27427-92-5Relevant articles and documents
Development of a new benzophenone-diketopiperazine-type potent antimicrotubule agent possessing a 2-pyridine structure
Hayashi, Yoshiki,Takeno, Haruka,Chinen, Takumi,Muguruma, Kyohei,Okuyama, Kohei,Taguchi, Akihiro,Takayama, Kentaro,Yakushiji, Fumika,Miura, Masahiko,Usui, Takeo,Hayashi, Yoshio
, p. 1094 - 1098 (2014)
A new benzophenone-diketopiperazine-type potent antimicrotubule agent was developed by modifying the structure of the clinical candidate plinabulin (1). Although the right-hand imidazole ring with a branched alkyl chain at the 5-position in 1 was critical for the potency of the antimicrotubule activity, we successfully substituted this moiety with a simpler 2-pyridyl structure by converting the left-hand ring from a phenyl to a benzophenone structure without decreasing the potency. The resultant compound 6b (KPU-300) exhibited a potent cytotoxicity, with an IC50value of 7.0 nM against HT-29 cells, by strongly binding to tubulin (Kd= 1.3 μM) and inducing microtubule depolymerization.
Screening Platform Based on Inductively Coupled Plasma Mass Spectrometry for β-Site Amyloid Protein Cleaving Enzyme 1 (BACE1) Inhibitors
Jin, Xin,Yang, Limin,Yan, Xiaowen,Wang, Qiuquan
, p. 1093 - 1099 (2021/05/06)
β-Site amyloid protein cleaving enzyme 1 (BACE1) is a promising therapeutic target for developing inhibitors to alleviate Alzheimer's disease (AD). Herein, we established an inductively coupled plasma mass spectrometry (ICPMS)-based inhibitor screening platform. A biotin-labeled lanthanide-coded peptide probe (LCPP; biotin-PEG2-EVNLDAEC-DOTA-Ln) was designed to determine the activity of BACE1 and evaluate the degree of inhibition of inhibitors. The platform was first validated with two commercially available inhibitors (BSI I and BSI IV) in terms of IC50 values and then applied to two newly designed inhibitors (inhibitors II and III) based on the crystal structure of BACE1 interacting with inhibitor I, and each of them contained an acylguanidine core structure. We found that their inhibition effects were improved as evaluated by the sensitive and accurate LCPP-ICPMS platform, demonstrating its ability for new drug screening.
Inhibition of the Cysteine Protease Human Cathepsin L by Triazine Nitriles: Amide???Heteroarene π-Stacking Interactions and Chalcogen Bonding in the S3 Pocket
Giroud, Maude,Ivkovic, Jakov,Martignoni, Mara,Fleuti, Marianne,Trapp, Nils,Haap, Wolfgang,Kuglstatter, Andreas,Benz, J?rg,Kuhn, Bernd,Schirmeister, Tanja,Diederich, Fran?ois
supporting information, p. 257 - 270 (2017/02/15)
We report an extensive “heteroarene scan” of triazine nitrile ligands of the cysteine protease human cathepsin L (hCatL) to investigate π-stacking on the peptide amide bond Gly67–Gly68 at the entrance of the S3 pocket. This heteroarene???peptide bond stacking was supported by a co-crystal structure of an imidazopyridine ligand with hCatL. Inhibitory constants (Ki) are strongly influenced by the diverse nature of the heterocycles and specific interactions with the local environment of the S3 pocket. Binding affinities vary by three orders of magnitude. All heteroaromatic ligands feature enhanced binding by comparison with hydrocarbon analogues. Predicted energetic contributions from the orientation of the local dipole moments of heteroarene and peptide bond could not be confirmed. Binding of benzothienyl (Ki=4 nm) and benzothiazolyl (Ki=17 nm) ligands was enhanced by intermolecular C?S???O=C interactions (chalcogen bonding) with the backbone C=O of Asn66 in the S3 pocket. The ligands were also tested for the related enzyme rhodesain.
