118171-79-2Relevant academic research and scientific papers
Elastase Inhibitor Cyclotheonellazole A: Total Synthesis and in Vivo Biological Evaluation for Acute Lung Injury
Cui, Yingjun,Zhang, Mengyi,Xu, Honglei,Zhang, Tingrong,Zhang, Songming,Zhao, Xiuhe,Jiang, Peng,Li, Jing,Ye, Baijun,Sun, Yuanjun,Wang, Mukuo,Deng, Yangping,Meng, Qing,Liu, Yang,Fu, Qiang,Lin, Jianping,Wang, Liang,Chen, Yue
, p. 2971 - 2987 (2022/01/27)
Acute lung injury/acute respiratory distress syndrome (ALI/ARDS) is one of the most common complications in COVID-19. Elastase has been recognized as an important target to prevent ALI/ARDS in the patient of COVID-19. Cyclotheonellazole A (CTL-A) is a nat
Peptidotriazolamers Inhibit Aβ(1–42) Oligomerization and Cross a Blood-Brain-Barrier Model
Tonali, Nicolo,Hericks, Loreen,Schr?der, David C.,Kracker, Oliver,Krzemieniecki, Rados?aw,Kaffy, Julia,Le Joncour, Vadim,Laakkonen, Pirjo,Marion, Antoine,Ongeri, Sandrine,Dodero, Veronica I.,Sewald, Norbert
, p. 840 - 851 (2021/05/05)
In peptidotriazolamers every second peptide bond is replaced by a 1H-1,2,3-triazole. Such foldamers are expected to bridge the gap in molecular weight between small-molecule drugs and protein-based drugs. Amyloid β (Aβ) aggregates play an important role in Alzheimer's disease. We studied the impact of amide bond replacements by 1,4-disubstituted 1H-1,2,3-triazoles on the inhibitory activity of the aggregation “hot spots” K16LVFF20 and G39VVIA42 in Aβ(1–42). We found that peptidotriazolamers act as modulators of the Aβ(1–42) oligomerization. Some peptidotriazolamers are able to interfere with the formation of toxic early Aβ oligomers, depending on the position of the triazoles, which is also supported by computational studies. Preliminary in vitro results demonstrate that a highly active peptidotriazolamer is also able to cross the blood-brain-barrier.
Small molecule peptidomimetic trypsin inhibitors: validation of an EKO binding mode, but with a twist
Burgess, Kevin,Joy, Shaon,Laganowsky, Arthur,Lyu, Rui-Liang,Packianathan, Charles
supporting information, p. 2075 - 2080 (2022/03/31)
Examination of a series of naturally-occurring trypsin inhibitor proteins, led to identification of a set of three residues (which we call the “interface triplet”) to be determinant of trypsin binding affinity, hence excellent templates for small molecule mimicry. Consequently, we attempted to use the Exploring Key Orientation (EKO) strategy developed in our lab to evaluate small molecules that mimic the interface triplet regions of natural trypsin inhibitors, and hence potentially might bind and inhibit the catalytic activity of trypsin. A bis-triazole scaffold (“TT-mer”) was the most promising of the molecules evaluated in silico. Twelve such compounds were synthesized and assayed against trypsin, among which the best showed a Kd of 2.1 μM. X-ray crystallography revealed a high degree of matching between an illustrative TT-mer's actual binding mode and that of the mimics that overlaid the interface triplet in the crystal structure. Deviation of the third side chain from the PPI structure seems to be due to alleviation of an unfavorable dipole-dipole interaction in the small molecule's actual bound conformation.
Synthesis, SAR and biological studies of sugar amino acid-based almiramide analogues: N-methylation leads the way
Das, Dipendu,Khan, Hina P. A.,Shivahare, Rahul,Gupta, Suman,Sarkar, Jayanta,Siddiqui, Mohd. Imran,Ampapathi, Ravi Sankar,Chakraborty, Tushar Kanti
, p. 3337 - 3352 (2017/04/21)
Leishmaniasis, caused by the protozoan parasites of the genus Leishmania, is one of the most neglected diseases endemic in many continents posing enormous global health threats and therefore the discovery of new antileishmanial compounds is of utmost urgency. The antileishmanial activities of a library of sugar amino acid-based linear lipopeptide analogues were examined with the aim to identify potential drug candidates to treat visceral leishmaniasis. It was found that among the synthesized analogues, most of the permethylated compounds exhibited more activity in in vitro studies against intra-macrophagic amastigotes than the non-methylated analogues. SAR and NMR studies revealed that introduction of the N-methyl groups inhibited the formation of any turn structure in these molecules, which led to their improved activities.
Synthesis and biological activity evaluation of dolastatin 10 analogues with N-terminal modifications
Wang, Xin,Dong, Suzhen,Feng, Dengke,Chen, Yazhou,Ma, Mingliang,Hu, Wenhao
, p. 2255 - 2266 (2017/03/24)
We have described the synthesis of the two complex units (2R,3R,4S)-dolaproine (Dap) and (3R,4S,5S)-dolaisoleuine (Dil) of dolastatin 10 from natural amino acids. The stereoselective syntheses of N-Boc-Dap (4a) and N-Boc-(2S)-iso-Dap (4b) were performed by employing crotylation of N-Boc-L-prolinal as a key step. Barbier-type allylation of N-Boc-L-isoleucinal provided a mild and convenient approach for the synthesis of N-Boc-Dil (5a) and N-Boc-(3S)-iso-Dil (5b). Ten dolastatin 10 analogues have been designed and synthesized with N-terminal modifications based on the known compound monomethylauristatin F (MMAF, 3). In comparison with MMAF (3), four of the compounds showed enhanced potency against HCT 116 human colon cancer cells in?vitro.
Enzymatic Macrocyclization of 1,2,3-Triazole Peptide Mimetics
Oueis, Emilia,Jaspars, Marcel,Westwood, Nicholas J.,Naismith, James H.
supporting information, p. 5842 - 5845 (2016/05/09)
The macrocyclization of linear peptides is very often accompanied by significant improvements in their stability and biological activity. Many strategies are available for their chemical macrocyclization, however, enzyme-mediated methods remain of great interest in terms of synthetic utility. To date, known macrocyclization enzymes have been shown to be active on both peptide and protein substrates. Here we show that the macrocyclization enzyme of the cyanobactin family, PatGmac, is capable of macrocyclizing substrates with one, two, or three 1,4-substituted 1,2,3-triazole moieties. The introduction of non-peptidic scaffolds into macrocycles is highly desirable in tuning the activity and physical properties of peptidic macrocycles. We have isolated and fully characterized nine non-natural triazole-containing cyclic peptides, a further ten molecules are also synthesized. PatGmac has now been shown to be an effective and versatile tool for the ring closure by peptide bond formation.
Chemo- and Diastereoselective N-Heterocyclic Carbene-Catalyzed Cross-Benzoin Reactions Using N-Boc-α-amino Aldehydes
Haghshenas, Pouyan,Gravel, Michel
supporting information, p. 4518 - 4521 (2016/09/28)
N-Boc-α-amino aldehydes are shown to be excellent partners in cross-benzoin reactions with aliphatic or heteroaromatic aldehydes. The chemoselectivity of the reaction and the facial selectivity on the amino aldehyde allow cross-benzoin products to be obtained in good yields and good diastereomeric ratios. The developed method is utilized as the key step in a concise total synthesis of d-arabino-phytosphingosine.
Effect of Substitution on the Aniline Moiety of the GPR88 Agonist 2-PCCA: Synthesis, Structure-Activity Relationships, and Molecular Modeling Studies
Jin, Chunyang,Decker, Ann M.,Harris, Danni L.,Blough, Bruce E.
, p. 1418 - 1432 (2016/10/31)
GPR88, an orphan receptor richly expressed in the striatum, is implicated in a number of basal ganglia-associated disorders. In order to elucidate the functions of GPR88, an in vivo probe appropriate for CNS investigation is required. We previously reported that 2-PCCA was able to modulate GPR88-mediated cAMP production through a Gαi-coupled pathway. Early structure-activity relationship (SAR) studies suggested that the aniline moiety of 2-PCCA is a suitable site for diverse modifications. Aimed at elucidating structural requirements in this region, we have designed and synthesized a series of analogues bearing a variety of substituents at the phenyl ring of the aniline moiety. Several compounds (e.g., 5j, 5o) showed improved or comparable potency, but have lower lipophilicity than 2-PCCA (clogP 6.19). These compounds provide the basis for further optimization to probe GPR88 in vivo functions. Computational studies confirmed the SAR trends and supported the notion that 4′-substituents on the biphenyl ring exit through a largely hydrophobic binding site to the extracellular loop.
A rapid and efficient one-pot method for the reduction of N-protected α-amino acids to chiral α-amino aldehydes using CDI/DIBAL-H
Ivkovic, Jakov,Lembacher-Fadum, Christian,Breinbauer, Rolf
supporting information, p. 10456 - 10460 (2015/11/10)
N-Protected amino acids can be easily converted into chiral α-amino aldehydes in a one-pot reaction by activation with CDI followed by reduction with DIBAL-H. This method delivers Boc-, Cbz- and Fmoc-protected amino aldehydes from proteinogenic amino acids in very good isolated yields and complete stereointegrity.
Synthesis, pharmacological characterization, and structure - Activity relationship studies of small molecular agonists for the orphan GPR88 receptor
Jin, Chunyang,Decker, Ann M.,Huang, Xi-Ping,Gilmour, Brian P.,Blough, Bruce E.,Roth, Bryan L.,Hu, Yang,Gill, Joseph B.,Zhang, X. Peter
, p. 576 - 587 (2014/08/05)
GPR88 is an orphan G-protein-coupled receptor (GPCR) enriched in the striatum. Genetic deletion and gene expression studies have suggested that GPR88 plays an important role in the regulation of striatal functions and is implicated in psychiatric disorder
