613675-78-8Relevant academic research and scientific papers
Virtual screening of peptide and peptidomimetic fragments targeted to inhibit bacterial dithiol oxidase DsbA
Duprez, Wilko,Bachu, Prabhakar,Stoermer, Martin J.,Tay, Stephanie,McMahon, Róisín M.,Fairlie, David P.,Martin, Jennifer L.
, (2015)
Antibacterial drugs with novel scaffolds and new mechanisms of action are desperately needed to address the growing problem of antibiotic resistance. The periplasmic oxidative folding system in Gram-negative bacteria represents a possible target for anti-virulence antibacterials. By targeting virulence rather than viability, development of resistance and side effects (through killing host native microbiota) might be minimized. Here, we undertook the design of peptidomimetic inhibitors targeting the interaction between the two key enzymes of oxidative folding, DsbA and DsbB, with the ultimate goal of preventing virulence factor assembly. Structures of DsbB - or peptides - complexed with DsbA revealed key interactions with the DsbA active site cysteine, and with a hydrophobic groove adjacent to the active site. The present work aimed to discover peptidomimetics that target the hydrophobic groove to generate non-covalent DsbA inhibitors. The previously reported structure of a Proteus mirabilis DsbA active site cysteine mutant, in a non-covalent complex with the heptapeptide PWATCDS, was used as an in silico template for virtual screening of a peptidomimetic fragment library. The highest scoring fragment compound and nine derivatives were synthesized and evaluated for DsbA binding and inhibition. These experiments discovered peptidomimetic fragments with inhibitory activity at millimolar concentrations. Although only weakly potent relative to larger covalent peptide inhibitors that interact through the active site cysteine, these fragments offer new opportunities as templates to build non-covalent inhibitors. The results suggest that non-covalent peptidomimetics may need to interact with sites beyond the hydrophobic groove in order to produce potent DsbA inhibitors.
Design, synthesis, and preliminary bioactivity evaluation of N1-hydroxyterephthalamide derivatives with indole cap as novel histone deacetylase inhibitors
Wang, Xue,Li, Xiaoyang,Li, Jingyao,Hou, Jinning,Qu, Ying,Yu, Chenggong,He, Feng,Xu, Wenfang,Wu, Jingde
, p. 38 - 46 (2016/12/16)
Histone deacetylases inhibitors (HDACIs) have been widely recognized as significant therapeutic approach to cancers. In our efforts to develop novel histone deacetylases inhibitors (HDACIs) as potential anticancer agents, a series of N1-hydroxyterephthalamide derivatives with an indole cap group were designed and synthesized. Compound 12m was identified to be the most potent one (IC50?=?0.074?μm against HeLa nuclear extract) and showed higher inhibitory activity than the positive control SAHA (IC50?=?0.131?μm), which was also verified by further molecular docking studies into active site of HDAC2. The results of selectivity on the inhibition of HDACs exhibited 12m being with similar isoform selective profile with PXD101. In addition, the representative compounds (8d, 12d, 12j, 12m) based on the outcomes of preliminary tumor cell screening demonstrated more potent or comparable to SAHA in the next antiproliferative activity assays. Collectively, the results encouraged further development of this chemical template to provide more potent analogs as HDACIs.
C ring may be dispensable for β-carboline: Design, synthesis, and bioactivities evaluation of tryptophan analog derivatives based on the biosynthesis of β-carboline alkaloids
Huang, Yuanqiong,Liu, Yongxian,Liu, Yuxiu,Song, Hongjian,Wang, Qingmin
, p. 462 - 473 (2016/01/25)
According to our previous work and the latest research on the biosynthesis of β-carboline, and using the reverse thinking strategy, tryptophan, the biosynthesis precursor of β-carboline alkaloids, and their derivatives were synthesized, and their biological activities and structure-activity relationships were studied. This bioassay showed that these compounds exhibited good inhibitory activities against tobacco mosaic virus (TMV); especially (S)-2-amino-3-(1H-indol-3-yl)-N-octylpropanamide (4) (63.3 ± 2.1%, 67.1 ± 1.9%, 68.7 ± 1.3%, and 64.5 ± 3.1%, 500 μg/mL) exhibited the best antiviral activity both in vitro and in vivo. Compound 4 was chosen for the field trials and the acute oral toxicity test, the results showed that the compound exhibited good anti-TMV activity in the field and low acute oral toxicity. We also found that these compounds showed antifungal activities and insecticidal activities.
Small-molecule inhibitors that target protein-protein interactions in the RAD51 family of recombinases
Scott, Duncan E.,Coyne, Anthony G.,Venkitaraman, Ashok,Blundell, Tom L.,Abell, Chris,Hyv?nen, Marko
supporting information, p. 296 - 303 (2015/02/05)
The development of small molecules that inhibit protein-protein interactions continues to be a challenge in chemical biology and drug discovery. Herein we report the development of indole-based fragments that bind in a shallow surface pocket of a humanised surrogate of RAD51. RAD51 is an ATP-dependent recombinase that plays a key role in the repair of doublestrand DNA breaks. It both self-associates, forming filament structures with DNA, and interacts with the BRCA2 protein through a common "FxxA" tetrapeptide motif. We elaborated previously identified fragment hits that target the FxxA motif site and developed small-molecule inhibitors that are approximately 500-fold more potent than the initial fragments. The lead compounds were shown to compete with the BRCA2-derived Ac-FHTA-NH2 peptide and the self-association peptide of RAD51, but they had no effect on ATP binding. This study is the first reported elaboration of small-molecular-weight fragments against this challenging target.
Condensation of α-Amino Acid with Amine in the Absence of a Coupling Agent
Yamaguchi, Jun-Ichi,Nagai, Shinya,Fukuoka, Emi,Suyama, Takayuki
, p. 830 - 831 (2007/10/03)
Treatment of N-(4-nitrophenoxycarbonyl)amino acid with an equimolar amount of amine in the absence of a coupling agent gave the corresponding α-amino acid amide in high yield.
Development of peptide 3D structure mimetics: Rational design of novel peptoid cholecystokinin receptor antagonists
Low,Black,Broughton,Buck,Davies,Dunstone,Hull,Kalindjian,McDonald,Pether,Shankley,Steel
, p. 3505 - 3517 (2007/10/03)
The two hormones cholecystokinin and gastrin share the same C-terminal sequence of amino acids, namely Gly29-Trp30-Met31-Asp32-Phe33-NH2. Nevertheless, this congruence has not precluded usi
