Stable 5,5′-Substituted 2,2′-Bipyrroles: Building Blocks for Macrocyclic and Materials Chemistry

The preparation and characterization of a family of stable 2,2′-bipyrroles substituted at positions 5 and 5′ with thienyl, phenyl, TMS-ethynyl, and vinyl groups is reported herein. The synthesis of these new bipyrroles comprises three steps: formation of the corresponding 5,5′-unsubstituted bipyrrole, bromination, and Stille or Suzuki coupling. The best results in the coupling are obtained using the Stille reaction under microwave irradiation. The new compounds have been fully characterized by UV–vis absorption, fluorescence, and IR spectroscopies and cyclic voltammetry. X-ray single-crystal analysis of four of the synthesized bipyrroles indicates a trans coplanar geometry of the pyrrole rings. Furthermore, the substituents at positions 5,5′ remain coplanar to the central rings. This particular geometry extends the π-conjugation of the systems, which is in agreement with a red-shifting observed for the λ_max of the substituted molecules compared to the unsubstituted bipyrrole. All of these new compounds display a moderate fluorescence. In contrast with unsubstituted bipyrroles, these bipyrroles are endowed with a high chemical and thermal stability and solubility in organic solvents

Noncyclam Tetraamines Inhibit CXC Chemokine Receptor Type 4 and Target Glioma-Initiating Cells

The three stereoisomers of the noncyclam compound <b>1</b> (<b>1</b>(<i>R,R</i>), <b>1</b>(<i>S,S</i>), and the <i>meso</i> form <b>1</b>(<i>S,R</i>)) and their corresponding tetrahydrochlorides <b>11</b> were prepared from (<i>S</i>)- and (<i>R</i>)-2-methylpiperidine. We have evaluated their inhibitory activity on the CXC chemokine receptor type 4 (CXCR4), toxicity properties, and assessment of their effect on glioma initiating cells (GICs) in comparison with the prototype compound AMD3100. The IC₅₀ values determined on human recombinant (CHO) cells showed very similar inhibitory activities albeit a lower <i>K</i>_B for AMD3100, with the <b>1</b>(<i>R,R</i>) isomer being second in potency. All the compounds showed low cardiac toxicity but, contrary to AMD3100, gave maximum nonlethal doses of around 2.0 mg/kg. The CXCR4 inhibitors had an effect on the state of differentiation of GICs, decreasing the percentage of CD44+ cells in glioblastoma multiform neurospheres in vitro. Moreover, these CXCR4 inhibitors blocked the capacity of cells to initiate orthotopic tumors in immunocompromised mice