Tetrahedral Anion Cage: Self‐Assembly of a (PO4)4L4 Complex from a Tris(bisurea) Ligand

Wu, Biao; Cui, Fengjuan; Lei, Yibo; Li, Shaoguang; Amadeu, Nader de Sousa; Janiak, Christoph; Lin, Yue‐Jian; Weng, Linhong; Wang, Yao‐Yu; Xiao, Yang

doi:10.1002/ange.201209930

Cited by 43 publications

(25 citation statements)

References 67 publications

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“…The other cell-penetrant biligand, which is uptaken to a greater extent by cells, have more intramolecular interactions, and has fewer cholesterol molecules associated with it, which aids in its cell-penetration. While synthetic cyclic polyamine/amide scaffolds 27 or divalent metal chelate complexes like zinc dipicolylamine have been developed as binders to the phosphoryl group in phosphorylated amino acids, phosphorylated peptides, and phosphorylated proteins in vitro 28 , to the best of our knowledge, this is the first macrocyclic reagent that can selectively recognize a specific phosphoprotein in live cells.…”

Section: Introductionmentioning

confidence: 99%

Stereochemical engineering of a peptide macrocycle allosteric inhibitor of phospho-Akt2 controls cell penetration by fine-tuning macrocycle-cell membrane interactions

Nag

Mafi

Das

et al. 2021

Preprint

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We report the development of a cell-penetrant cyclic loop biligand that selectively binds, in vitro, to the phosphorylated Ser474 site of Protein Kinase B (p-Akt2) with high affinity (KD = 10 nM). The cyclic loop biligand consists of a linear peptide joined to a macrocycle peptide through triazole linkage, and it was isolated through two iterative in situ screens. This biligand allosterically inhibited kinase activity of Akt2 but it was cell-impermeable, as isolated from the screening process. Since Akt2 is an oncoprotein hyperactivated via phosphorylation at Ser474 in cancers, we sought to visualize p-Akt2 in live cancer cells using the developed biligand. To this end, we matured this biligand into a cell-penetrant reagent through systematic iterations of its chemical structure to promote cell-penetrating properties, while retaining its binding and inhibition for p-Akt2. Two retro-inverso, N-methylated versions of the macrocyclic ligand were developed which were uptaken by live cancer cells, while retaining their high affinities for pAkt2. Interestingly, the stereochemistry of two amino acid residues in the cell-penetrant ligands exhibited strong influence on their extent of cell penetration. This phenomenon of difference in cell penetration was explored through metadynamics simulations of each ligand in the cell membrane. It was found that the ligand uptaken to a greater extent by cells had more intramolecular interactions with itself and had fewer cholesterol molecules associated with it, which aided in its cell-penetration.

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Section: Introductionmentioning

confidence: 99%

Stereochemical engineering of a peptide macrocycle allosteric inhibitor of phospho-Akt2 controls cell penetration by fine-tuning macrocycle-cell membrane interactions

Nag

Mafi

Das

et al. 2021

Preprint

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“…In recent years, we have developed a new strategy, the anion-coordination-driven assembly (ACDA), for the construction of well-defined supramolecular architectures. − The successful assembly of the A 4 L 4 and A 4 L 6 (A = anion) anion tetrahedra is facilitated by the anion-coordination properties that are similar to conventional metal-coordination (see Figure S13). Moreover, the flexibility of anion complexes (by multiple hydrogen bonds) enables more adaptive guest binding behavior in the cage, such as the ability to encapsulate large cations (with ultrahigh packing coefficients up to 99.5%) and the significant templation effect of peripheral guests .…”

Section: Introductionmentioning

confidence: 99%

Site-Selective Binding of Peripheral Chiral Guests Induces Stereospecificity in A₄L₆ Tetrahedral Anion Cages

Zheng

Zhang

et al. 2020

J. Am. Chem. Soc.

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Herein we report an unprecedented chiral induction of anion-coordination-driven tetrahedra (A4L6-type) by peripheral guests, S-, R-α-methylcholine and S-, R-β-methylcholine, which are bound along the tetrahedral edges in a highly site-specific fashion. This “peripheral templation”, which has proven indispensable for the formation of tetrahedral structure, is also an effective approach to encoding chiral information to the tetrahedron. Moreover, the site-selective binding of chiral choline derivatives to the anion cage with induced one-handedness may imply applications of such metal-free, labile systems in the study of biological processes such as selective recognition of structurally similar molecules.

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“…Structures of various shapes have been created over the last few decades . Significant advances in the synthesis of beautiful molecular objects at the nanometer scale have been elegantly realized, including geometric stars, self-similar fractals, Archimedean polyhedrals, mechanically interlocked objects, and others . Among these, geometric star structures are common in nature and art, such as in multipetal flowers, snowflakes, Star of David, and pinwheels.…”

Section: Introductionmentioning

confidence: 99%

Construction of Macromolecular Pinwheels Using Predesigned Metalloligands

et al. 2020

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Developing a methodology to build target structures is one of the major themes of synthetic chemistry. However, it has proven to be immensely challenging to achieve multilevel elaborate molecular architectures in a predictable way. Herein, we describe the self-assembly of a series of pinwheel-shaped starlike supramolecules through three rationally preorganized metalloligands L1−L3. The key octa-uncomplexed terpyridine (tpy) metalloligand L3, synthesized with an 8-fold Suzuki coupling reaction to metal-containing complexes, has four different types of terpyridines connected with three ⟨tpy-Ru 2+ -tpy⟩ units, making this the most subunits known so far for a preorganized module. Based on the principle of geometric complementation and the high "density of coordination sites", these metalloligands were assembled with Zn 2+ ions to form a pinwheel-shaped star trigon P1, pentagram P2, and hexagram P3 with precisely controlled shapes in nearly quantitative yields. With molecular weights ranging from 16756 to 56053 Da and diameters of 6.7−13.6 nm, the structural composition, shape, and rigidity of these pinwheel-shaped architectures have been fully characterized by 1D and 2D (NMR), electrospray ionization mass spectrometry, traveling-wave ion mobility mass spectrometry, and transmission electron microscopy.

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Tetrahedral Anion Cage: Self‐Assembly of a (PO₄)₄L₄ Complex from a Tris(bisurea) Ligand

Cited by 43 publications

References 67 publications

Stereochemical engineering of a peptide macrocycle allosteric inhibitor of phospho-Akt2 controls cell penetration by fine-tuning macrocycle-cell membrane interactions

Stereochemical engineering of a peptide macrocycle allosteric inhibitor of phospho-Akt2 controls cell penetration by fine-tuning macrocycle-cell membrane interactions

Site-Selective Binding of Peripheral Chiral Guests Induces Stereospecificity in A₄L₆ Tetrahedral Anion Cages

Construction of Macromolecular Pinwheels Using Predesigned Metalloligands

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Tetrahedral Anion Cage: Self‐Assembly of a (PO4)4L4 Complex from a Tris(bisurea) Ligand

Cited by 43 publications

References 67 publications

Stereochemical engineering of a peptide macrocycle allosteric inhibitor of phospho-Akt2 controls cell penetration by fine-tuning macrocycle-cell membrane interactions

Stereochemical engineering of a peptide macrocycle allosteric inhibitor of phospho-Akt2 controls cell penetration by fine-tuning macrocycle-cell membrane interactions

Site-Selective Binding of Peripheral Chiral Guests Induces Stereospecificity in A4L6 Tetrahedral Anion Cages

Construction of Macromolecular Pinwheels Using Predesigned Metalloligands

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Tetrahedral Anion Cage: Self‐Assembly of a (PO₄)₄L₄ Complex from a Tris(bisurea) Ligand

Site-Selective Binding of Peripheral Chiral Guests Induces Stereospecificity in A₄L₆ Tetrahedral Anion Cages