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Histone Deacetylase Inhibitory and Cytotoxic Activities of The Iranian Journal of Basic Medical Sciences ijbms.mums.ac.ir Histone deacetylase inhibitory and cytotoxic activities of the constituents from the roots of three species of Ferula Saba Soltani 1, Gholamreza Amin 1, Mohammad Hossein Salehi-Sourmaghi 1, Mehrdad Iranshahi 2* 1 Department of Pharmacognosy, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran 2 Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran A R T I C L E I N F O A B S T R A C T Article type: Objective(s): Histone deacetylase inhibitory and cytotoxic activities of 18 naturally occuring terpenoids Original article (ferutinin, stylosin, tschimgine and guaiol), coumarins (umbelliprenin, farnesiferone B, conferone, Article history: persicasulphides A and C) from the roots of three species of ( and Received: Aug 20, 2018 Ferula Ferula latisecta, Ferula ovina Accepted: Nov 12, 2018 feselol,Ferula flabelliloba ligupersin) wereA, conferdione, evaluated. conferoside) and sulfur-containing derivatives (latisulfies A-E, Materials and Methods: The cytotoxic activity of compounds was evaluated against human cancer cell lines Keywords: (HeLa, HCT116, A2780 and A549) by AlamarBlue® assay using vorinostat as the positive control. On the Apiaceae other hand, we aimed to evaluate their inhibitory activities against pan-HDAC. Ferula latisecta Results: The methanolic extract of the roots of F. flabelliloba was subjected to silica gel column Ferula ovina Ferula flabelliloba Histone deacetylase - isolation of guaiol (1), persicasulphide C (3) and conferoside (10) from the roots of . inhibitors chromatography. Further purification by preparative thin-layer chromatography F.(PTLC) flabelliloba and Cytotoxic activities semipreparative RP-HPLC yielded twelve known compounds (1-12). This is the first report on the showed cytotoxic activity with IC50 SixHDAC compounds inhibitory including activity with persicasulfide IC50 A, conferone, feselol, latisufide C, conferoside and ferutinin Conclusion: values in the range of 11.61-49.40 μM against cancer cells and pan- values in the range of 1.06-35.27 μM. HDAC inhibitory Results activity indicated with that IC50 persicasulfide A (2), conferone (6) and feselol (7) showed moderate cytotoxicity with IC50 values in the range of 11.76-39.24 μM against cancer cells and potent pan- values in the range of 1.06-10.73 μM. Conferone was more active ►Please cite this article as: than others with a higher potency for HDAC inhibition (1.06- 1.17 μM). Soltani S, Amin GhR, Salehi-Sourmaghi MH, Iranshahi M. Histone deacetylase inhibitory and cytotoxic activities of the constituents from the roots of three species of Ferula. Iran J Basic Med Sci 2019; 22:93-98. doi: 10.22038/IJBMS.2018.34338.8151 Introduction the roots of Ferula flabelliloba and three constituents Acetylation process is an important post-translational from the roots of Ferula ovina (Figure 1), were screened for their cytotoxic activity against four different cancer families of enzymes with antagonistic functions: histone cell lines that typically overexpress HDAC enzymes, modificationacetyl transferases that regulated(HATs) and by histonethe activity deacetylases of two including colon (HCT116), human cervical (HeLa), lung (HDACs) (1). Recent evidence shows that epigenetics (A549) and ovarian (A2780) cancer cells (12-14). In play an important role in the origin, development, and addition, we evaluated the inhibitory activities of the metastasis of cancer, thus providing a novel therapeutic mentioned natural compounds against pan-HDAC. strategy (2). Naturally occurring inhibitors of histone Materials and Methods anticancer agents (3). At present, there are continuing General experimental procedures deacetylases are currently finding applications as Nuclear magnetic resonance (NMR) spectra were isoforms and that may be used to treat other types of obtained using Bruker AVANCE-300 spectrometer researchdiseases. to find new compounds that inhibit HDAC Ferula is a large genus of perennial herbs belongs (ppm) using TMS as an internal standard. Analytical to the Apiaceae family which includes some 180 (Bruker,TLC was Germany).performed Chemicalon silica shiftsgel 60 are F254 given (Merck, as δ species (4). The phytochemical analysis of more than Germany). Preparative TLC was performed on silica gel seventy Ferula species revealed that this genus contains 60 GF254 (Merck, Germany). Column chromatography biologically active compounds such as sesquiterpene (CC) was conducted with Si gel 230–400 mesh (Merck, derivatives and sulfur containing compounds (5- Germany). Observation of plates was carried out under 8). Since the last decade, natural products from the UV CAMAG spectrometer (Berlin, Germany) at 254 nm. genus Ferula has been received considerable attention Semipreparative HPLC was performed on a KNAUER towards the potential biological activities (9, 10). In the liquid chromatograph system with a quaternary pump (Smartline Pump 1000) and semi-prep c18 column our previous study (11), ten isolated compounds from (onyx monolithic; 100×10 mm). Diode array detector present study, five sulfur-containing compounds from *Corresponding author: Mehrdad Iranshahi. Biotechnology Research Center, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran. Tel: +98- 51-38823255; Fax: +98-51-38823251; Email: [email protected] Soltani et al. Histone deacetylase inhibitors from the roots of Ferula species Figure 1. Structures of the isolated compounds from Ferula species (Smartline DAD 2800) and EZ Chrom Elite software was Mashhad University of Medical Sciences. used for detection and processing of data, respectively. Extraction and isolation Plant material The dried roots of F. flabelliloba (250 g) The roots of F. flabelliloba were powdered and extracted three times by Dr M Iranshahi, in May 2014, from Khorasan-Razavi with MeOH (3×1000 ml, 24 hr each) using province, Golmakan. A voucher were collectedspecimen and (No. identified 13064) maceration method at ambient temperature. The was deposited in the Herbarium of School of Pharmacy, MeOH extracts were combined and the solvents 94 Iran J Basic Med Sci, Vol. 22, No. 1, Jan 2019 Histone deacetylase inhibitors from the roots of Ferula species Soltani et al. evaporated under vacuum pressure leaving 50 g of a compounds. Triplicate plates for three wells of each brown residue. Part of the extract (35 g) was subjected concentration were seeded. The test compounds, were to silica gel chromatography (55×5 cm) using PET: EtOAc and EtOAc- MeOH [(1:0 to 0:1 and 1:1, 0:1, v/v) × of DMSO per well was 0.1% V/V). Then, the cells 2 L] as a gradient solvent system. Thirty eight fractions dissolvedwere treated in dimethylwith the sulfoxidedifferent (finalconcetrations concentrations of the were collected and combined into eight major fractions control, negative control and cell culture medium as testblank compounds for 48 hr in (100, a 5% 50, CO 225, 12.5, 6.25 μM), positive on the basis of their TLC profiles: A [1 – 8; PET: EtOAc of AlamarBlue® reagent was added and incubated for (9 : 1); 4.5 g; TLC (Hex: EtOAc 9 : 1.5)], B [9 – 14; PET: another 4 hr. Then, absorbance incubator. was measured Thereafter, at 10 600 μl EtOAc (9:1 and 8 : 1); 10.4 g; TLC (Hex: EtOAc 9 : 2)], C nm using an ELISA microplate reader (Epoch; USA). IC50 [15 – 16; PET: EtOAc (8 : 1 and 7:1); 2.43 g; TLC (Hex: values were calculated by nonlinear regression analysis EtOAc 9 : 2)], D [17; PET: EtOAc (7 : 1); 2.3 g; TLC (Hex: using GraphPad prism (Version 6.0) software. Positive EtOAc 9 : 2.5)], E [18-21; PET: EtOAc (6:1); 2.0 g; TLC (Hex: EtOAc 9 : 2.5)], F [22 – 24; PET: EtOAc (6:1 and USA). 5:1); 2.2 g; TLC (Hex: EtOAc 9 : 2.5)], G [24 – 30; PET: control was vorinostat (purity ≥98%; Sigma-Aldrich, EtOAc (4:1 and 3:1); 3.2 g; TLC (Hex: EtOAc 9 : 4)], and Whole-cell HDAC inhibition assay H [31 – 38; PET: EtOAc (2:1, 1:1 and 0:1), EtOAc: MeOH1 The HDAC assay was based on an assay by Marek (1:1,(10 mg, 0:1); Rf 7.2 g; 0.55) TLC and (EtOAc: 2 (90 mg,MeOH Rf 9 : 1)].0.44) Fractionswas obtained A–D et al. werefrom fractionfurther Apurified using DCM using system. PTLC. CompoundFinally, compound 3 (12 mg, HCT116 cells, were seeded in 96-well microplates (1.5 Rf 0.6) was obtained from fraction C using PET: EtOAc × 104 (17)cells/90 with µl minor culture modifications. medium per well).Briefly, Three HeLa wells and (4:1.5) system. Fraction B afforded off-white crystals of compound 4 (130 mg). Compound 5 (51 mg, Rf 0.37) as background and three wells for each concentration was obtained from fraction D using DCM: MeOH (10:1) definedwere seeded. as 100% After initial 24 activity hr, the and cells three werewells definedfurther system. Fraction E afforded white crystals of compound incubated for 18 hr with increasing concentrations of 6 (148 mg). Fraction F afforded white crystals as an test compounds, positive control vorinostat and cell inseparable mixture of Compounds 11 and 12 (77 5% CO2. The test compounds, were dissolved in dimethyl Semipreparative HPLC with a gradient of MeOH–H2O culture medium alone as negative control at 37 °C with mg).on a Fractionsemi-prep G wasC18 separated (onyx monolithic; and further 100×10 purified mm) by 0.1% V/V) and their concentrations adjusted to 70, 40, column to yield compounds 7 (25 mg, tR 5.48 min), sulfoxide (final concentrations of DMSO per well was 8 (15 mg, tR 6.15 min) and 9 (36 mg, tR 6.57 min). The first step of reaction was started by adding 10 µl 20, 5, 1 μM through dilution with the growth medium. Fractionafford compound H was subjected 10 to silica gel CC (5 × 80 cm) of 3 mM Boc-Lys (ε-Ac)-AMC (Bachem, Switzerland) to by0.43)].
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