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Cytotoxicity Activity of Geldanamycin Derivatives Against Various Cancer Cell Lines

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Cytotoxicity Activity of Geldanamycin Derivatives Against Various Cancer Cell Lines Journal of Applied Pharmaceutical Science Vol. 10(06), pp 012-021, June, 2020 Available online at http://www.japsonline.com DOI: 10.7324/JAPS.2020.10603 ISSN 2231-3354 Cytotoxicity activity of geldanamycin derivatives against various cancer cell lines Thongchai Taechowisan1*, Tipparat Samsawat1, Winyou Puckdee1, Waya S. Phutdhawong2 1Department of Microbiology, Faculty of Science, Silpakorn University, Nakhon Pathom 7300, Thailand. 2Department of Chemistry, Faculty of Science Silpakorn University, Nakhon Pathom 7300, Thailand. ARTICLE INFO ABSTRACT Received on: 12/10/2019 Geldanamycin (1) was isolated as a major compound from Streptomyces zerumbet W14. It was then used as a precursor to Accepted on: 02/04/2020 synthesize two new geldanamycins: 17-(tryptamine)-17-demethoxygeldanamycin (2) and 17-(5′-methoxytryptamine)- Available online: 05/06/2020 17-demethoxygeldanamycin (3). The cytotoxicity activity of these two new compounds was evaluated and compared with the cytotoxicity of compound 1. Cytotoxicity activity was evaluated against a normal cell line, and three cancer cell lines using an 3-(4, 5-Dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) colorimetric assay. The Key words: solubility of these compounds was also determined. The solubility of compounds 2 and 3 in water was 290.69 Anticancer activity, cancer and 348.18 µM, higher than that of compound 1 by about 1.91 and 2.29 times, respectively. Compounds 2 and 3 cell lines, cytotoxicity showed moderate cytotoxic activity on Vero and human cervical carcinoma cells with IC50 values of >200.00 µg/ activity, solubility, ml. The strongest cytotoxicity of compound 3 was observed in human breast carcinoma cells (MCF-7) and human tryptamine-geldanamycin hepatocellular carcinoma cell line (HepG2) cells with IC50 values of 82.50 and 114.35 µg/ml, respectively, while the hybrids. IC50 values of compound 2 against MCF-7 and HepG2 cells were 105.62 and 124.57 µg/ml, respectively. The findings showed that these new geldanamycin derivatives exhibited selective cytotoxicity toward some cancer cells at a lower concentration. Therefore, future studies on these compounds could be useful for the management of some cancers. INTRODUCTION unacceptable as a therapeutic profile. This toxicity seemed to Geldanamycin was the first benzoquinone ansamycin be caused by metabolisms of the benzoquinone moiety. Second, antibiotic that exhibited anticancer activity by inhibiting kinase geldanamycin is metabolically unstable and poorly soluble folding by the Hsp90 chaperone complex in a wide range of in water. Accordingly, variants of geldanamycin have been cancers (Whitesell et al., 1994). The blockage of Hsp90 function developed, most notably by altering the quinone ring structure, induced the proteasome-dependent degradation of cancer which have led to improvements in tolerance, potency, metabolic relevant target proteins, known as client proteins (Mimnaugh stability, and water solubility (Le Brazidec et al., 2004). et al., 1996). Despite its anticancer potential in vitro, the clinical Although, the synthesized series of geldanamycin derivatives to use of geldanamycin has not been considered due to several make new types of Hsp90 inhibitor with weak toxicity and high limitations (Supko et al., 1995). First, it exhibited severe efficiency have been attempting Jurczyszyn( et al., 2014; Lee, hepatotoxicity and nephrotoxicity at therapeutic recommended 2018; Lin et al., 2015; Vasilevskaya et al., 2003). However, there doses in animal models, limiting effective doses, and thus was was a limit number of water solubility of these geldanamycin derivatives. Tryptamine was derived by the decarboxylation of tryptophan. Tryptamine has been used in the past as * Corresponding Author a neurotransmitter and neuromodulator, vasoconstrictor, Thongchai Taechowisan, Department of Microbiology, Faculty of Science, and vasodilator, and as antibacterial, antifungal, antiviral, Silpakorn University, Nakhon Pathom 7300, Thailand. E-mail: tewson84 @ hotmail.com antioxidant, and anti-inflammatory agent Kousara( et al., 2017). © 2020 Thongchai Taechowisan et al. This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/). Taechowisan et al. / Journal of Applied Pharmaceutical Science 10 (06); 2020: 012-021 013 Its modification has led to many compounds of pharmacological MATERIALS AND METHODS importance. Recently, tryptamine-based compounds have been synthesized as anticancer agents (Guo et al., 2019; Isolation and cultivation of endophytic actinomycete Malik et al., 2019; Wang et al., 2016). It has been an effective Actinomycete strain W14 was isolated from the tool for improving water solubility, biological potency, and rhizome tissue of Zingiber zerumbet (L.) Smith, collected from pharmacokinetic properties of many natural products (Kousara Chanthaburi province, Thailand. The samples were used to et al., 2017). According to these effects, the invention of isolate the endophytic actinomycetes by surface-sterilization tryptamine-geldanamycin hybrids has been designed. The C17 technique and validation of surface sterilization was performed methoxyl of the geldanamycin molecule can allow for various as described in the previous studies (Coombs and Franco, nucleophiles to be introduced. Thus, geldanamycin from the 2003; Taechowisan et al., 2017). Strain W14 was selected and beginning has been a popular template for semi-synthetic identified using morphological, cultural, physiological, and analogs (Lin et al., 2015; Modi et al., 2011; Supko et al., 1995; biochemical characteristics, chemotaxonomy and 16S rDNA Tian et al., 2004; Wrona et al., 2010). In this study, two new sequencing (Taechowisan and Lumyong, 2003; Taechowisan geldanamycin derivatives were synthesized in form tryptamine- et al., 2019). This strain was grown on ISP-2 agar at 30°C for geldanamycin hybrids by substituting with tryptamine and 14 days, and then the culture medium was cut into small pieces 5-methoxytryptamine that consist of heterocyclic and strong that were extracted with ethyl acetate (3 × 500 ml). This organic polar groups in the 17-position to improve the pharmacokinetic solvent was taken to dryness under rotary evaporation. The solid properties. To our knowledge, this is the first report to describe was separated by column chromatography using silica gel 60 the screening of tryptamine-geldanamycin hybrids as anticancer (Merck, 0.040–0.063 mm), and 30%, 50%, 75%, and 100% of agents. The aim of the present study was to evaluate the ethyl acetate in hexane as the eluent to give 17 main fractions anticancer activity of the synthesized tryptamine-geldanamycin (F1–F17). Fraction F13 (30.3 mg) gave a very prominent single hybrids against some cancer cell lines: [human breast carcinoma spot of pure compound on thin-layer chromatography (TLC) and cells (MCF-7); human cervical carcinoma cells (HeLa); and was used to investigate on nuclear magnetic resonance (NMR) human hepatocellular carcinoma cells (HepG2)] and their water spectroscopy. The spectral data revealed this compound to be solubility was also determined. geldanamycin (C29H40N2O9) (1). Figure 1. Geldanamycin chemical structure (1) and structures and synthesis of two derivatives; 17-(tryptamine)-17- demethoxygeldanamycin (2) and 17-(5′-methoxytryptamine)-17-demethoxygeldanamycin (3). 014 Taechowisan et al. / Journal of Applied Pharmaceutical Science 10 (06); 2020: 012-021 Synthesis of geldanamycin derivatives dimethyl sulfoxide (DMSO) concentrations in all assays did All procedures and experiments described were not exceed 0.1%. Cells were washed once before adding 50 µl geladanamycin derivative synthesis. FBS-free medium containing 5 mg/ml 3-(4, 5-Dimethylthiazol- Geladanamycin derivatives; 17-(tryptamine)- 2-yl)-2, 5-diphenyltetrazolium bromide (MTT). After 4 hours of inoculation at 37°C, the medium was discarded and the formazan 17-demethoxygeldanamycin (C38H48N4O8) (2) and 17-(5′-methoxytryptamine)-17-demethoxygeldanamycin blue, which formed in the cells, was dissolved in 50 µl DMSO. The optical density was measured at 570 nm. Consecutively, (C39H50N4O9) (3) were synthesized from geldanamycin (Fig. 1). To a solution of geldanamycin (0.84 g, 100 mmol) in measurements for concentration required for 50% (IC50) dichloromethane (15 ml) at 25°C, tryptamine (0.29 g, 150 mmol) inhibition were noted. Cell viability percent was calculated using (Sigma-Aldrich) or 5′-methoxytryptamine (0.36 g, 150 mmol) the formula given below: (Sigma-Aldrich) was added. The reaction mixture was stirred Percentage (%) of cell viability = A570 of treated cells at 25°C for 30 minutes before the addition of saturated aqueous A570 of control cells CaCl2 (5 ml). The organic layer was removed and washed with saturated CaCl2 solution (3 × 5 ml) and dried (Na2SO4). The × 100 mixture was filtered over Celite, rinsed with ethyl acetate, and The graph was plotted with the Y-axis showing the concentrated under reduced pressure to give a dark purple solid. percentage of viability of cells and X-axis showing the compound Purification by flash chromatography (silica, 60% ethyl acetate/ concentration. hexanes) affords compound 2 (1.01 g, 97 mmol, 96.8%) or The therapeutic index was calculated as the ratio of IC compound 3 (1.03 g, 95 mmol, 94.7%). 50 of normal cells to IC50 of cancer cells. Water solubility test Statistical analysis The water solubility of geldanamycin and its derivatives Values are expressed as means
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