Cell penetration of oxadiazole-containing macrocycles.

Passive membrane permeability is an important property in drug discovery and biological probe design. To elucidate the cell-penetrating ability of oxadiazole-containing (Odz) peptides, we employed the Chloroalkane Penetration Assay. The present study demonstrates that Odz cyclic peptides can be highly cell-penetrant depending on the position of specific side chains and the chloroalkane tag.

Single Atom Ring Contraction of Peptide Macrocycles Using Cornforth Rearrangement.

Site-selective transformations of densely functionalized scaffolds have been a topic of intense interest in chemical synthesis. Herein we have repurposed the rarely used Cornforth rearrangement as a tool to effect a single-atom ring contraction in cyclic peptide backbones. Investigations into the kinetics of the rearrangement were carried out to understand the impact of electronic factors, ring size, and linker type on the reaction efficiency.

Two-Dimensional Barriers for Probing Conformational Shifts in Macrocycles.

We describe the development and use of composite two-dimensional barriers in macrocyclic backbones. These tunable constructs derive their mode of action from heterocyclic rearrangements. The Boulton-Katritzky reaction has been identified as a particularly versatile means to effect a composite barrier, allowing the examination of the influence of heterocycle translocation on conformation.

Amidine Functionality As a Conformational Probe of Cyclic Peptides.

The amidine functionality switches between hydrogen bond donor and acceptor roles depending on pH. Herein, the amidine was incorporated to select amides in cyclo(d-Ala-Pro-d-Phe-Pro-Gly). The unprotonated amidine-containing macrocyclic conformation resembles its oxoamide counterpart.

Toward F-Labeled Theranostics: A Single Agent that Can Be Labeled with F, Cu, or Lu.

We report a single-molecule radiotracer that can be labeled independently with F-fluoride or radiometals ( Cu, Lu) in a single step. A prostate-specific membrane antigen (PSMA)-targeting ligand, armed with both an organotrifluoroborate and a metal-chelator (DOTA), was designed to optionally afford F-, Cu- or Lu-labeled products that were injected into mice bearing prostate cancer (LNCaP) xenografts. PET/CT images and ex vivo biodistribution data show high, specific tumor uptake irrespective of which radionuclide is used, thereby demonstrating a new approach to combining, in a single molecule, F-labeling capabilities for PET imaging with radiometalation for potential imaging and therapeutic applications.

Conformational Control of Macrocycles by Remote Structural Modification.

The conformational analysis of macrocycles is a complex and challenging problem. There are many factors that contribute to this complexity. These include a large number of degrees of freedom, transannular interactions such as hydrogen bonds and hydrophobic interactions, and a range of steric interactions, along with ring strain effects.

A Metal-Free DOTA-Conjugated F-Labeled Radiotracer: [F]DOTA-AMBF-LLP2A for Imaging VLA-4 Over-Expression in Murine Melanoma with Improved Tumor Uptake and Greatly Enhanced Renal Clearance.

DOTA is commonly used for radiometal chelation in molecular imaging. Yet in the absence of a radiometal, DOTA is hypothesized to promote renal clearance of F-labeled peptide tracers. In light of an increasing interest in the use of F18 for PET, here the effect of DOTA is evaluated for the first time with an F-labeled tracer and is found to significantly improve the quality of images acquired through positron emission tomography (PET).

Preliminary evaluation of F-labeled LLP2A-trifluoroborate conjugates as VLA-4 (αβ integrin) specific radiotracers for PET imaging of melanoma.

Introduction: The transmembrane αβ integrin receptor, or very-late antigen 4 (VLA-4), is associated with tumor metastasis and angiogenesis, the development of chemotherapeutic drug resistance, and is overexpressed in multiple myelomas, osteosarcomas, lymphomas, leukemias, and melanomas. The peptidomimetic, LLP2A, is a high-affinity ligand with specificity for the extracellular portion of VLA-4 and several conjugates have been evaluated in vivo by NIR-fluorescence, In-SPECT and Ga- and Cu-PET imaging, but to date, not with F-PET.

Methods: Using two highly stable organotrifluoroborate prosthetic groups: ammoniumdimethyl-trifluoroborate (AMBF) and a new N-pyridinyl-para-trifluoroborate (N-Pyr-p-BF), both capable of facile aqueous F-labeling by isotope exchange (IEX), we present the first PET imaging evaluations of two [F]R-BF-PEG-LLP2A tracers using VLA-4 overexpressing B16-F10 murine melanoma tumor mouse models.

Canted Antiferromagnetism on Rectangular Layers of Fe in Polymorphic CaFeSeO.

From stoichiometric amounts of CaO, Fe, and Se, pure powders and single crystals of quaternary [Formula: see text] can be obtained by solid-state reaction and self-flux growth, respectively. The as-synthesized compound exhibits a polymorphic crystal structure, where the two modifications have different stacking sequences of [Formula: see text] layers. The two polymorphs have similar unit cells but different crystal symmetries (Cmc2 and Pnma), of which the former is non-centrosymmetric.