Browse
Submit Data
Databases
API
Help

Dataset Information

16 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Synthesis of the 6-Substituted Imidazo[1,2-a]Pyridine-3-yl-2- Phosphonopropionic Acids as Potential Inhibitors of Rab Geranylgeranyl Transferase.

ABSTRACT: Twelve phosphonopropionates derived from 2-hydroxy-3-imidazo[1,2-a]pyridin-3-yl-2-phosphonopropionic acid (3-IPEHPC) were synthesized and evaluated for their activity as inhibitors of protein geranylgeranylation. The nature of the substituent in the C6 position of imidazo[1,2-a]pyridine ring was responsible for the compound's activity against Rab geranylgeranyl transferase (RGGT). The most active inhibitors disrupted Rab11A prenylation in the human cervical carcinoma HeLa cell line. The esterification of carboxylic acid in the phosphonopropionate moiety turned the inhibitor into an inactive analog.

SUBMITTER: Kusy D

PROVIDER: S-EPMC7815931 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Synthesis of the 6-Substituted Imidazo[1,2-a]Pyridine-3-yl-2- Phosphonopropionic Acids as Potential Inhibitors of Rab Geranylgeranyl Transferase.

Kusy Damian D Marchwicka Aleksandra A Małolepsza Joanna J Justyna Katarzyna K Gendaszewska-Darmach Edyta E Błażewska Katarzyna Magdalena KM

Frontiers in chemistry 20210106

Twelve phosphonopropionates derived from 2-hydroxy-3-imidazo[1,2-a]pyridin-3-yl-2-phosphonopropionic acid (3-IPEHPC) were synthesized and evaluated for their activity as inhibitors of protein geranylgeranylation. The nature of the substituent in the C6 position of imidazo[1,2-a]pyridine ring was responsible for the compound's activity against Rab geranylgeranyl transferase (RGGT). The most active inhibitors disrupted Rab11A prenylation in the human cervical carcinoma HeLa ce ...[more]

PMID: 33490034

Similar Datasets

Rational design, optimization, and biological evaluation of novel α-Phosphonopropionic acids as covalent inhibitors of Rab geranylgeranyl transferase.

Project description:Rab geranylgeranyltransferase (GGTase-II, RGGT) catalyses the post-translational modification of eukaryotic Rab GTPases, proteins implicated in several pathologies, including cancer, diabetes, neurodegenerative, and infectious diseases. Thus, RGGT inhibitors are believed to be a potential platform for the development of drugs and tools for studying processes related to the abnormal activity of Rab GTPases. Here, a series of new α-phosphonocarboxylates have been prepared in the first attempt of rational design of covalent inhibitors of RGGT derived from non-covalent inhibitors. These compounds were equipped with electrophilic groups capable of binding cysteines, which are present in the catalytic cavity of RGGT. A few of these analogues have shown micromolar activity against RGGT, which correlated with their ability to inhibit the proliferation of the HeLa cancer cell line. The proposed mechanism of this inhibitory activity was rationalised by molecular docking and mass spectrometric measurements, supported by stability and reactivity studies.

| S-EPMC8973367 | biostudies-literature

2-(Ethyl-sulfin-yl)imidazo[1,2-a]pyridine-3-sulfonamide.

Project description:The supra-molecular structure of the title compound, C(9)H(11)N(3)O(3)S(2), is defined by two inter-molecular hydrogen bonds. Pairs of N-H⋯N hydrogen bonds link the mol-ecules into centrosymmetric dimers and N-H⋯O hydrogen bonds link the dimers into a tubular chain structure running parallel to the a axis.

| S-EPMC3344477 | biostudies-literature

Imidazo[1,2-a]pyridine-based peptidomimetics as inhibitors of Akt.

Project description:We report the design, synthesis, and biological evaluation of imidazopyridine-based peptidomimetics based on the substrate consensus sequence of Akt, an AGC family serine/threonine kinase hyperactivated in over 50% of human tumors. Our ligand-based approach led to the identification of novel substrate mimetic inhibitors of Akt1 featuring an unnatural extended dipeptide surrogate. Compound 11 inhibits Akt isoforms in the sub-micromolar range and exhibits improved proteolytic stability relative to a parent pentapeptide.

| S-EPMC4176526 | biostudies-literature

2-Methyl-6-(trifluoro-meth-yl)imidazo[1,2-a]pyridine-3-carbonitrile.

Project description:In the title compound, C(10)H(6)F(3)N(3), the imidazo[1,2-a]pyridine group is essentially planar with a maximum deviation of 0.021 (1) Å. The F atoms in the trifluoro-methyl group and the methyl H atoms are each disordered over two sets of sites with refined site occupancies of 0.68 (1):0.32 (1). In the crystal, mol-ecules are linked into infinite chains through two C-H⋯N inter-actions forming R(2) (2)(12) and R(2) (2)(8) hydrogen-bond ring motifs. These chains are stacked along the a axis.

| S-EPMC3052008 | biostudies-literature

Identification of novel imidazo[1,2-a]pyridine inhibitors targeting M. tuberculosis QcrB.

Project description:Mycobacterium tuberculosis is a major human pathogen and the causative agent for the pulmonary disease, tuberculosis (TB). Current treatment programs to combat TB are under threat due to the emergence of multi-drug and extensively-drug resistant TB. Through the use of high throughput whole cell screening of an extensive compound library a number of imidazo[1,2-a]pyridine (IP) compounds were obtained as potent lead molecules active against M. tuberculosis and Mycobacterium bovis BCG. The IP inhibitors (1-4) demonstrated minimum inhibitory concentrations (MICs) in the range of 0.03 to 5 µM against a panel of M. tuberculosis strains. M. bovis BCG spontaneous resistant mutants were generated against IP 1, 3, and 4 at 5× MIC and subsequent whole genome sequencing identified a single nucleotide polymorphism (937)ACC>(937)GCC (T313A) in qcrB, which encodes the b subunit of the electron transport ubiquinol cytochrome C reductase. This mutation also conferred cross-resistance against IP 1, 3 and 4 demonstrating a common target. Gene dosage experiments confirmed M. bovis BCG QcrB as the target where over-expression in M. bovis BCG led to an increase in MIC from 0.5 to >8 µM for IP 3. An acute murine model of TB infection established bacteriostatic activity of the IP series, which await further detailed characterization.

| S-EPMC3534098 | biostudies-literature

Ethyl 8-(4-nitro-phen-yl)imidazo[1,2-a]pyridine-7-carboxyl-ate.

Project description:In the title compound, C(16)H(13)N(3)O(4), the imidazo[1,2-a]pyridine and benzene rings make a dihedral angle of 56.21?(2)°. The crystal packing is stabilized by weak ?-? stacking inter-actions [centroid-centroid distances = 3.787?(2)?Å] and C-H?O inter-molecular hydrogen-bonding inter-actions.

| S-EPMC3011613 | biostudies-literature

Rab geranylgeranyl transferase alpha mutation in the gunmetal mouse reduces Rab prenylation and platelet synthesis.

Project description:Few molecular events important to platelet biogenesis have been identified. Mice homozygous for the spontaneous, recessive mutation gunmetal (gm) have prolonged bleeding, thrombocytopenia, and reduced platelet alpha- and delta-granule contents. Here we show by positional cloning that gm results from a G-->A substitution mutation in a splice acceptor site within the alpha-subunit of Rab geranylgeranyl transferase (Rabggta), an enzyme that attaches geranylgeranyl groups to Rab proteins. Most Rabggta mRNAs from gm tissues skipped exon 1 and lacked a start codon. Rabggta protein and Rab geranylgeranyl transferase (GGTase) activity were reduced 4-fold in gm platelets. Geranylgeranylation and membrane association of Rab27, a Rab GGTase substrate, were significantly decreased in gm platelets. These findings indicate that geranylgeranylation of Rab GTPases is critical for hemostasis. Rab GGTase inhibition may represent a new treatment for thrombocytosis and clotting disorders.

| S-EPMC18176 | biostudies-literature

Multicomponent Synthesis and Binding Mode of Imidazo[1,2- a]pyridine-Capped Selective HDAC6 Inhibitors.

Project description:The multicomponent synthesis of a mini-library of histone deacetylase inhibitors with imidazo[1,2- a]pyridine-based cap groups is presented. The biological evaluation led to the discovery of the hit compound MAIP-032 as a selective HDAC6 inhibitor with promising anticancer activity. The X-ray structure of catalytic domain 2 from Danio rerio HDAC6 complexed with MAIP-032 revealed a monodentate zinc-binding mode.

| S-EPMC5999327 | biostudies-literature

2-(4-Chloro-phen-yl)imidazo[1,2-a]pyridine-3-carbaldehyde.

Project description:The asymmetric unit of the title compound, C(14)H(9)ClN(2)O, contains two mol-ecules with dihedral angles of 33.52?(11) and 34.58?(11)° between their benzene rings and imidazole ring systems. In the crystal, C-H?N and C-H?O inter-actions are observed. The crystal examined was found to be a racemic twin.

| S-EPMC2971907 | biostudies-other

2-Phenyl-imidazo[1,2-a]pyridine-3-carbaldehyde.

Project description:In the title compound, C(14)H(10)N(2)O, the dihedral angle between the imidazo[1,2-a]pyridine and phenyl rings is 28.61 (4)° The mol-ecules are connected into broad chains parallel to the a axis by weak C-H⋯O and C-H⋯N hydrogen bonds. The linking of the ribbons is provided by π-π stacking inter-actions between neighbouring pyridine rings, with a centroid-centroid distance of 3.7187 (7) Å.

| S-EPMC2961188 | 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