated Synthesis

et al. 2019

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An expedited synthesis of endo-hydroxamic acid aminocarboxylic acid (endo-HXA) compounds has been developed. These monomeric ligands are relevant to the synthesis of metal-macrocycle complexes using metal-templated synthesis (MTS), and the downstream production of apomacrocycles. Macrocycles can display useful drug properties and be used as ligands for radiometals in medical imaging applications, which supports methodological advances in accessing this class of molecule. Six endo-HXA ligands were prepared that contained methylene groups, ether atoms, or thioether atoms in different regions of the monomer (1-6). MTS using a 1:2 Fe(III)/ligand ratio furnished six dimeric hydroxamic acid macrocycles complexed with Fe(III) (1a-6a). The corresponding apomacrocycles (1b-6b) were produced upon treatment with diethylenetriaminepentaacetic acid (DTPA). Constitutional isomers of the apomacrocycles that contained one ether oxygen atom in the diamine-containing (2b) or dicarboxylic acid-containing (3b) region were well resolved by reverse-phase high-performance liquid chromatography (RP-HPLC). Density functional theory calculations were used to compute the structures and solvated molecular properties of 1b-6b and showed that the orientation of the amide bonds relative to the pseudo-C2 axis was close to parallel in 1b, 2b, and 4b-6b but tended toward perpendicular in 3b. This conformational constraint in 3b reduced the polarity compared with 2b, consistent with the experimental trend in polarity observed using RP-HPLC. The improved synthesis of endo-HXA ligands allows expanded structural diversity in MTS-derived macrocycles and the ability to modulate macrocycle properties.

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Section: Introductionmentioning

confidence: 68%

endo-Hydroxamic Acid Monomers for the Assembly of a Suite of Non-native Dimeric Macrocyclic Siderophores Using Metal-Templated Synthesis

et al. 2019

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“…The CSD-Crossminer is the novel software of the Cambridge Crystallographic Data Centre first appeared as part of the CSD-Enterprise in 2018. Its utility is based on ideas previously demonstrated on the example of carboxylate/tetrazolate [115], hydrate/peroxosovate [116], and maleate/saccharinate [82] behavior in solids and potential of 3D macrocyclic analogues of small-molecules to serve as drugs [117]. Particularly, molecules which form similar intermolecular interactions and have comparable size and shape tend to form similar supramolecular associates, and hence are able to form isotypical solvates, or bind with similar functional groups within a binding pocket of a macromolecule.…”

Section: Csd-crossminermentioning

confidence: 99%

Intermolecular Interactions in Functional Crystalline Materials: From Data to Knowledge

Вологжанина

2019

Crystals

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Intermolecular interactions of organic, inorganic, and organometallic compounds are the key to many composition-structure and structure-property networks. In this review, some of these relations and the tools developed by the Cambridge Crystallographic Data Center (CCDC) to analyze them and design solid forms with desired properties are described. The potential of studies supported by the Cambridge Structural Database (CSD)-Materials tools for investigation of dynamic processes in crystals, for analysis of biologically active, high energy, optical, (electro)conductive, and other functional crystalline materials, and for the prediction of novel solid forms (polymorphs, co-crystals, solvates) are discussed. Besides, some unusual applications, the potential for further development and limitations of the CCDC software are reported. Crystals 2019, 9, 478 2 of 40 these fields, the manuscript cites only (i) recent works devoted to the analysis of correlations between intermolecular interactions and properties of a small molecule (for example its inclination to form polymorphs, solvates, and co-crystals), or a corresponding solid (from a well-known requirement for non-linear optical materials to crystallize in acentric space groups, to recent studies devoted to the effect of solvent presence on mechanical properties), and (ii) the corresponding software developed to investigate these correlations and to design novel solid forms with desired physicochemical properties. As the description of structure-property networks describes mainly the papers published in the last 10 years in the field of organic, organometallic, and coordination crystals, then the software under discussion will be limited with those developed by the Cambridge Crystallographic Data Centre (CCDC) for material chemistry and crystallography. Various examples of applications of the CCDC software to functional materials including their combination with other software, and restrictions found, will be given.First, the Cambridge Structural Database (CSD) and components of the CSD-Enterprise will be described in Section 2. Then, some properties related to the appearance of a given supramolecular associate, and the tools to search for an associate in the CSD will be reported in Section 3. The properties of solids dependent on the crystal morphology, the Bravais, Friedel, Donnay, and Harker (BFDH) tool for crystal morphology prediction and its' application to affect crystal morphology, polymorphism, and solvatomorphism will be reported in Section 4. Knowledge-based predictions of H-bonded polymorphism, co-crystal formation, mapping of likely intermolecular interactions, and conformer generation for the synthesis of novel functional materials will be discussed in Section 5, and the analysis of local connectivity and whole architectures of solvent molecules in Section 6. Finally, Section 7 contains information about Python API algorithms compatible with the CSD-Enterprise and about some examples of the successful combination of the CSD-Enterprise tools with exte...

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“…In pharmaceutical discovery, a macrocycle is defined as a ring system of 12 or more atoms, and it has shown great potential in drug development due to its attractive features . Compared to acyclic structures, macrocycles limit the rotation of internal bonds, resulting in the ability to remain in an active conformation with a degree of conformational stability .…”

Section: Background and Originality Contentmentioning

confidence: 99%

Design and Synthesis of a Series of Novel Macrocycle Janus Kinase 2 Inhibitors

Wang

et al. 2019

Chin. J. Chem.

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Summary of main observation and conclusion Macrocycle has attracted the attention of many researchers in the field of medicinal chemistry due to its unique advantages and good prospects, but the difficulties in drug design and synthesis of macrocycle limit its applications. In this study, a series of macrocyclic derivatives designed from anaplastic lymphoma kinase (ALK) inhibitor lorlatinib were synthesized as Janus kinase 2 (JAK2) selective inhibitors. Among them, 17f had the best inhibitory activity (IC50 = 0.177 μmol·L–1) and selectivity for JAK2 over JAK1 and JAK3, which indicated that design of the macrocyclic derivatives might be a feasible strategy for the discovery of novel selective JAK2 inhibitors.

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Structure-Based Macrocycle Design in Small-Molecule Drug Discovery and Simple Metrics To Identify Opportunities for Macrocyclization of Small-Molecule Ligands

Cited by 81 publications

References 90 publications

endo-Hydroxamic Acid Monomers for the Assembly of a Suite of Non-native Dimeric Macrocyclic Siderophores Using Metal-Templated Synthesis

endo-Hydroxamic Acid Monomers for the Assembly of a Suite of Non-native Dimeric Macrocyclic Siderophores Using Metal-Templated Synthesis

Intermolecular Interactions in Functional Crystalline Materials: From Data to Knowledge

Design and Synthesis of a Series of Novel Macrocycle Janus Kinase 2 Inhibitors

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