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.

Cancer is currently a major public health concern worldwide. Previous studies have shown that heat shock protein 90 (Hsp90) is the key common cause of cancer. Thus, Hsp90 is one of the important molecular targets for the development of Hsp90 cancer drug based on geldanamycin (GDM) and alvespimycin (17-DMAG). Herein, novel geldanamycin derivatives, S1-S6 were designed as potential Hsp90 cancer drug by targeting signal transduction pathway, especially against oncogenic client protein from Hsp90. The binding of S1-S6 in the cavity of Hsp90 were investigated by molecular docking using the iGEMDOCK v2.1 software. The results illustrated that S1-S6 bound in the binding site of Hsp90 with similar manner to GDM and 17-DMAG. The binding energies of S1-S6 in Hsp90 (PDB ID:1YET) (-137.49 to -123.24 kcal/mol) were comparable to that of GDM (-133.06 kcal/mol) while the binding energies of S1-S6 in Hsp90 (PDB ID:1OSF) (-137.49 to -131.22 kcal/mol) were slightly higher than that of 17-DMAG (-145.31 kcal/mol). S1-S6 interacted well by hydrogen bonding with key amino acids in the binding site of Hsp90, which could inhibit the cancer cell growth. Therefore, S1-S6 containing novel geldanamycin derivatives could be promising molecules for anti-cancer drug against Hsp90 2 types in the future.

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.

Geldanamycin (GDM) is an antibiotic isolated from Streptomyces zerumbet W14 that specifically targets and deactivates heat shock protein 90 (Hsp90), directed to the functional protein deficiency. The utilization management of GDM has been limited by its poor water solubility and hepatotoxicity. Five new dopamine-geldanamycin hybrids (DGH), compounds 2 to 6, were synthesized from GDM (1). Solubility, cytotoxicity, anticancer activity, molecular docking, and ADMET analyses were carried out. The solubility of DGH in water was 0.386-5.464 mM, higher than that of compound 1. These compounds showed weak cytotoxic activity against Vero cells and LLC-MK2, with IC50 values in the range of 104.52-496.31 µg/ml. Compounds 2, 3, and 6 were also active against MDA-MB231 cells with IC 50 values of 41.88, 52.12, and 70.93 µg/ml, respectively. They interacted positively with Hsp90, showing binding free energy (∆G) of −97.03 to −101.06 kcal/mol, which indicated lower Hsp90 affinity compared with that of GDM (−133.06 kcal/mol) and 17-dimethylamino ethylamino-17-demethoxygeldanamycin (−136.55 kcal/mol), despite being partly bound in the active site (compounds 2, 3, and 6) or outside the active site (compound 4). Since compound 4 bound outside the active side and compound 5 did not bind to any part of Hsp90, they were not active on cytotoxicity against both normal cells and cancer cells. The predicted results showed that the ADMET parameters of DGH were similar to those of GDM. Furthermore, the experimental results are associated with a theoretical basis by molecular docking and ADMET analysis. The study findings revealed, through molecular docking and ADMET analysis, that the development of DGH improved the pharmacokinetic profiles of solubility, cytotoxicity, and anticancer activities. We, therefore, recommend DGH as a potential alternative treatment agent for some cancers.