Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Aza Analogs of the TRPML1 Inhibitor Estradiol Methyl Ether (EDME).

ABSTRACT: Estradiol methyl ether (EDME) has recently been described by us as a very potent and subtype-specific inhibitor of the lysosomal cation channel TRPML1. Following the principle of bioisosteres, we worked out efficient synthetic approaches to ring-A aza-analogs of EDME, namely a methoxypyridine and a methoxypyrimidine analog. Both target compounds were obtained in good overall yields in six and eight steps starting from 19-nortestosterone via the oxidative cleavage of ring A followed over several intermediates and with the use of well-selected protective groups by re-cyclization to provide the desired hetero-analogs. The methoxypyridine analog largely retained its TRPML1-inhibitory activity, whereas the methoxypyrimidine analog significantly lost activity.

SUBMITTER: Ruhl P

PROVIDER: S-EPMC10647736 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Aza Analogs of the TRPML1 Inhibitor Estradiol Methyl Ether (EDME).

Rühl Philipp P Bracher Franz F

Molecules (Basel, Switzerland) 20231104 21

Estradiol methyl ether (<b>EDME</b>) has recently been described by us as a very potent and subtype-specific inhibitor of the lysosomal cation channel TRPML1. Following the principle of bioisosteres, we worked out efficient synthetic approaches to ring-A aza-analogs of EDME, namely a methoxypyridine and a methoxypyrimidine analog. Both target compounds were obtained in good overall yields in six and eight steps starting from 19-nortestosterone via the oxidative cleavage of ring A followed over s ...[more]

PMID: 37959848

Similar Datasets

Estradiol analogs attenuate autophagy, cell migration and invasion by direct and selective inhibition of TRPML1, independent of estrogen receptors.

Project description:The cation channel TRPML1 is an important regulator of lysosomal function and autophagy. Loss of TRPML1 is associated with neurodegeneration and lysosomal storage disease, while temporary inhibition of this ion channel has been proposed to be beneficial in cancer therapy. Currently available TRPML1 channel inhibitors are not TRPML isoform selective and block at least two of the three human isoforms. We have now identified the first highly potent and isoform-selective TRPML1 antagonist, the steroid 17β-estradiol methyl ether (EDME). Two analogs of EDME, PRU-10 and PRU-12, characterized by their reduced activity at the estrogen receptor, have been identified through systematic chemical modification of the lead structure. EDME and its analogs, besides being promising new small molecule tool compounds for the investigation of TRPML1, selectively affect key features of TRPML1 function: autophagy induction and transcription factor EB (TFEB) translocation. In addition, they act as inhibitors of triple-negative breast cancer cell migration and invasion.

| S-EPMC8050276 | biostudies-literature

Tridentate Phosphine Ligands Bearing Aza-Crown Ether Lariats.

Project description:Crown ethers are useful macrocycles that act as size-selective binding sites for alkali metals. These frameworks have been incorporated into a number of macromolecular assemblies that use simple cations as reporters and/or activity triggers. Incorporating crown ethers into secondary coordination sphere ligand frameworks for transition metal chemistry will lead to new potential methods for controlling bond formation steps, and routes that couple traditional ligand frameworks with these moieties are highly desirable. Herein we report the syntheses of a family of tridentate phosphine complexes bearing tethered aza-crown ethers (lariats) designed to modularize the variation of aza-crown size, lariat length, and distal phosphine substituents, followed by the synthesis and solid-state structures of Mo(III) complexes bearing cations in the pendent crown ethers.

| S-EPMC6027750 | biostudies-literature

Desoxyhemigossypol 6-methyl ether.

Project description:THE TITLE SESQUITERPENE [SYSTEMATIC NAME: 6-methoxy-10-methyl-7-(propan-2-yl)-2-oxatricyclo[6.3.1.0(4,12)]dodeca-1(11),4,6,8(12),9-pentaen-5-ol], C(16)H(18)O(3), was isolated from pathogen-infected stele tissue of Gossypium barbadense. There are two mol-ecules in the asymmetric unit and the dihedral angle between their naphtho-furan systems is 86.48 (2)°. In the crystal, O-H⋯O hydrogen bonds between the hy-droxy groups and etheric O atoms link the mol-ecules into centrosymmetric tetra-mers. These tetra-mers are assembled into (010) layers via stacking inter-actions between the naphtho-furan systems [inter-planar distance 3.473 (3) Å] and short C-H⋯O contacts.

| S-EPMC3569821 | biostudies-literature

Hydrazine-Selective Fluorescent Turn-On Probe Based on Ortho-Methoxy-Methyl-Ether (o-MOM) Assisted Retro-aza-Henry Type Reaction.

Project description:Hydrazine (N2H4) is one of the most widely used industrial chemicals that can be utilized as a precursor of pesticides, pharmaceutics, and rocket propellant. Due to its biological and environmental toxicity with potential health risks, various sensing tools have been developed. Among them, fluorescence-based molecular sensing systems have been highlighted due to its simple-operation, high selectivity and sensitivity, and biocompatibility. In our recent report, we disclosed a ratiometric type fluorescent probe, called HyP-1, for the detection of hydrazine, which is based on ortho-methoxy-methyl-ether (o-MOM) moiety assisted hydrazone-formation of the donor (D)-acceptor (A) type naphthaldehyde backbone. As our follow-up research, we disclose a turn-on type fluorescent probe, named HyP-2, as the next-generation hydrazine probe. The sensing rational of HyP-2 is based on the o-MOM assisted retro-aza-Henry type reaction. The dicyanovinyl moiety, commonly known as a molecular rotor, causes significant emission quenching of a fluorescent platform in aqueous media, and its cleavage with hydrazone-formation, which induces a significant fluorescence enhancement. The high selectivity and sensitivity of HyP-2 shows practical explicabilities, including real-time paper strip assay, vapor test, soil analysis, and real water assay. We believe its successful demonstrations suggest further applications into a wide variety of fields.

| S-EPMC6832147 | biostudies-literature

Lacinilene C 7-methyl ether.

Project description:The title compound, C16H20O3 [systematic name: 1-hy-droxy-7-meth-oxy-1,6-dimethyl-4-(propan-2-yl)naphthalen-2(1H)-one], is a sesquiterpene isolated from foliar tissues of the cotton plant and is of inter-est with respect to its anti-bacterial properties. Its phenyl ring is ideally planar, and the maximum of deviation in the second ring is 0.386 (3) Å. The hy-droxy group and the methyl group are oriented in an equatorial fashion and axial, respectively, to the second ring. In the crystal, inversion dimers are formed through pairs of O-H⋯O hydrogen bonds. Weak C-H⋯O hydrogen bonds link the dimers into columns along the c axis. These columns form a crystal structure with a crystal packing factor of 0.66.

| S-EPMC3884496 | biostudies-literature

Semisynthetic roxburghin tetra-methyl ether.

Project description:The title mol-ecule, (E)-2,3',4,5-tetra-methoxy-stilbene, C(18)H(20)O(4), is virtually planar. The angle between the two benzene rings is 4.06?(6)°. The inter-molecular inter-actions present in the structure are weak. There are C-H?O hydrogen bonds and C-H??-electron ring inter-actions. The mol-ecules are ordered into planes that are parallel to (01). The distance between adjacent planes is about 3.3?Å and therefore ?-? electron inter-actions between the aromatic planes are also plausible.

| S-EPMC2961722 | biostudies-literature

Alternariol 9-O-methyl ether.

Project description:The title compound (AME; systematic name: 3,7-dihy-droxy-9-meth-oxy-1-methyl-6H-benzo[c]chromen-6-one), C(15)H(12)O(5), was isolated from an endophytic fungi Alternaria sp., from Catharanthus roseus (common name: Madagascar periwinkle). There is an intramolecular O-H⋯O hydrogen bond in the essentially planar mol-ecule (r.m.s. deviation 0.02 Å). In the crystal, the molecule forms an O-H⋯O hydrogen bond with its centrosymmetric counterpart with four bridging inter-actions (two O-H⋯O and two C-H⋯O). The almost planar sheets of the dimeric units thus formed are stacked along b axis via C-H⋯π and π-π contacts [with C⋯C short contacts between aromatic moieties of 3.324 (3), 3.296 (3) and 3.374 (3) Å].

| S-EPMC3344582 | biostudies-literature

Phospholipid ether analogs for the detection of colorectal tumors.

Project description:The treatment of localized colorectal cancer (CRC) depends on resection of the primary tumor with adequate margins and sufficient lymph node sampling. A novel imaging agent that accumulates in CRCs and the associated lymph nodes is needed. Cellectar Biosciences has developed a phospholipid ether analog platform that is both diagnostic and therapeutic. CLR1502 is a near-infrared fluorescent molecule, whereas 124/131I-CLR1404 is under clinical investigation as a PET tracer/therapeutic agent imaged by SPECT. We investigated the use of CLR1502 for the detection of intestinal cancers in a murine model and 131I-CLR1404 in a patient with metastatic CRC. Mice that develop multiple intestinal tumors ranging from adenomas to locally advanced adenocarcinomas were utilized. After 96 hours post CLR1502 injection, the intestinal tumors were analyzed using a Spectrum IVIS (Perkin Elmer) and a Fluobeam (Fluoptics). The intensity of the fluorescent signal was correlated with the histological characteristics for each tumor. Colon adenocarcinomas demonstrated increased accumulation of CLR1502 compared to non-invasive lesions (total radiant efficiency: 1.76×10(10) vs 3.27×10(9) respectively, p = 0.006). Metastatic mesenteric tumors and uninvolved lymph nodes were detected with CLR1502. In addition, SPECT imaging with 131I-CLR1404 was performed as part of a clinical trial in patients with advanced solid tumors. 131I-CLR1404 was shown to accumulate in metastatic tumors in a patient with colorectal adenocarcinoma. Together, these compounds might enhance our ability to properly resect CRCs through better localization of the primary tumor and improved lymph node identification as well as detect distant disease.

| S-EPMC4186834 | biostudies-literature

Salvinorin B meth-oxy-methyl ether.

Project description:The title compound [MOM-SalB; systematic name: methyl (2S,4aR,6aR,7R,9S,10aS,10bR)-2-(3-fur-yl)-9-meth-oxy-meth-oxy-6a,10b-dimethyl-4,10-dioxo-2,4a,5,6,7,8,9,10a-octa-hydro-1H-benzo[f]isochromene-7-carboxyl-ate], C(23)H(30)O(8), is a deriv-ative of the ?-opioid salvinorin A with enhanced potency, selectivity, and duration of action. Superimposition of their crystal structures reveals, surprisingly, that the terminal C and O atoms of the MOM group overlap with the corresponding atoms in salvinorin A, which are separated by an additional bond. This counter-intuitive isosterism is possible because the MOM ether adopts the 'classic anomeric' conformation (gauche-gauche), tracing a helix around the planar acetate of salvinorin A. This overlap is not seen in the recently reported structure of the tetra-hydro-pyranyl ether, which is less potent. The classic anomeric conformation is strongly favoured in alk-oxy-methyl ethers, but not in substituted acetals, which may contribute to their reduced potency. This structure may prove useful in evaluating models of the activated ?-opioid receptor.

| S-EPMC3515309 | biostudies-literature

Arborinol methyl ether from Areca catechu L.

Project description:The title compound isolated from Areca catechu L. (common name: arborinol methyl ether; a member of the arborane family) was established as 3α-methoxyarbor-9(11)-ene, C(31)H(52)O. Rings A/B/C/D assume a chair conformation, while ring E has an envelope conformation. The absolute configuration was determined to be (3R,5R,8S,10S,13R,14S,17S,18S, 21S) by analysis of Bijvoet pairs based on resonant scattering of light atoms, yielding a Hooft parameter y of -0.03 (3).

| S-EPMC3007998 | 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