Morphology Transformation of Foldamer Assemblies Triggered by Single Oxygen Atom on Critical Residue Switch.

The synthesis of morphologically well-defined peptidic materials via self-assembly is challenging but demanding for biocompatible functional materials. Moreover, switching morphology from a given shape to other predictable forms by molecular modification of the identical building block is an even more complicated subject because the self-assembly of flexible peptides is prone to diverge upon subtle structural change. To accomplish controllable morphology transformation, systematic self-assembly studies are performed using congener short ß-peptide foldamers to find a minimal structural change that alters the self-assembled morphology. Introduction of oxygen-containing ß-amino acid (ATFC) for subtle electronic perturbation on hydrophobic foldamer induces a previously inaccessible solid-state conformational split to generate the most susceptible modification site for morphology transformation of the foldamer assemblies. The site-dependent morphological switching power of ATFC is further demonstrated by dual substitution experiments and proven by crystallographic analyses. Stepwise morphology transformation is shown by modifying an identical foldamer scaffold. This study will guide in designing peptidic molecules from scratch to create complex and biofunctional assemblies with nonspherical shapes.

Directing Foldamer Self-Assembly with a Cyclopropanoyl Cap.

The rational design of self-assembling organic materials is extremely challenging due to the difficulty in precisely predicting solid-state architectures from first principles, especially if synthons are conformationally flexible. A tractable model system to study self-assembly was constructed by appending cyclopropanoyl caps to the N termini of helical α/ß-peptide foldamers, designed to form both N-H⋅⋅⋅O and Cα -H⋅⋅⋅O hydrogen bonds, which then rapidly self-assembled to form foldectures (foldamer architectures). Through a combined analytical and computational investigation, cyclopropanoyl capping was observed to markedly enhance self-assembly in recalcitrant substrates and direct the formation of a single intermolecular N-H⋅⋅⋅O/Cα -H⋅⋅⋅O bonding motif in single crystals, regardless of peptide sequence or foldamer conformation. In contrast to previous studies, foldamer constituents of single crystals and foldectures assumed different secondary structures and different molecular packing modes, despite a conserved N-H⋅⋅⋅O/Cα -H⋅⋅⋅O bonding motif. DFT calculations validated the experimental results by showing that the N-H⋅⋅⋅O/Cα -H⋅⋅⋅O interaction created by the cap was sufficiently attractive to influence self-assembly. This versatile strategy to harness secondary noncovalent interactions in the rational design of self-assembling organic materials will allow for the exploration of new substrates and speed up the development of novel applications within this increasingly important class of materials.

Torsional and Electronic Factors Control the C-H⋠⋠⋠O Interaction.

The precise role of non-conventional hydrogen bonds such as the C-H⋅⋅⋅O interaction in influencing the conformation of small molecules remains unresolved. Here we survey a series of ß-turn mimetics using X-ray crystallography and NMR spectroscopy in conjunction with quantum calculation, and conclude that favourable torsional and electronic effects are important for the population of states with conformationally influential C-H⋅⋅⋅O interactions. Our results also highlight the challenge in attempting to deconvolute a myriad of interdependent noncovalent interactions in order to focus on the contribution of a single one. Within a small molecule that is designed to resemble the complexity of the environment within peptides and proteins, the interplay of different steric burdens, hydrogen-acceptor/-donor properties and rotational profiles illustrate why unambiguous conclusions based solely on NMR chemical shift data are extremely challenging to rationalize.

Enantioselective Synthesis of 4- and 6-Azaindolines by a Cation-Directed Cyclization.

Functionalized 4- and 6-azaindolines are accessible with high levels of enantioselectivity by the cation-directed cyclization of aminopyridine-derived imines via phase-transfer catalysis. The extension of this methodology to diastereoselective cyclizations is also described.

A Counterion-Directed Approach to the Diels-Alder Paradigm: Cascade Synthesis of Tricyclic Fused Cyclopropanes.

An approach to the intramolecular Diels-Alder reaction has led to a cascade synthesis of complex carbocycles composed of three fused rings and up to five stereocenters with complete stereocontrol. Computational analysis reveals that the reaction proceeds by a Michael/Michael/cyclopropanation/epimerization cascade in which size and coordination of the counterion is key.

The formation of right-handed and left-handed chiral nanopores within a single domain during amino acid self-assembly on Au(111).

We report the formation of both right- and left-handed chiral nanopores within a single domain during the self-assembly of an amino acid derivative on an inert Au(111) surface using STM. DFT calculations employed to rationalize this unusual result identified that intermolecular interactions between chiral, windmill-shaped tetramers are crucial for self-assembly.

Helix Nucleation by the Smallest Known α-Helix in Water.

Cyclic pentapeptides (e.g. Ac-(cyclo-1,5)-[KAXAD]-NH2 ; X=Ala, 1; Arg, 2) in water adopt one α-helical turn defined by three hydrogen bonds. NMR structure analysis reveals a slight distortion from α-helicity at the C-terminal aspartate caused by torsional restraints imposed by the K(i)-D(i+4) lactam bridge. To investigate this effect on helix nucleation, the more water-soluble 2 was appended to N-, C-, or both termini of a palindromic peptide ARAARAARA (≤5 % helicity), resulting in 67, 92, or 100 % relative α-helicity, as calculated from CD spectra. From the C-terminus of peptides, 2 can nucleate at least six α-helical turns. From the N-terminus, imperfect alignment of the Asp5 backbone amide in 2 reduces helix nucleation, but is corrected by a second unit of 2 separated by 0-9 residues from the first. These cyclic peptides are extremely versatile helix nucleators that can be placed anywhere in 5-25 residue peptides, which correspond to most helix lengths in protein-protein interactions.

Unambiguous characterization of anisotropic foldamer packing in a foldecture with an elongated hexagonal plate shape.

Herein we correlate secondary structure perturbation with changes in the solid-state molecular architectures of an elongated hexagonal plate-shaped foldecture derived from the self-assembly of rigid 12-helical ß-peptide foldamers to which a flexible C-terminus α-leucine moiety has been appended. This study provides the first complete characterization of the directional molecular packing patterns of individual foldamer components within a foldecture, from which a 3D molecular-level picture of the entire foldecture was unambiguously constructed.

A Hollow Foldecture with Truncated Trigonal Bipyramid Shape from the Self-Assembly of an 11-Helical Foldamer.

The creation of self-assembling microscale architectures that possess new and useful physical properties remains a significant challenge. Herein we report that an 11-helical foldamer self-assembles in a controlled manner to form a series of 3D foldectures with unusual three-fold symmetrical shapes that are distinct from those generated from 12-helical foldamers. The foldamer packing motif was revealed by powder X-ray diffraction technique, and provides an important link between the molecular-level symmetry and the microscale morphologies. The utility of foldectures with hollow interiors as robust and well-defined supramolecular hosts was demonstrated for inorganic, organic, and even protein guests. This work will pave the way for the design of functional foldectures with greater 3D shape diversity and for the development of biocompatible delivery vehicles and containment vessels.

Foldecture as a core material with anisotropic surface characteristics.

The synthesis of microscale, polyhedrally shaped, soft materials with anisotropic surface functionality by a bottom-up approach remains a significant challenge. Herein we report a microscale molecular architecture (foldecture) with facet-dependent surface characteristics that can potentially serve as a well-defined catalytic template. Rhombic rod shaped foldectures with six facets were obtained by the aqueous self-assembly of helical ß-peptide foldamers with a C-terminal carboxylic acid. An analysis of the molecular packing by X-ray diffraction revealed that carboxylic acid groups were exposed exclusively on the two (001) rhombic facets due to antiparallel packing of the helical peptides. A surface energy calculation by molecular dynamics simulation was performed to provide a plausible explanation for the development of anisotropy during foldecture formation. The expected facet-selective surface properties of the foldecture were experimentally confirmed by selective deposition of metal nanoparticles on the (001) facets, leading to a new class of sequentially constructed, heterogeneous "foldecture core" materials.

A cation-directed two-component cascade approach to enantioenriched pyrroloindolines.

A cascade approach to complex pyrroloindolines bearing all-carbon quaternary stereocentres has been developed. This two-component process uses a chiral ammonium salt to control diastereo- and enantioselectivity in the addition of isocyanides to functionalized alkenes to afford pyrroloindolines with up to three stereocentres. A mechanistic proposal involving intramolecular hydrogen bond activation of the isocyanide is described.

Comparative α-helicity of cyclic pentapeptides in water.

Helix-constrained polypeptides have attracted great interest for modulating protein-protein interactions (PPI). It is not known which are the most effective helix-inducing strategies for designing PPI agonists/antagonists. Cyclization linkers (X1-X5) were compared here, using circular dichroism and 2D NMR spectroscopy, for α-helix induction in simple model pentapeptides, Ac-cyclo(1,5)-[X1-Ala-Ala-Ala-X5]-NH2, in water. In this very stringent test of helix induction, a Lys1→Asp5 lactam linker conferred greatest α-helicity, hydrocarbon and triazole linkers induced a mix of α- and 310-helicity, while thio- and dithioether linkers produced less helicity. The lactam-linked cyclic pentapeptide was also the most effective α-helix nucleator attached to a 13-residue model peptide.

Downsizing human, bacterial, and viral proteins to short water-stable alpha helices that maintain biological potency.

Recombinant proteins are important therapeutics due to potent, highly specific, and nontoxic actions in vivo. However, they are expensive medicines to manufacture, chemically unstable, and difficult to administer with low patient uptake and compliance. Small molecule drugs are cheaper and more bioavailable, but less target-specific in vivo and often have associated side effects. Here we combine some advantages of proteins and small molecules by taking short amino acid sequences that confer potency and selectivity to proteins, and fixing them as small constrained molecules that are chemically and structurally stable and easy to make. Proteins often use short alpha-helices of just 1-4 helical turns (4-15 amino acids) to interact with biological targets, but peptides this short usually have negligible alpha-helicity in water. Here we show that short peptides, corresponding to helical epitopes from viral, bacterial, or human proteins, can be strategically fixed in highly alpha-helical structures in water. These helix-constrained compounds have similar biological potencies as proteins that bear the same helical sequences. Examples are (i) a picomolar inhibitor of Respiratory Syncytial Virus F protein mediated fusion with host cells, (ii) a nanomolar inhibitor of RNA binding to the transporter protein HIV-Rev, (iii) a submicromolar inhibitor of Streptococcus pneumoniae growth induced by quorum sensing pheromone Competence Stimulating Peptide, and (iv) a picomolar agonist of the GPCR pain receptor opioid receptor like receptor ORL-1. This approach can be generally applicable to downsizing helical regions of proteins with broad applications to biology and medicine.

A cyclic beta-strand tripeptide with an alpha-helix like CD spectrum.

A protein alpha-helix is defined by 3.6 amino acids per turn. Cyclization of the tripeptide Alanine-Leucine-Glutamate through a side chain to the N-terminus lactam bond produces cyclo-(1,3)-[ALE]-NH(2) which displays a circular dichroism spectrum typical of an alpha-helix backbone. However, proton NMR spectra show a novel cyclic peptide featuring two non-hydrogen-bonded antiparallel beta-strands connected by an Ala-Leu cis-amide bond. This example highlights that the common practice of characterizing alpha-helices by CD spectra alone can be misleading.

Synthesis and pharmacology of new camptothecin drugs.

Camptothecin (CPT) drugs exhibit antineoplastic activity against colorectal, breast, lung and ovarian cancers. This review briefly summarizes the pharmacology of CPT drugs, examines four strategies and methods for the synthesis of camptothecins, and finally discusses homocamptothecins and silatecans, two new classes of CPT analog.