53481-48-4Relevant articles and documents
Exploring Structural Determinants of Inhibitor Affinity and Selectivity in Complexes with Histone Deacetylase 6
Osko, Jeremy D.,Porter, Nicholas J.,Narayana Reddy, Poli Adi,Xiao, You-Cai,Rokka, Johanna,Jung, Manfred,Hooker, Jacob M.,Salvino, Joseph M.,Christianson, David W.
, p. 295 - 308 (2020/02/20)
Inhibition of histone deacetylase 6 (HDAC6) has emerged as a promising therapeutic strategy for the treatment of cancer, chemotherapy-induced peripheral neuropathy, and neurodegenerative disease. The recent X-ray crystal structure determination of HDAC6 enables an understanding of structural features directing affinity and selectivity in the active site. Here, we present the X-ray crystal structures of five HDAC6-inhibitor complexes that illuminate key molecular features of the inhibitor linker and capping groups that facilitate and differentiate binding to HDAC6. In particular, aromatic and heteroaromatic linkers nestle within an aromatic cleft defined by F583 and F643, and different aromatic linkers direct the capping group toward shallow pockets defined by the L1 loop, the L2 loop, or somewhere in between these pockets. These results expand our understanding of factors contributing to the selective inhibition of HDAC6, particularly regarding interactions that can be targeted in the region of the L2 pocket.
1-Ethyl 2-halopyridinium salts, highly efficient coupling reagents for hindered peptide synthesis both in solution and the solid-phase
Li, Peng,Xu, Jie-Cheng
, p. 8119 - 8131 (2007/10/03)
1-Ethyl-2-halopyridinium salts, BEP, FEP, BEPH and FEPH, were synthesized and proved to be very effective for the synthesis of hindered peptides containing N-methylated or C(α),C(α)-dialkylated amino acid residues. HPLC monitoring of model reactions indicated that these pyridinium salts demonstrated higher reactivities, lower racemization than the commonly used halogenated uronium and phosphonium salts. The efficiency of these pyridinium type coupling reagents was further proved by the synthesis of a series of hindered oligopeptides and active esters with good yields and convenient workup. The 8-11 tetrapeptide fragment of Cyclosporin A (CsA) and the pentapeptide moiety of Dolastatin 15 were also successfully synthesized using these pyridinium salts. The efficiency of these pyridinium type coupling reagents for SPPS was also demonstrated by the solid-phase synthesis of the extremely hindered 8-11 peptide segment of CsA and the linear undecapeptide of CsO. The mechanism of the pyridinium salt mediated coupling reactions was also studied by 1H NMR, IR and HPLC. It was proposed that the major reactive intermediates were the corresponding acyl halide and acyloxypyridinium salts of the N-protected amino acid or peptide. (C) 2000 Elsevier Science Ltd.
Synthesis of a Wasp Venom Tetradecapeptide, Mastoparan, with a New Cleaving System for 4-Methoxy-2,2,6-trimethylbenzenesulfonyl (Mtr) Amino-Protecting Group
Saito, Kazuki,Higashijima, Tsutomu,Miyazawa, Tatsuo,Wakimasu, Mitsuhiro,Fujino, Masahiko
, p. 2187 - 2193 (2007/10/02)
The 4-methoxy-2,3,6-trimethylbenzenesulfonyl (Mtr) group was introduced for protection of the ε-amino function of lysine and its acid lability was examined.The cleavage of Lys(Mtr) was accelerated by addition of methyl sulfide, as a second scavenger, to methanesulfonic acid-containing trifluoroacetic acid-thioanisole.In order to examine the usefulness of the new cleaving system with methyl sulfide, a wasp venom peptide, mastoparan, was synthesized.This system was found to give a highly pure product in good yield.Keywords - 4-methoxy-2,3,6-trimethylbenzenesulfonyl (Mtr); Nε-4-methoxy-2,3,6-trimethylbenzenesulfonyllysine; methanesulfonic acid-trifluoracetic acid-thioanisole-methyl sulfide deprotection; mastoparan; wasp venom peptide
