Aims: The purpose of this study was to synthesis novel amine-geldanamycin hybrids (AGH) and evaluate their biological properties. Study Design: Experimental study. Place and Duration of Study: The study was carried out at the Department of Microbiology and Department of Chemistry, Faculty of Science, Silpakorn University, from December 2019 - November 2020. Methodology: Three new amine-geldanamycin hybrids (AGH); compounds 2 to 4 were synthesised by nucleophilic substitution of geldanamycin (1). The solubility, cytotoxicity, antiviral activity and molecular docking analyses were carried out. Results: The solubility of AGH in water was 1.918-5.571 mM, higher than that of compound 1. Compound 2 exhibited weak cytotoxicity activity against Vero and LLC-MK2 cells, with IC50 values of 229.19 and 330.58 µg/ml, respectively. All compounds inhibited influenza virus propagation in embryonated chicken eggs at the lowest amount of 1.25 µg per egg. They interacted positively with Hsp90, showing a binding free energy (DG) of -112.00 to -116.34 kcal/mol, which indicated lower Hsp90 affinity compared with that of geldanamycin (-133.06 kcal/mol) and 17-dimethylamino ethylamino-17-demethoxygeldanamycin (-136.55 kcal/mol), despite being bound in the similar active site. For the viral absorption, only AGH inhibited hemagglutination at a concentration of 25 µg/ml. Conclusion: The study findings revealed, through molecular docking analysis, that the development of AGH improved the antiviral activity. The AGH inhibited not only influenza virus propagation, but also viral absorption. Therefore, AGH could be considered a new choice for antiviral agents.

Strain W08 was isolated from the pseudostem tissue of Amomum krervanh Pierre (Zingiberaceae) and identified as Streptomyces sp. by analyzing its morphology, chemotaxonomy, and 16SrDNA sequence. It was shown to exert bactericidal effects against Bacillus cereus, Bacillus subtilis, Staphylococcus aureus, and methicillin-resistant S. aureus. Crude extract of its culture inhibited the tested bacteria, with minimum inhibitory concentrations of 32-128 µg/ml. The cytotoxicity of the crude extract was also assessed against cell lines using [3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide] colorimetric assay. The crude extract showed weak cytotoxic activity on L929 and Vero cells with IC50 values of 453.22 and >512.00 µg/ml, respectively. The most powerful cytotoxicity of the crude extract was observed in human cervical carcinoma cells and human breast carcinoma cells with IC50 values of 78.45 and 106.50 µg/ml, respectively, while the IC50 value of human hepatocellular carcinoma cells was 425.86 µg/ml. The bioactive compounds in the extract were isolated by column chromatography and thin-layer chromatography, which were revealed by IR and NMR analyses to be 1-hydroxy-2-methyl-6-methoxyanthraquinone (1) and 6-methoxy-2methylquinizarin (2). The findings showed that the crude extract of Streptomyces sp. W08 containing the bioactive compounds exhibited antibacterial activity and selective cytotoxicity toward some cancer cells. The studies on these compounds could thus lead to useful approaches for managing some bacterial infections and cancers in the future.

No abstract

No abstract

Three new geldanamycin (GDM) derivatives, 17-((S)-2-amino-3-(1H-indol-3-ylpropan-1-ol)-17demethoxygeldanamycin (2), 17-((S)-2-amino-3-phenylpropan-1-ol)-17-demethoxygeldanamycin (3), and 17-((S)-4-(2-amino-3-hydroxypropyl)phenol)-17-demethoxygeldanamycin ( 4), were synthesized by nucleophilic substitution of GDM (1). The binding ability of these compounds at the N-terminal domain of heat shock protein [Protein Data Bank (PDB) ID: 1OSF] derived from the PDB was analyzed by ligand-protein docking. Hydrogen-bonding interactions of compounds 2 and 3 were equal to those of 17-dimethylamino-ethylamino-17-demethoxygeldanamycin (17-DMAG), with binding energies of −98.33 and −122.41 kcal/mol, respectively. The solubility of the synthesized compounds was ascertained. The solubilities of compounds 2, 3, and 4 in water were 5.571 mM, 1.963 mM, and 1.918 mM, higher than that of compound 1 by approximately 36.65, 12.91, and 12.62 times, respectively. The cytotoxicity activity of the synthesized compounds was also evaluated against cancer cell lines using a tetrazolium-based colorimetric assay. These compounds showed high anticancer activity against human cervical carcinoma cells cells, with inhibitory concentration (IC 50 ) values in the range of 19.36-45.66 µg/ml, which were better than that of compound 1, with IC 50 values of 110.46 µg/ml. Compound 3 also exhibited cytotoxic activity against human hepatocellular carcinoma cells cells, with an IC 50 value of 24.62 µg/ml. These compounds were less active against MDA-MB-231 cells, compared with compound 1. Compound 2 also showed weak cytotoxic activity on Vero and LLC-MK2 cells, with IC 50 values of 229.19 and 330.58 µg/ml, respectively. The predicted results indicated that these compounds have similar absorption, distribution, metabolism, excretion, and toxicity () parameters as well as structures predictive of hepatotoxicity. The results showed that some of the synthesized compounds revealed selective cytotoxicity toward some cancer cells. Therefore, further studies on the synthesized compounds could be helpful in the treatment of some cancers.