58792-53-3Relevant articles and documents
Affinity-Enhanced Luminescent Re(I)- and Ru(II)-Based Inhibitors of the Cysteine Protease Cathepsin L
Huisman, Matthew,Kodanko, Jacob P.,Arora, Karan,Herroon, Mackenzie,Alnaed, Marim,Endicott, John,Podgorski, Izabela,Kodanko, Jeremy J.
, p. 7881 - 7891 (2018)
Two new Re(I)- and Ru(II)-based inhibitors were synthesized with the formulas [Re(phen)(CO)3(1)](OTf) (7; phen = 1,10-phenanthroline, OTf = trifluoromethanesulfonate) and [Ru(bpy)2(2)](Cl)2 (8; bpy = 2,2′-bipyridine), where 1 and 2 are the analogues of CLIK-148, an epoxysuccinyl-based cysteine cathepsin L inhibitor (CTSL). Compounds 7 and 8 were characterized using various spectroscopic techniques and elemental analysis; 7 and 8 both show exceptionally long excited state lifetimes. Re(I)-based complex 7 inhibits CTSL in the low nanomolar range, affording a greater than 16-fold enhancement of potency relative to the free inhibitor 1 with a second-order rate constant of 211000 ± 42000 M-1 s-1. Irreversible ligation of 7 to papain, a model of CTSL, was analyzed with mass spectroscopy, and the major peak shown at 24283 au corresponds to that of papain-1-Re(CO)3(phen). Compound 7 was well tolerated by DU-145 prostate cancer cells, with toxicity evident only at high concentrations. Treatment of DU-145 cells with 7 followed by imaging via confocal microscopy showed substantial intracellular fluorescence that can be blocked by the known CTSL inhibitor CLIK-148, consistent with the ability of 7 to label CTSL in living cells. Overall this study reveals that a Re(I) complex can be attached to an enzyme inhibitor and enhance potency and selectivity for a medicinally important target, while at the same time allowing new avenues for tracking and quantification due to long excited state lifetimes and non-native element composition.
Use of a Compact Tripodal Tris(bipyridine) Ligand to Stabilize a Single-Metal-Centered Chirality: Stereoselective Coordination of Iron(II) and Ruthenium(II) on a Semirigid Hexapeptide Macrocycle
Kobayashi, Yuka,Hoshino, Masaru,Kameda, Tomoshi,Kobayashi, Kazuya,Akaji, Kenichi,Inuki, Shinsuke,Ohno, Hiroaki,Oishi, Shinya
supporting information, p. 5475 - 5485 (2018/05/17)
Fe(II)-coordinating hexapeptides containing three 2,2′-bipyridine moieties as side chains were designed and synthesized. A cyclic hexapeptide having three [(2,2′-bipyridin)-5-yl]-d-alanine (d-Bpa5) residues, in which d-Bpa5 and Gly are alternately arranged with 3-fold rotational symmetry, coordinated with Fe(II) to form a 1:1 octahedral Fe(II)-peptide complex with a single facial-? configuration of the metal-centered chirality. NMR spectroscopy and molecular dynamics simulations revealed that the Fe(II)-peptide complex has an apparent C3-symmetric conformations on the NMR time scale, while the peptide backbone is subject to dynamic conformational exchange between three asymmetric β/γ conformations and one C3-symmetric γ/γ/γ conformation. The semirigid cyclic hexapeptide preferentially arranged these conformations of the small octahedral Fe(II)-bipyridine complex, as well as the Ru(II) congener, to underpin the single configuration of the metal-centered chirality.
DIPYRIDINIUM DERIVATIVES
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Paragraph 0346; 0347; 0348; 0349, (2014/03/25)
Compounds of Formula (I): α-x-β (I) and pharmaceutically acceptable salts and solvates thereof, wherein α, x, and β have the meanings as indicated in the specification, are useful for treating a disease or disorder characterised by pathologically proliferating cells, particularly cancer. Pharmaceutical compositions that contain the compounds and processes for preparing the compounds are also described.
