Water-soluble 4-(dimethylaminomethyl)heliomycin exerts greater antitumor effects than parental heliomycin by targeting the tNOX-SIRT1 axis and apoptosis in oral cancer cells DOI Open Access
Atikul Islam,

Xiao Chi Chen,

Chia-Wei Weng

et al.

Published: Aug. 25, 2023

The antibiotic heliomycin (resistomycin), which is generated from Streptomyces resistomycificus , has multiple activities, including anticancer effects. Heliomycin was first described in the 1960s, but its clinical applications have been hindered by extremely low solubility. A series of 4-aminomethyl derivatives were synthesized to increase water solubility; studies showed that they had anti-proliferative effects, drug targets remained unknown. In this study, we conducted cellular thermal shift assays and molecular docking simulations identify validate intracellular water-soluble derivative, 4-(dimethylaminomethyl)heliomycin (designated compound 4-dmH), p53-functional SAS p53-mutated HSC-3 oral cancer cells. Consistent with our silico studies, (CETSA) revealed that, addition SIRT1, 4-dmH preferentially targeted a tumor-associated NADH oxidase called tNOX or ENOX2. direct binding inhibited activity enhanced ubiquitin-proteasomal protein degradation both Moreover, inhibition decreased oxidation NAD + diminished -dependent SIRT1 deacetylase activity, ultimately inducing apoptosis significant cytotoxicity cell types. We also observed upregulated tumor tissues patients compared adjacent normal tissues, suggesting their relevance. Finally, better therapeutic efficacy confirmed tumor-bearing mice, greater downregulation volume reduction when treated heliomycin. Taken together, vitro vivo findings suggest multifaceted properties enable it offer superior antitumor value parental heliomycin, indicated functions through targeting tNOX-NAD -SIRT1 axis induce

Language: Английский

Synthesis, molecular docking, drug likeness, in silico toxicity and DFT studies of small molecules as p53-MDM2 interaction and COX-2 dual inhibitors DOI
N. Jeelan Basha,

K. T. Akshay,

Raju Mohan

et al.

Journal of Molecular Structure, Journal Year: 2024, Volume and Issue: unknown, P. 140393 - 140393

Published: Oct. 1, 2024

Language: Английский

Citations

0
Water-soluble 4-(dimethylaminomethyl)heliomycin exerts greater antitumor effects than parental heliomycin by targeting the tNOX-SIRT1 axis and apoptosis in oral cancer cells DOI Creative Commons
Atikul Islam,

Yu-Chun Chang,

Xiao-Chi Chen

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: March 29, 2023

Abstract The antibiotic heliomycin (resistomycin), which is generated from Streptomyces resistomycificus , has multiple activities, including anticancer effects. Heliomycin was first described in the 1960s, but its clinical applications have been hindered by extremely low solubility. A series of 4-aminomethyl derivatives were synthesized to increase water solubility; studies showed that they had anti-proliferative effects, drug targets remained unknown. In this study, we conducted cellular thermal shift assays (CETSA) and molecular docking simulations identify validate water-soluble derivative, 4-(dimethylaminomethyl)heliomycin (designated compound 4-dmH) engaged targeted with sirtuin-1 (SIRT1) p53-functional SAS p53-mutated HSC-3 oral cancer cells. We further addressed outcome SIRT1 inhibition these compounds found that, addition SIRT1, 4-dmH preferentially a tumor-associated NADH oxidase (tNOX, ENOX2). direct binding tNOX decreased oxidation NAD + diminished -dependent deacetylase activity, ultimately inducing apoptosis significant cytotoxicity both cell types, as opposed parental heliomycin-induced autophagy. also observed upregulated tumor tissues patients compared adjacent normal tissues, suggesting their relevance. Finally, better therapeutic efficacy confirmed tumor-bearing mice, greater downregulation volume reduction when treated heliomycin. Taken together, our vitro vivo findings suggest multifaceted properties enable it offer superior antitumor value heliomycin, indicated functions through targeting tNOX-NAD -SIRT1 axis induce

Language: Английский

Citations

0
Synthesis, Antimicrobial Activity, and Drug-likeness profiles of 5-Phenylselenanyl-2-benzylthiopyrimidine Analogs DOI Creative Commons

Jeelan

Research Square (Research Square), Journal Year: 2023, Volume and Issue: unknown

Published: April 12, 2023

Abstract Given literature findings on the biological importance of pyrimidine and thiazolidine, we herein report synthesis antimicrobial activity 5-phenylselenanyl-2-benzylthio- pyrimidin-4-yl) thiazolidine-4-one analogs 4( a, b ). Compound 5-phenylselenenyl-4-hydrazino-2-benzylthiopyrimidines ( 2 ) condensation with substituted aromatic aldehydes afforded corresponding Schiff bases 5-phenylselenenyl-4-(substituted benzylidenehydrazino)-2-benzylthiopyrimidine 3( a-c Finally, cyclization compounds thioglycolic acid in benzene as solvent yielded target The structures synthesized were characterized by spectral studies such IR, 1 H-NMR, Mass spectra. Results obtained screening these for reveal that only 1, 2, 3a, 3b, 4a exhibited good antibacterial against P. aeruginosa compared to standard drug gentamycin. Among all analogs, compound 4b has shown antifungal fungal strain A. niger terreus . Other have moderate poor when fluconazole. Also, ADMET properties studied compounds.

Language: Английский

Citations

0
Water-soluble 4-(dimethylaminomethyl)heliomycin exerts greater antitumor effects than parental heliomycin by targeting the tNOX-SIRT1 axis and apoptosis in oral cancer cells DOI Open Access
Atikul Islam,

Xiao Chi Chen,

Chia-Wei Weng

et al.

Published: Aug. 25, 2023

The antibiotic heliomycin (resistomycin), which is generated from Streptomyces resistomycificus , has multiple activities, including anticancer effects. Heliomycin was first described in the 1960s, but its clinical applications have been hindered by extremely low solubility. A series of 4-aminomethyl derivatives were synthesized to increase water solubility; studies showed that they had anti-proliferative effects, drug targets remained unknown. In this study, we conducted cellular thermal shift assays and molecular docking simulations identify validate intracellular water-soluble derivative, 4-(dimethylaminomethyl)heliomycin (designated compound 4-dmH), p53-functional SAS p53-mutated HSC-3 oral cancer cells. Consistent with our silico studies, (CETSA) revealed that, addition SIRT1, 4-dmH preferentially targeted a tumor-associated NADH oxidase called tNOX or ENOX2. direct binding inhibited activity enhanced ubiquitin-proteasomal protein degradation both Moreover, inhibition decreased oxidation NAD + diminished -dependent SIRT1 deacetylase activity, ultimately inducing apoptosis significant cytotoxicity cell types. We also observed upregulated tumor tissues patients compared adjacent normal tissues, suggesting their relevance. Finally, better therapeutic efficacy confirmed tumor-bearing mice, greater downregulation volume reduction when treated heliomycin. Taken together, vitro vivo findings suggest multifaceted properties enable it offer superior antitumor value parental heliomycin, indicated functions through targeting tNOX-NAD -SIRT1 axis induce

Language: Английский

Citations

0