Browse
Submit Data
Databases
API
Help

Dataset Information

7 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Ahp-Cyclodepsipeptide Inhibitors of Elastase: Lyngbyastatin 7 Stability, Scalable Synthesis, and Focused Library Analysis.

ABSTRACT: Due to the potency and selectivity of lyngbyastatin 7 in inhibiting neutrophil elastase, a serine protease involved in numerous diseases, this cyclodepsipeptide was considered as a promising lead and subjected to further developmental studies. Lyngbyastatin 7 displayed a favorable serum and microsomal stability profile. The large-scale synthesis of key building blocks was performed on gram scale with improved yields and simplified purification procedures. To tailor the complex structure, define the minimal pharmacophore, and modulate the physicochemical properties of the lead scaffold, the first pilot library of analogues was designed and synthesized for structure-activity relationship studies. We uncovered the essential role of the side chain, indicating that the minimal structural requirements for elastase inhibition extended beyond the 3-amino-6-hydroxy-2-piperidone (Ahp) and 2-aminobutenoic acid (Abu) moieties conventionally known to convey antiprotease activity and elastase selectivity, respectively. Our studies will facilitate the design and development of this class of elastase inhibitors.

SUBMITTER: Luo D

PROVIDER: S-EPMC7153021 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Photochemical synthesis of an epigenetic focused tetrahydroquinoline library.

Project description:Discovery of epigenetic chemical probes is an important area of research with potential to deliver drugs for a multitude of diseases. However, commercially available libraries frequently used in drug discovery campaigns contain molecules that are focused on a narrow range of chemical space primarily driven by ease of synthesis and previously targeted enzyme classes (e.g., kinases) resulting in low hit rates for epigenetic targets. Here we describe the design and synthesis of a compound collection that augments current screening collections by the inclusion of privileged isosteres for epigenetic targets.

| S-EPMC8528209 | biostudies-literature

Design and Synthesis of a Focused Library of Diamino Triazines as Potential Mycobacterium tuberculosis DHFR Inhibitors.

Project description:We report design of a series of 2,4-diamino triazines as Mycobacterium tuberculosis (Mtb) dihydrofolate reductase inhibitors. The synthesized compounds were evaluated against Mtb (H37Rv and Dormant stage H37Ra), their cytotoxicity was assessed (HepG2 and A549 cell lines), and selectivity toward Mtb was evaluated by testing against other bacterial strains. Some derivatives showed promising activity along with low cytotoxicity. The most potent compound in the whole cell assay (MIC 0.325 ?M against H37Rv) showed selectivity in the enzyme assay and exhibited synergy with second line anti-TB agent p-amino salicylic acid. This study therefore provides promising molecules for further development as antituberculosis DHFR inhibitors.

| S-EPMC4645240 | biostudies-literature

Ahp-Cyclodepsipeptides as tunable inhibitors of human neutrophil elastase and kallikrein 7: Total synthesis of tutuilamide A, serine protease selectivity profile and comparison with lyngbyastatin 7.

Project description:We describe the total synthesis of tutuilamide A, a potent porcine pancreatic elastase (PPE) inhibitor and a representative member of the 3-amino-6-hydroxy-2-piperidone (Ahp) cyclodepsipeptide family, isolated from marine cyanobacteria. The Ahp unit serves as a pharmacophore and the adjacent 2-amino-2-butenoic acid (Abu) is a main driver of the selectivity among serine proteases. We adapted our previous convergent strategy to generate the macrocycle, common with lyngbyastatin 7 and related elastase inhibitors, and then appended the tutuilamide A-specific side chain bearing a vinyl chloride. Tutuilamide A and lyngbyastatin 7 were evaluated side by side for the inhibition of the disease-relevant human neutrophil elastase (HNE). Tutuilamide A and lyngbyastatin 7 were approximately equipotent against HNE, while tutuilamide A was previously shown to be more active against PPE compared with lyngbyastatin 7, further demonstrating that the side chain provides opportunities to not only modulate potency but also selectivity among proteases of the same function from different organisms. Profiling of tutuilamide A against mainly human serine proteases revealed high selectivity for HNE (IC50 0.73 nM) and pleiotropic activity against kallikrein 7 (KLK7, IC50 5.0 nM), without affecting other kallikreins, similarly to lyngbyastatin 7 (IC50 0.85 nM for HNE and 3.1 nM for KLK7). A comprehensive molecular docking study for elastases and KLK7 afforded deeper insight into the intricate differences between inhibitor interactions with HNE and PPE, accounting for the differential activities for both compounds. The synthesis and molecular studies serve as a proof-of-concept that the macrocyclic scaffold can be diversified to fine-tune the activity of serine protease inhibitors.

| S-EPMC8209782 | biostudies-literature

Cyclodepsipeptide alveolaride C: total synthesis and structural assignment.

Project description:First stereoselective total synthesis of naturally occurring bioactive cyclodepsipeptide alveolaride C has been achieved using a convergent approach. This synthetic study enabled us to establish unambiguously the stereochemistry of three unassigned chiral centres embedded in the nonpeptidic segment as well as revised the stereochemistry of the proposed β-phenylalanine counterpart of the molecule. The key strategic features of this synthesis include Sharpless asymmetric dihydroxylation for installing the vicinal diol moiety, Julia-Kocienski olefination for constructing the aliphatic side chain, the Shiina protocol for intermolecular esterification, amide coupling and macrolactamization for the ring formation.

| S-EPMC8162944 | biostudies-literature

Scalable synthesis and structural characterization of reversible KLK6 inhibitors.

Project description:Scalable asymmetric syntheses of two kallikrein-related protease 6 (KLK6) inhibitors are reported. The inhibitors are assembled by linking enantiomerically enriched fragments via amide bond formation, followed by conversion of a cyano group to an amidine. One fragment, an amine, was prepared using the Ellman auxiliary, and a lack of clarity in the literature regarding the stereochemical outcome of this reaction was solved via X-ray crystallographic analysis of two derivatives. Complexes of the inhibitors bound to human KLK6 were solved by X-ray crystallography, revealing the binding poses.

| S-EPMC9490775 | biostudies-literature

Total synthesis of the marine cyanobacterial cyclodepsipeptide apratoxin A.

Project description:A total synthesis of apratoxin A was developed. Apratoxin A, isolated from Lyngbya spp. cyanobacteria, is representative of a growing class of marine cyanobacterial cyclodepsipeptides wherein discrete polypeptide and polyketide domains are merged by ester and amide or amide-derived linkages. In the apratoxins, the N terminus of the peptide domain [(Pro)-(N-Me-Ile)-(N-Me-ala)-(O-Me-Tyr)-(moCys)] is a modified vinylogous cysteine that is joined to a novel ketide [3,7-dihydroxy-2,5,8,8-tetramethylnonanoic acid (Dtna)] by an acid-sensitive thiazoline. The C-terminal proline is esterified to a hindered hydroxyl vicinal to the ketide's tert-butyl terminus. Major synthetic challenges included assembly and maintenance the thiazoline-containing moiety and macrolide formation involving acylation of the C39 hydroxyl. The Dtna domain was assembled in the biogenetic direction beginning with a Brown allylation of trimethylacetaldehyde to establish the C39 alcohol configuration. Diastereofacial selective addition of a higher-order dimethylcuprate upon a ring-closing metathesis-derived alpha,beta-unsaturated valerolactone installed the C37 methyl-bearing center. A Paterson anti-aldol process was used to incorporate the remaining two ketide stereogenic centers at C34 and C35. Although attempts to incorporate the thiazoline moiety by condensations of thiol esters bearing alpha-amino carbamate derivatives failed, an intramolecular Staudinger reduction-aza-Wittig process using alpha-azido thiol esters was uniquely successful. Late-stage macrocycle closure proceeded well by lactam formation between Pro and N-Me-Ile residues, but attempted lactonizations of the Pro carboxylate with the C39 hydroxyl failed. Optimization of C35 hydroxyl group protection-deprotection completed the effort, which culminated in the first total synthesis of apratoxin A and will enable analog generation toward improving differential cytotoxicity.

| S-EPMC514436 | biostudies-literature

A convergent, scalable and stereoselective synthesis of azole CYP51 inhibitors.

Project description:The study and development of azole-based CYP51 inhibitors is an active area of research across disciplines of biochemistry, pharmacology and infectious disease. Support of in vitro and in vivo studies require the development of robust asymmetric routes to single enantiomer products of this class of compounds. Herein, we describe a scalable and enantioselective synthesis to VNI and VFV, the two potent inhibitors of protozoan sterol 14?-demethylase (CYP51) that are currently under consideration for clinical trials for Chagas disease. A key transformation is the Jacobsen Hydrolytic Kinetic Resolution (HKR) reaction. The utility of the synthetic route is illustrated by the preparation of >25 g quantities of single enantiomers of VNI and VFV.

| S-EPMC5777588 | biostudies-literature

A focused library synthesis and cytotoxicity of quinones derived from the natural product bolinaquinone.

Project description:Bolinaquinone is a natural product that is a structurally complex, cytotoxic sesquiterpene quinone. A scaffold simplification and focused library approach using a microwave-assisted Suzuki coupling gave 32 bolinaquinone analogues with good-to-excellent cytotoxicity profiles. Mono-arylbenzoquinones, Library A, were preferentially toxic towards BE2-C (neuroblastoma) cells with growth inhibition (GI50) values of 4-12?µM; only the 3,4-dimethoxyphenyl 23 and 3-biphenyl 28 variants were broad-spectrum active-HT29 (colon carcinoma), U87 and SJ-G2 (glioblastoma), MCF-7 (breast carcinoma), A2780 (ovarian carcinoma), H460 (lung carcinoma), A431 (skin carcinoma), Du145 (prostate carcinoma), BE2-C (neuroblastoma), MIA (pancreatic carcinoma) and SMA (spontaneous murine astrocytoma). Library B with a second aryl moiety exhibited broad-spectrum cytotoxicity with MCF-7 cells' GI50 values of 5.6?±?0.7 and 5.1?±?0.5?µM for 2,5-dimethoxy-3-(naphthalene-1-yl)-6-(naphthalene-3-yl) 33 and 2,5-dimethoxy-3-(biaryl-2-yl)-6-(naphthalene-3-yl) 36, respectively. Similar potencies were also noted with 2,5-dimethoxy-3,6-diphenyl 30 against A2780 (GI50?=?5.9?±?0.0?µM) and with 2,5-dimethoxy-3-(biaryl-3-yl)-6-(naphthalene-3-yl) 37 against HT29 (GI50?=?5.4?±?0.4?µM), while the 3,4-dimethoxy mono-aryl analogue 23 exhibited good levels of activity against A2780 (GI50?=?3.8?±?0.75?µM), the neuroblastoma cell line BE2-C (GI50?=?3?±?0.35?µM) and SMA (GI50?=?3.9?±?0.54?µM). Introduction of the amino-substituted Library C gave 2-(naphthalen-1-yl)-5-(naphthalen-3-yl)-3,6-bis(propylamino) 43, with excellent activity against HT29 (0.08?±?0.0?µM), MCF-7 (0.17?±?0.1?µM), A2780 (0.14?±?0.1?µM), A431 (0.11?±?0.0?µM), Du145 (0.16?±?0.1?µM), BE2-C (0.08?±?0.0?µM) and MIA (0.1?±?0.0?µM).

| S-EPMC5936891 | biostudies-literature

Synthesis and evaluation of benzenesulfonic acid derivatives as human neutrophil elastase (hNE) inhibitors.

Project description:Herein we report our investigation concerning the development of Human neutrophil elastase (hNE) inhibitors for the treatment of Acute Respiratory Distress Syndrome (ARDS). Various benzenesulfonic acid derived compounds were synthesized and evaluated as competitive inhibitors of hNE. Biological screening revealed that compound 4f shows moderate inhibitory activity (IC50?=?35.2??M) against hNE. Compound 4f was also superimposed onto the active center of hNE to understand the binding mode.

| S-EPMC7801566 | biostudies-literature

Discovery of Inhibitors of Trypanosoma brucei by Phenotypic Screening of a Focused Protein Kinase Library.

Project description:A screen of a focused kinase inhibitor library against Trypanosoma brucei rhodesiense led to the identification of seven series, totaling 121 compounds, which showed >50?% inhibition at 5??m. Screening of these hits in a T.?b.?brucei proliferation assay highlighted three compounds with a 1H-imidazo[4,5-b]pyrazin-2(3H)-one scaffold that showed sub-micromolar activity and excellent selectivity against the MRC5 cell line. Subsequent rounds of optimisation led to the identification of compounds that exhibited good in vitro drug metabolism and pharmacokinetics (DMPK) properties, although in general this series suffered from poor solubility. A scaffold-hopping exercise led to the identification of a 1H-pyrazolo[3,4-b]pyridine scaffold, which retained potency. A number of examples were assessed in a T.?b.?brucei growth assay, which could differentiate static and cidal action. Compounds from the 1H-imidazo[4,5-b]pyrazin-2(3H)-one series were found to be either static or growth-slowing and not cidal. Compounds with the 1H-pyrazolo[3,4-b]pyridine scaffold were found to be cidal and showed an unusual biphasic nature in this assay, suggesting they act by at least two mechanisms.

| S-EPMC4648050 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data