Browse
Submit Data
Databases
API
Help

Dataset Information

22 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Synthesis, Biological Evaluation and Docking Studies of Ring-Opened Analogues of Ipomoeassin F.

ABSTRACT: The plant-derived macrocyclic resin glycoside ipomoeassin F (Ipom-F) binds to Sec61α and significantly disrupts multiple aspects of Sec61-mediated protein biogenesis at the endoplasmic reticulum, ultimately leading to cell death. However, extensive assessment of Ipom-F as a molecular tool and a therapeutic lead is hampered by its limited production scale, largely caused by intramolecular assembly of the macrocyclic ring. Here, using in vitro and/or in cellula biological assays to explore the first series of ring-opened analogues for the ipomoeassins, and indeed all resin glycosides, we provide clear evidence that macrocyclic integrity is not required for the cytotoxic inhibition of Sec61-dependent protein translocation by Ipom-F. Furthermore, our modeling suggests that open-chain analogues of Ipom-F can interact with multiple sites on the Sec61α subunit, most likely located at a previously identified binding site for mycolactone and/or the so-called lateral gate. Subsequent in silico-aided design led to the discovery of the stereochemically simplified analogue 3 as a potent, alternative lead compound that could be synthesized much more efficiently than Ipom-F and will accelerate future ipomoeassin research in chemical biology and drug discovery. Our work may also inspire further exploration of ring-opened analogues of other resin glycosides.

SUBMITTER: O'Keefe S

PROVIDER: S-EPMC9320607 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Design, synthesis and biological evaluation of fucose-truncated monosaccharide analogues of ipomoeassin F.

Project description:Ipomoeassin F is a plant-derived macrocyclic glycolipid with single-digit nanomolar IC50 values against cancer cell growth. In previous structure-activity relationship studies, we have demonstrated that certain modifications around the fucoside moiety did not cause significant cytotoxicity loss. To further elucidate the effect of the fucoside moiety on the biological activity, we describe here the design and synthesis of several fucose-truncated monosaccharide analogues of ipomoeassin F. Subsequent biological evaluation strongly suggests that the 6-membered ring of the fucoside moiety is essential to the overall conformation of the molecule, thereby influencing bioactivity.

| S-EPMC5502735 | biostudies-literature

Novel phthalimide based analogues: design, synthesis, biological evaluation, and molecular docking studies.

Project description:Pyrazolylphthalimide derivative 4 was synthesized and reacted with different reagents to afford the target compounds imidazopyrazoles 5-7, pyrazolopyrimidines 9, 12, 14 and pyrazolotriazines 16, 17 containing phthalimide moiety. The prepared compounds were established by different spectral data and elemental analyses. Additionally, all synthesized derivatives were screened for their antibacterial activity against four types of Gram + ve and Gram-ve strains, and for antifungal activity against two fungi micro-organisms by well diffusion method. Moreover, the antiproliferative activity was tested for all compounds against human liver (HepG-2) cell line in comparison with the reference vinblastine. Moreover, drug-likeness and toxicity risk parameters of the newly synthesized compounds were calculated using in silico studies. The data from structure-actvity relationship (SAR) analysis suggested that phthalimide derivative bearing 3-aminopyrazolone moiety, 4 illustrated the best antimicrobial and antitumor activities and might be considered as a lead for further optimization. To investigate the mechanism of the antimicrobial and anticancer activities, enzymatic assay and molecular docking studies were carried out on E. coli topoisomerase II DNA gyrase B and VEGFR-2 enzymes.

| S-EPMC6691772 | biostudies-literature

A novel medium size lactam ring analoges as antibacterial agents: Synthesis, biological evaluation and molecular docking studies.

Project description:A novel series of medium size (S)-3-alkyl-3,4,6,7-tetrahydro-1H-benzo[e][1,4]diazonine-2,5-dione (6a-f) analogues were synthesized from (E)-3-(2-nitrophenyl)acrylicacid (2) reacting with various amino acid esters using Di-isopropyl Carbodiimide as a coupling agent. The final cyclization is carried out by using reagent 1-Ethyl-3(3-dimethylaminopropyl) Carbodiimide Hydrochloride. The synthesized compounds have been supported by Mass, 1H-NMR and 13C-NMR. Further antibacterial studies were conducted, where some molecules are noticed with potent activity, especially molecule 6d shown highest activity which was also supported by molecular docking studies. All final molecules were docked with enzyme peptide deformylase to determine the probable binding conformation.

| S-EPMC5735333 | biostudies-literature

Synthesis and Biological Evaluation of Several Bryostatin Analogues Bearing a Diacylglycerol Lactone C-Ring.

Project description:As an initial step in designing a simplified bryostatin hybrid molecule, three bryostatin analogues bearing a diacylglycerol lactone-based C-ring, which possessed the requisite pharmacophores for binding to protein kinase C (PKC) together with a modified bryostatin-like A- and B-ring region, were synthesized and evaluated. Merle 46 and Merle 47 exhibited binding affinity to PKC alpha with Ki values of 7000 ± 990 and 4940 ± 470 nM, respectively. Reinstallation of the trans-olefin and gem-dimethyl group present in bryostatin 1 in Merle 48 resulted in improved binding affinity, 363 ± 42 nM. While Merle 46 and 47 were only marginally active biologically, Merle 48 showed sufficient activity on the U937 cells to confirm that it was PMA-like for growth and attachment, as predicted by the substitution pattern of its A- and B-rings.

| S-EPMC6957265 | biostudies-literature

Bioinspired Pyrano[2,3-<i>f</i>]chromen-8-ones: Ring C-Opened Analogues of Calanolide A: Synthesis and Anti-HIV-1 Evaluation.

Project description:We have designed and synthesized a series of bioinspired pyrano[2,3-f]coumarin-based Calanolide A analogs with anti-HIV activity. The design of these new calanolide analogs involved incorporating nitrogen heterocycles or aromatic groups in lieu of ring C, effectively mimicking and preserving their bioactive properties. Three directions for the synthesis were explored: reaction of 5-hydroxy-2,2-dimethyl-10-propyl-2H,8H-pyrano[2,3-f]chromen-8-one with (i) 1,2,4-triazines, (ii) sulfonylation followed by Suzuki cross-coupling with (het)aryl boronic acids, and (iii) aminomethylation by Mannich reaction. Antiviral assay of the synthesized compounds showed that compound 4 has moderate activity against HIV-1 on enzymes and poor activity on the cell model. A molecular docking study demonstrates a good correlation between in silico and in vitro HIV-1 reverse transcriptase (RT) activity of the compounds when docked to the nonnucleoside RT inhibitor binding site, and alternative binding modes of the considered analogs of Calanolide A were established.

| S-EPMC10813249 | biostudies-literature

Indole Derivatives as Cyclooxygenase Inhibitors: Synthesis, Biological Evaluation and Docking Studies.

Project description:A new series of 2-(5-methoxy-2-methyl-1H-indol-3-yl)-N?-[(E)-(substituted phenyl) methylidene] acetohydrazide derivatives (S1?S18) were synthesized and evaluated for their anti-inflammatory activity, analgesic activity, ulcerogenic activity, lipid peroxidation, ulcer index and cyclooxygenase expression activities. All the synthesized compounds were in good agreement with spectral and elemental analysis. Three synthesized compounds (S3, S7 and S14) have shown significant anti-inflammatory activity as compared to the reference drug indomethacin. Compound S3 was further tested for ulcerogenic index and cyclooxygenase (COX) expression activity. It was selectively inhibiting COX-2 expression and providing the gastric sparing activity. Docking studies have revealed the potential of these compounds to bind with COX-2 enzyme. Compound S3 formed a hydrogen bond between OH of Tyr 355 and NH? of Arg 120 with carbonyl group and this hydrogen bond was similar to that formed by indomethacin. This study provides insight for compound S3, as a new lead compound as anti-inflammatory agent and selective COX-2 inhibitor.

| S-EPMC6100013 | biostudies-literature

Synthesis, Biological Evaluation and Docking Studies of Benzoxazoles Derived from Thymoquinone.

Project description:Thymoquinone (TQ), a natural compound with antimicrobial and antitumor activity, was used as the starting molecule for the preparation of 3-aminothymoquinone (ATQ) from which ten novel benzoxazole derivatives were prepared and characterized by elemental analysis, IR spectroscopy, mass spectrometry and NMR (¹H, 13C) spectroscopy in solution. The crystal structure of 4-methyl-2-phenyl-7-isopropyl-1,3-benzoxazole-5-ol (1a) has been determined by X-ray diffraction. All compounds were tested for their antibacterial, antifungal and antitumor activities. TQ and ATQ showed better antibacterial activity against tested Gram-positive and Gram-negative bacterial strains than benzoxazoles. ATQ had the most potent antifungal effect against Candida albicans, Saccharomyces cerevisiae and Aspergillus brasiliensis. Three benzoxazole derivatives and ATQ showed the highest antitumor activities. The most potent was 2-(4-fluorophenyl)-4-methyl-7-isopropyl-1,3-benzoxazole-5-ol (1f). Western blot analyses have shown that this compound inhibited phosphorylation of protein kinase B (Akt) and Insulin-like Growth Factor-1 Receptor (IGF1R ?) in HeLa and HepG2 cells. The least toxic compound against normal fibroblast cells, which maintains similar antitumor activities as TQ, was 2-(4-chlorophenyl)-4-methyl-7-isopropyl-1,3-benzoxazole-5-ol (1e). Docking studies indicated that 1e and 1f have significant effects against selected receptors playing important roles in tumour survival.

| S-EPMC6321291 | biostudies-literature

Triazolo Based-Thiadiazole Derivatives. Synthesis, Biological Evaluation and Molecular Docking Studies.

Project description:The goal of this research is to investigate the antimicrobial activity of nineteen previously synthesized 3,6-disubstituted-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazole derivatives. The compounds were tested against a panel of three Gram-positive and three Gram-negative bacteria, three resistant strains, and six fungi. Minimal inhibitory, bactericidal, and fungicidal concentrations were determined by a microdilution method. All of the compounds showed antibacterial activity that was more potent than both reference drugs, ampicillin and streptomycin, against all bacteria tested. Similarly, they were also more active against resistant bacterial strains. The antifungal activity of the compounds was up to 80-fold higher than ketoconazole and from 3 to 40 times higher than bifonazole, both of which were used as reference drugs. The most active compounds (2, 3, 6, 7, and 19) were tested for their inhibition of P. aeruginosa biofilm formation. Among them, compound 3 showed significantly higher antibiofilm activity and appeared to be equipotent with ampicillin. The prediction of the probable mechanism by docking on antibacterial targets revealed that E. coli MurB is the most suitable enzyme, while docking studies on antifungal targets indicated a probable involvement of CYP51 in the mechanism of antifungal activity. Finally, the toxicity testing in human cells confirmed their low toxicity both in cancerous cell line MCF7 and non-cancerous cell line HK-2.

| S-EPMC8300616 | biostudies-literature

Total Synthesis and Biological Evaluation of Ipomoeassin F and Its Unnatural 11R-Epimer.

Project description:Ipomoeassin F, a macrolide glycoresin containing an embedded disaccharide, possesses potent in vitro antitumor activity with an unknown mechanism of function. It inhibits tumor cell growth with single-digit nanomolar IC50 values, superior to many clinical chemotherapeutic drugs. To facilitate translation of its bioactivity into protein function for drug development, we report here a new synthesis for the gram-scale production of ipomoeassin F (3.8% over 17 linear steps) from commercially available starting materials. The conformation-controlled subtle reactivity differences of the hydroxyl groups in carbohydrates were utilized to quickly construct the disaccharide core, which, along with judicial selection of protecting groups, made the current synthesis very efficient. The same strategy was also applied to the smooth preparation of the 11R-epimer of ipomoeassin F for the first time. Cytotoxicity assays demonstrated the crucial role of the natural 11S configuration. In addition, cell cycle analyses and apoptosis assays on ipomoeassin F and/or its epimer were conducted. This work has laid a solid foundation for understanding the medicinal potential of the ipomoeassin family of glycolipids in the future.

| S-EPMC4651627 | biostudies-literature

Design, synthesis, and biological evaluation of ring-constrained novobiocin analogues as hsp90 C-terminal inhibitors.

Project description:Hsp90 C-terminal inhibitors represent a novel and alternative chemotherapeutic approach for the treatment of cancer. Novobiocin was the first natural product identified as an Hsp90 C-terminal inhibitor; however, it manifests poor antiproliferative activity. In contrast to N-terminal inhibitors, novobiocin does not induce the pro-survival heat shock response. Structural investigations on novobiocin have elucidated some structure-activity relationships and several promising compounds. On the basis of structure-activity relationships and computational studies, a library of ring-constrained novobiocin analogues was designed, synthesized, and evaluated in antiproliferative assays. Results obtained from these studies provide insights into the Hsp90 C-terminal binding site, and new analogues that were developed manifest low micromolar to mid-nanomolar antiproliferative activity resulting from Hsp90 inhibition.

| S-EPMC4329597 | 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