Sub-Doppler Electronic Spectra of Benzene–(H₂)_<i>n</i> Complexes

Excitation spectra of the benzene–(H₂)_<i>n</i> (<i>n</i> = 1–3) van der Waals (vdW) complexes in the vicinity of the <i>S</i>₁ ← <i>S</i>₀ 6₀¹ vibronic transition of the monomer were recorded with sub-Doppler resolution by utilizing mass-selective two-color resonance-enhanced two-photon ionization. Two distinguished isomers, correlating to <i>para</i>- and <i>ortho</i>-H₂, are identified for <i>n</i> = 1 and 2. This finding is the manifestation of the internal rotation of the H₂ unit(s) located above (and below) the benzene molecular plane within the complexes. For the observation of the weaker binding para species, a gas sample of pure <i>para</i>-H₂ was used. Rotationally resolved spectra allowed us to fix the cluster geometry unambiguously. Three vibronic bands involving vdW-mode excitation were observed for the ortho species with <i>n</i> = 1, yielding to probable sets of vibrational frequencies of all the three vdW modes. One of them correlates to the splitting between the <i>m</i> = 0 and ±1 sublevels in the <i>j</i> = 1 state of a freely rotating H₂ molecule, and the potential barrier for the hindered internal rotation has been evaluated from the values. Rotationally resolved spectrum of benzene–(<i>ortho</i>-H₂)₃ is consistent with a (2 + 1) binding motif, where two H₂ molecules on one side of the benzene plane seem to scramble their positions and roles. All the complexes examined with rotational resolution exhibited homogeneous line broadening, which corresponds to the upper-state lifetimes in the subnanosecond regime, most probably due to vibrational predissociation in the <i>S</i>₁ 6¹ manifold

Discovery of TP0597850: A Selective, Chemically Stable, and Slow Tight-Binding Matrix Metalloproteinase‑2 Inhibitor with a Phenylbenzamide–Pentapeptide Hybrid Scaffold

Matrix metalloproteinase-2 (MMP2) is a zinc-dependent endopeptidase and a promising target for various diseases, including cancer and fibrosis. Herein, we report the discovery of a novel MMP2-selective inhibitor with high chemical stability and slow tight-binding features. Based on the degradation mechanism of our small-molecule–peptide hybrid 1, the tripeptide linker {5-aminopentanoic acid [Ape(5)]–Glu–Asp} of 1 was replaced by a shorter linker (γ-D-Glu). Phenylbenzamide was suitable for the new generation of MMP2 inhibitors as an S1′ pocket-binding group. The introduction of (4S)-aminoproline dramatically increased the chemical stability while maintaining high subtype selectivity because of its interaction with Glu130. TP0597850 (18) exhibited high stability over a wide range of pH values as well as potent MMP2 inhibition (Ki = 0.034 nM) and ≥2000-fold selectivity determined using the inhibition constants. A kinetic analysis revealed that it possesses slow tight-binding nature with a long MMP2 dissociative half-life (t1/2 = 265 min)

Discovery of TP0597850: A Selective, Chemically Stable, and Slow Tight-Binding Matrix Metalloproteinase‑2 Inhibitor with a Phenylbenzamide–Pentapeptide Hybrid Scaffold

Matrix metalloproteinase-2 (MMP2) is a zinc-dependent endopeptidase and a promising target for various diseases, including cancer and fibrosis. Herein, we report the discovery of a novel MMP2-selective inhibitor with high chemical stability and slow tight-binding features. Based on the degradation mechanism of our small-molecule–peptide hybrid 1, the tripeptide linker {5-aminopentanoic acid [Ape(5)]–Glu–Asp} of 1 was replaced by a shorter linker (γ-D-Glu). Phenylbenzamide was suitable for the new generation of MMP2 inhibitors as an S1′ pocket-binding group. The introduction of (4S)-aminoproline dramatically increased the chemical stability while maintaining high subtype selectivity because of its interaction with Glu130. TP0597850 (18) exhibited high stability over a wide range of pH values as well as potent MMP2 inhibition (Ki = 0.034 nM) and ≥2000-fold selectivity determined using the inhibition constants. A kinetic analysis revealed that it possesses slow tight-binding nature with a long MMP2 dissociative half-life (t1/2 = 265 min)

Discovery of TP0597850: A Selective, Chemically Stable, and Slow Tight-Binding Matrix Metalloproteinase‑2 Inhibitor with a Phenylbenzamide–Pentapeptide Hybrid Scaffold

Matrix metalloproteinase-2 (MMP2) is a zinc-dependent endopeptidase and a promising target for various diseases, including cancer and fibrosis. Herein, we report the discovery of a novel MMP2-selective inhibitor with high chemical stability and slow tight-binding features. Based on the degradation mechanism of our small-molecule–peptide hybrid 1, the tripeptide linker {5-aminopentanoic acid [Ape(5)]–Glu–Asp} of 1 was replaced by a shorter linker (γ-D-Glu). Phenylbenzamide was suitable for the new generation of MMP2 inhibitors as an S1′ pocket-binding group. The introduction of (4S)-aminoproline dramatically increased the chemical stability while maintaining high subtype selectivity because of its interaction with Glu130. TP0597850 (18) exhibited high stability over a wide range of pH values as well as potent MMP2 inhibition (Ki = 0.034 nM) and ≥2000-fold selectivity determined using the inhibition constants. A kinetic analysis revealed that it possesses slow tight-binding nature with a long MMP2 dissociative half-life (t1/2 = 265 min)

Discovery of TP0597850: A Selective, Chemically Stable, and Slow Tight-Binding Matrix Metalloproteinase‑2 Inhibitor with a Phenylbenzamide–Pentapeptide Hybrid Scaffold

Matrix metalloproteinase-2 (MMP2) is a zinc-dependent endopeptidase and a promising target for various diseases, including cancer and fibrosis. Herein, we report the discovery of a novel MMP2-selective inhibitor with high chemical stability and slow tight-binding features. Based on the degradation mechanism of our small-molecule–peptide hybrid 1, the tripeptide linker {5-aminopentanoic acid [Ape(5)]–Glu–Asp} of 1 was replaced by a shorter linker (γ-D-Glu). Phenylbenzamide was suitable for the new generation of MMP2 inhibitors as an S1′ pocket-binding group. The introduction of (4S)-aminoproline dramatically increased the chemical stability while maintaining high subtype selectivity because of its interaction with Glu130. TP0597850 (18) exhibited high stability over a wide range of pH values as well as potent MMP2 inhibition (Ki = 0.034 nM) and ≥2000-fold selectivity determined using the inhibition constants. A kinetic analysis revealed that it possesses slow tight-binding nature with a long MMP2 dissociative half-life (t1/2 = 265 min)

Discovery of TP0597850: A Selective, Chemically Stable, and Slow Tight-Binding Matrix Metalloproteinase‑2 Inhibitor with a Phenylbenzamide–Pentapeptide Hybrid Scaffold

Matrix metalloproteinase-2 (MMP2) is a zinc-dependent endopeptidase and a promising target for various diseases, including cancer and fibrosis. Herein, we report the discovery of a novel MMP2-selective inhibitor with high chemical stability and slow tight-binding features. Based on the degradation mechanism of our small-molecule–peptide hybrid 1, the tripeptide linker {5-aminopentanoic acid [Ape(5)]–Glu–Asp} of 1 was replaced by a shorter linker (γ-D-Glu). Phenylbenzamide was suitable for the new generation of MMP2 inhibitors as an S1′ pocket-binding group. The introduction of (4S)-aminoproline dramatically increased the chemical stability while maintaining high subtype selectivity because of its interaction with Glu130. TP0597850 (18) exhibited high stability over a wide range of pH values as well as potent MMP2 inhibition (Ki = 0.034 nM) and ≥2000-fold selectivity determined using the inhibition constants. A kinetic analysis revealed that it possesses slow tight-binding nature with a long MMP2 dissociative half-life (t1/2 = 265 min)