A chemokine receptor, CXCR4, and its endogenous ligand, stromal cell-derived factor-1 (SDF-1), have been recognized to be involved in the metastasis of several types of cancers. T140 analogs are peptidic CXCR4 antagonists composed of 14 amino acid residues that were previously developed as anti-HIV agents having inhibitory activity against HIV-entry through its co-receptor, CXCR4. Herein, we report that these compounds e¡ectively inhibited SDF-1-induced migration of human breast cancer cells (MDA-MB-231), human leukemia T cells (Sup-T1) and human umbilical vein endothelial cells at concentrations of 10^100 nM in vitro. Furthermore, slow release administration by subcutaneous injection using an Alzet osmotic pump of a potent and bio-stable T140 analog, 4F-benzoyl-TN14003, gave a partial, but statistically signi¢cant (P 9 9 0.05 (t-test)) reduction in pulmonary metastasis of MDA-MB-231 in SCID mice, even though no attempt was made to inhibit other important targets such as CCR7. These results suggest that T140 analogs have potential use for cancer therapy, and that small molecular CXCR4 antagonists could potentially replace neutralizing antibodies as anti-metastatic agents for breast cancer. ß

Efficient downsizing of peptides: By combination of two orthogonal “conformation‐based” and “sequence‐based” libraries, the cyclic pentapeptide cyclo(‐L‐Nal 1‐Gly 2‐D‐Tyr 3‐L‐Arg 4‐L‐Arg 5‐) (Nal=L‐3‐(2‐naphthyl)alanine; see overlay of the five lowest energy structures), which exhibited strong CXCR4 antagonism (IC50=4 nM) comparable to that of a 14‐residue lead compound, T140, was discovered.

No abstract

Several recent papers support the involvement of an interaction between stromal cell-derived factor-1 (SDF-1/ CXCL12) and its receptor, chemokine receptor CXCR4, in memory T cell migration in the inflamed rheumatoid arthritis (RA) synovium. Analogs of the 14-mer peptide T140 were previously found to be specific CXCR4 antagonists that were characterized as not only HIV-entry inhibitors but also anticancer-metastatic agents. In this study, a T140 analog, 4F-benzoyl-TN14003, was proven to inhibit CXCL12-mediated migration of human Jurkat cells and mouse splenocyte in a dosedependent manner in vitro (IC 50 = 0.65 and 0.54 nM, respectively). Furthermore, slow release administration by subcutaneous injection (s.c.) of 4F-benzoyl-TN14003 using an Alzet osmotic pump significantly suppressed the delayed-type hypersensitivity response induced by sheep red blood cells in mice, and significantly ameliorated clinical severity in collagen-induced arthritis in mice. As such, T140 analogs might be attractive lead compounds for chemotherapy of RA.

No abstract

Peptide auf das Wesentliche beschränkt: Das Pentapeptid cyclo(‐L‐Nal 1‐Gly 2‐D‐Tyr 3‐L‐Arg 4‐L‐Arg 5‐) wurde durch Kombination einer konformationsbasierten mit einer sequenzbasierten Peptid‐Bibliothek als möglicher CXCR4‐Antagonist ermittelt (Nal=L‐3‐(2‐Naphthyl)alanin; Bild: Projektion der fünf energetisch günstigsten Strukturen). Mit einem IC50‐Wert von 4 nM ist es vergleichbar effektiv wie die 14‐Aminosäuren‐Stammverbindung T140.

The use of a BINOL-derived phosphate as a chiral anionic phase-transfer catalyst in a nonpolar solvent allows the enantioselective fluorination of enamides using Selectfluor as the fluorinating reagent. We demonstrate that a wide range of stable and synthetically versatile α-(fluoro)benzoylimines can be readily accessed with high enantioselectivity. These compounds have the potential to be readily elaborated into a range of highly stereodefined β-fluoroamines, compounds that constitute highly valuable building blocks of particular importance in the synthesis of pharmaceuticals.

L,L-Type and L,D-type (E)-alkene dipeptide isosteres (EADIs) that have unnatural side chains at the alpha-position were synthesized by the combination of stereoselective aziridinyl ring-opening reactions and organozinc-copper-mediated anti-S(N)2' reactions toward a single substrate of gamma,delta-cis-gamma,delta-epimino (E)-alpha,beta-enoate. The utility of this methodology was demonstrated by the stereoselective synthesis of a set of diastereomeric EADIs of L-Arg-L/D-3-(2-naphthyl)alanine (Nal) that is contained in a small CXCR4 antagonist FC131 [cyclo(-D-Tyr-Arg-Arg-Nal-Gly-)]. Furthermore, a (Nal-Gly)-type EADI was synthesized by samarium diiodide (SmI(2))-induced reduction of a gamma-acetoxy-alpha,beta-enoate. Several FC131 analogues, in which these EADIs were inserted for reduction of their peptide character, were synthesized with analogues containing reduced amide-type dipeptide isosteres to investigate the importance of these amide bonds for anti-HIV and CXCR4-antagonistic activity.