Host-guest inclusion systems of mangiferin and polyamine-β-cyclodextrins: Preparation, characterization and anti-cancer activity

Journal of Molecular Structure 1193 (2019) 207e214

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Journal of Molecular Structure journal homepage: http://www.elsevier.com/locate/molstruc

Host-guest inclusion systems of mangiferin and polyamine-b-cyclodextrins: Preparation, characterization and anti-cancer activity Jing Liang, Fanjie Li, Jieling Lin, Shuang Song, Xiali Liao, Chuanzhu Gao, Bo Yang* Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, 650500, PR China

a r t i c l e i n f o

a b s t r a c t

Article history: Received 31 October 2018 Received in revised form 4 May 2019 Accepted 6 May 2019 Available online 10 May 2019

This paper reports host-guest inclusion systems of mangiferin (MGF) with four polyamine-modified bcyclodextrins (PAbCDs). The inclusion complexes have been characterized by 1D and 2D nuclear magnetic resonance (NMR), thermal gravimetric analysis (TGA), X-ray powder diffraction (XRD) and scanning electron microscopy (SEM). The results show that MGF was encapsulated into the cavities of PAbCDs to form four complexes with 1:1 stoichiometry. The water solubility of the complexes was enhanced markedly, and the cytotoxicity of these complexes to normal cell line HEK293 was significantly reduced in comparison with native MGF. This satisfactory water solubilization and improvement of cytotoxicity with MGF/PAbCDs complexes will be potentially useful for its application as herbal medicine or healthcare products. © 2019 Published by Elsevier B.V.

Keywords: Polyamine-modified b-cyclodextrin Mangiferin Inclusion complex Solubilization Cytotoxicity

1. Introduction Mangiferin (MGF, Fig. 1), a 2-C-b-D-glucopyranosyl-1,3,6,7tetrahydroxyxanthone, was first isolated as a colouring matter from the leaves of Mangifera indica L. (Anacardiaceae) in 1908 [1,2]. MGF is a naturally occurring polyphenol, which possesses antitumor, monoamine oxidase inhibition, antiviral, anti-resorptive property, anti-inflammation, anti-oxidative and analgesic activities [3e8]. Recently, it was reported that MGF can delay the progression of diabetic nephropathy and protect the podocytes by enhancing autophagy under diabetic conditions via the AMPKmTOR-ULK1 pathway, and ameliorate fatty liver via modulation of autophagy and inflammation in high-fat-diet induced mice [9,10]. MGF was also confirmed to be an effective uric acid(UA)lowering agent with dual action of inhibiting production and promoting excretion of UA, and can efficiently inhibited cell growth and induced apoptosis in gastric cancer cells through inhibiting the PI3K/Akt pathways with relative safety [11e13]. However, MGF has poor water solubility and low oral bioavailability in result to greatly affects the its application. Much effort has been used to improve water solubility and stability of MGF, such as dripping pill and

* Corresponding author. Tel.: þ86 13064281879; fax: þ86 871 65920570. E-mail address: [email protected] (B. Yang). https://doi.org/10.1016/j.molstruc.2019.05.015 0022-2860/© 2019 Published by Elsevier B.V.

tablet [14]. It is still necessary to find a new approach to increase water solubility and bioavailability of mangiferin. Cyclodextrin (CD) is a common carrier used to enhance water solubility of drugs. The hydrophobic cavity of CD endows them with inclusion capacity with a variety of compounds ranging from small molecules, ions, proteins, to oligonucleotides [15]. CDs have been extensively utilized to form inclusion complexes with drugs through hosteguest interactions in pharmaceutical technologies [16]. So, CDs can been used in oral, rectal, sublingual, ocular, nasal, pulmonary, dermal and other novel drug delivery systems like liposome, microspheres, osmotic pump, peptide and protein delivery, site-specific drug targeting and nanoparticles [17]. In general, CDs increase bioavailability of guest with informing of the guest/CD complex, and the controlled release of the guest can be achieved after inclusion of guest with CDs [18,19]. b-CD is truncated-cone polysaccharides composed of seven D-glucose monomers linked by a-1,4-glucose bonds into a macrocycle and possess a hydrophilic exterior and an interior hydrophobic cavity, but native b-CD with limited aqueous solubility leads to poor water solubility of the inclusion complexes [16,20] Polyamine modifiedb-CDs have superior water solubility than native b-CD to extensively be applied in many fields such as medicinal chemistry and supramolecular chemistry [21]. In our previous work, we have used HP-bCD and b-CD to encapsulate MGF [22]. Herein, we study host-

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Fig. 1. Chemical structure of MGF (a) and PAbCDs (b).

guest inclusion systems of mangiferin (MGF) with four polyaminemodified b-cyclodextrins (PAbCDs), and evaluate their water solubility and cytotoxicity. 2. Experimental 2.1. Materials MGF (PC＞98%) was obtained from Kunming Pharmaceutical Corporation in Yunnan province, PR China. b-CD was purchased from Mengzhou Huaxin Biological Technology (Shanghai, China). Amino-b-CD (NH2-bCD), ethylenediamine-b-CD (EN-bCD), diethylentriamine-b-CD (DETA-bCD), and triethylenetetramine-b-CD (TETA-bCD) were synthesized according to a reported procedure [23]. Other chemicals and reagents were of analytical grade. All experiments were conducted in ultrapure water. 2.2. Methods 2.2.1. Preparation of MGF/NH2-bCD, MGF/EN-CD, MGF/DETA-bCD, and MGF/TETA-bCD inclusion complexes The solid inclusion complexes of MGF and PAbCDs were prepared by the suspension method. In brief, MGF (0.013 g, 0.03 mM) and PAbCDs (0.01 mM) were first dissolved in ultrapure water. After being stirred for 48 h at room temperature in the dark, any undissolved solid was filtered through a 0.22 mm Millipore membrane. The filtrate was evaporated and the residue was dried in vacuum to yield the MGF/PAbCDs complexes. 2.2.2. Preparation of the physical mixtures of MGF and NH2-bCD, EN-bCD, DETA-bCD, TETA-bCD MGF (0.0422 g, 0.1 mmol) and PAbCDs (0.1 mmol) were mixed thoroughly in a small beaker at room temperature for 5 min to give the 1:1 physical mixture. 2.2.3. Phase-solubility diagram Phase-solubility diagram was obtained by following the method from Higuchi and Connors [24]. Excess amount of MGF was added into the known concentration hosts (PAbCDs, range in 2e7 mM) in D2O (0.6 mL), and the vial was tightly sealed. The amounts of the used compounds were shown in Table S2. The amounts of the MGF in water depending on the b-CD concentration were shown in Table S4. The resulting mixture was vigorously shaken for 10 h at 25  C and then allowed to stand at room temperature for at least 12 h to achieve phase separation. After the MGF was discarded, the bottom clear solution containing hosts and dissolved guest was filtered through a 0.22 mM polythersulfone membrane before 1H NMR (600 MHz) measurement.

The concentration of the dissolved MGF can be calculated from the ratio of integrals of reference peak relative to the PAbCDs peak. Plotting the concentration of MGF versus the concentration of host, the slope can be obtained from the linear fitting of the data points. The value of the stability constant Ks of MGF and NH2-bCD, EN-bCD, DETA-bCD and TETA-bCD complexes were calculated from the fitted slope of the linear segment using the following formula:

Ks ¼

slope S0 ð1  slopeÞ

(1)

where S0 is the aqueous solubility of the MGF in water (S0 ¼ 0.111 mg/mL) [22] without NH2-bCD, EN-bCD, DETA-bCD and TETA-bCD. 2.2.4. 1H NMR and 2D NMR analysis Tetramethylsilane (TMS) was used as a reference. Samples were dissolved in 99.98% D2O and were filtered before use. 1H NMR and 2D ROESY NMR spectra were acquired on a Bruker Advance Ш HD spectrometer at 600 MHz and 298 K. The proton of PAbCDs in 1H NMR and the mass spectrometry: NH2-bCD, d 3.3e3.4 (14H, H-2, 4 of CD), 3.4e3.7 (26H, H-3, 5, 6 of CD), 4.8 (7H, H-1 of CD). MS (ESI): m/z 1134.3954 ([MþH]þ), calculated 1134.3930. Yield: 66%. EN-bCD, d 2.8e3.0 (4H, CH2CH2), 3.4e3.6 (14H, H-2, 4 of CD), 3.7e3.9 (26H, H-3, 5, 6 of CD), 4.98 (7H, H-1 of CD). MS (ESI): m/z 1177.4370 ([MþH]þ), calculated 1177.4352. Yield: 84%. DETA-bCD, d 2.8e3.0 (8H, CH2CH2), 3.4e3.6 (14H, H-2, 4 of CD), 3.7e3.9 (26H, H-3, 5, 6 of CD), 4.98 (7H, H-1 of CD). MS (ESI): m/z 1220.4792 ([MþH]þ), calculated 1220.4774. Yield: 68%. TETA-bCD, d 2.8e3.0 (12H, CH2CH2), 3.4e3.6 (14H, H-2, 4 of CD), 3.7e3.9 (26H, H-3, 5, 6 of CD), 4.98 (7H, H-1 of CD). MS (ESI): m/z 1263.5194 ([MþH]þ), calculated 1263.5196. Yield: 58%. 2.2.5. X-ray powder diffraction The X-ray Powder diffraction patterns were performed with a D/ Max-3B diffractometer using Cu-Ka radiation (k ¼ 1.5460 Å, 40 kV, 100 mA), with a 5 /min scanning rate. Powder samples were mounted on a vitreous sample holder and scanned with a step size of 2q ¼ 0.02 between 2q ¼ 5e70 。 2.2.6. Scanning electron microscopy The morphologies of the samples were performed on a scanning electron microscope (TESCAN, model VEGA3). Samples were distributed on metal stubs with double-sided adhesive tapes. Before examination, the samples were gold sputter-coated to render them electrically conductive, and the micrographs were obtained under reduced pressure.

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2.2.7. Thermal gravimetric analysis Thermal gravimetric analyses were recorded on a NETZSCH STA449F3 instrument, with a 10  C/min heating rate from 40 to 450  C under N2 flow (100 mL/min). The thermal properties of the MGF/PAbCD inclusion complexes, MGF/PAbCD physical mixtures, and pure MGF were investigated using a thermogravimetric analysis. 2.2.8. Solubilization test The water solubility of MGF/NH2-bCD, MGF/EN-bCD, MGF/ DETA-bCD and MGF/TETA-bCD inclusion complexes was assessed by the preparation of its saturated solution [25]. An excess amount of the complex was placed in 2 mL of water, and the mixture was stirred vigorously at room temperature for 2 h. Subsequently, the insoluble substance was removed by filtration and the residue was dosed by the UVevis spectrum. 2.2.9. In vitro cytotoxicity studies The cytotoxicity tests for MGF and its inclusion complexes with NH2-bCD, EN-bCD, DETA-bCD and TETA-bCD were evaluated in vitro for antitumor activity against human HepG2, HCT116, SY5Y cell lines and normal human cell line HEK293T as reference cell lines by the 3-(4,5-dimethyltriazol-2-yl) 2,5-diphenyltetrazolium bromide (MTT) cytotoxicity assay. The IC50 values that represented the concentration of drug required for 50% reduction of cellular growth have been calculated. Cells were cultured at 5  105 cells mL1 in RPMI 1640 supplemented with 10% heat-inactivated fetal bovine serum at 37  C in a humidified atmosphere of 5% CO2 in air. Cells were seeded at 1  105 cells mL1 and treated with the indicated amounts of the MGF and its inclusion complexes. The cytotoxic activities of the MGF and its inclusion complexes were evaluated as cell survival after treatment. Cell viability was evaluated by a microculture tetrazolium reduction assay using MTT.

Fig. 2. Phase solubility diagram of MGF in water depending on the PAbCDs concentration (MGF/NH2-bCD (1), MGF/EN-bCD (2), MGF/DETA-bCD (3), and MGF/TETA-bCD (4)).

Table 1 Stability constant (Ks) and Gibbs free energy change (-DG) for inclusion complex of host CD with MGF at 25  C. Host

Guest

NH2-bCD EN-bCD DETA-bCD TETA-bCD

MGF

Ks(L/mol)

logKs

-DG(KJ/mol)

2140 5043 6705 7655

3.33 3.70 3.83 3.88

18.99 21.12 21.83 22.16

3. Results and discussion 3.1. Phase-solubility The phase-solubility diagram of the PAbCDs/MGF systems (Fig. 2) showed drug solubility increased linearly with increasing MGF concentration. This diagram can be classified as AL type according to the model proposed by Higuchi and Connors’ theory. It proved that one MGF molecule forms a water-soluble complex with one PAbCDs molecule (1:1 complex). The stability constant (Ks) was calculated from the linear fit of the curve in Table 1. The Ks values of the complexes of MGF with NH2-bCD, EN-bCD, DETA-bCD, and TETA-bCD were 2140, 5043, 6705, and 7655 M1, respectively, to show that the PAbCDs have stronger binding ability with MGF (Ks value of the b-CD/MGF inclusion complex is 85.6 M-1, which was measured in the same condition of PAbCDs). Get Gibbs free energy according to formula (2) [26]：

DG ¼ RTlnKs

(2)

Extensive studies have revealed that the size/shapeefit concept plays a crucial role in the inclusion complexation of CD with guest molecules of various structures. On the basis of the size/shapeefit concept, weak intermolecular forces such as ionedipole, dipoleedipole, van der Waals, electrostatic, hydrogen bonding and hydrophobic interactions are known to co-operatively contribute to the inclusion complex. By comparing the enhancement effect of all kinds of PAbCDs for MGF, the NH2-bCD, EN-bCD, DETA-bCD, and TETA-bCD gave the higher Ks enhancement for MGF than, that of native bCD. It was

demonstrated that PAbCDs can enhance binding ability to guest due to several weak intermolecular forces cooperatively. From these factors, we may conclude that the guest MGF was better bound by the PAbCDs than native bCD. Considering the structural features of the hosts and guests, we deduce that, upon inclusion complexation, the hydrogen bond between the amino arm of NH2bCD, EN-bCD, DETA-bCD, and TETA-bCD, which was located close to the accommodated MGF molecule, and the hydroxyl group or the oxygen atom in MGF may strengthen the host-guest association. Therefore, PAbCDs displayed the obviously enhanced binding abilities for guest MGF, which was proved by NMR analysis. 3.2.

1

H NMR and 2D NMR analysis

In order to explore the possible inclusion mode of MGF with NH2-bCD, EN-bCD, DETA-bCD and TETA-bCD complex, we compared the 1H NMR spectra of four PAbCDs with/without of MGF (Fig. 6 and Fig. S5). Major chemical shifts of MGF protons were between 6.2 and 9.2 ppm, which were distinct from those of hosts, variations of chemical shifts of protons of hosts before and after inclusion complexation with MGF could be identified expediently (Table 2 and Table S3). 1H NMR of four PAbCDs were studied following the reported method [29]. It could be found that inner H3 and H-5 protons of NH2-bCD both underwent upfield shifts of 0.02 and 0.06 ppm, respectively. This might be ascribed to hydrogen bonding between protons of MGF and NH2-bCD inside

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Table 2 Chemical Shifts of protons of DETA-bCD before and after inclusion complexation with MGF at 25  C in D2O. Protons

H-1 H-2 H-3 H-4 H-5 H-6

Chemical shift (ppm)

dCD

dcomplex

Dd(dcomplex -dCD)

4.97 3.57 3.86 3.49 3.78 3.84

4.96 3.52 3.84 3.48 3.72 3.76

0.00 0.05 0.02 0.01 0.06 0.08

the cavity of NH2-bCD. Because of the poor water solubility of MGF, the 1H NMR of MGF was measured in DMSO‑d6. An evaluation of the MGF/PAbCDs complexes by 1H NMR clearly revealed that the framework protons of the MGF molecule was present and showed a significant increase in the solubility of MGF/CDs than the native MGF in D2O. As illustrated in Fig. 6, major chemical shifts of MGF protons were between 6.2 and 9.2 ppm, which were distinct from those of host NH2-bCD, EN-bCD, DETA-bCD, and TETA-bCD. 1H NMR of MGF/PAbCDs, 600 MHz, D2O: the MGF, d7.3 (s, 1H, H-8 of MGF), 6.6 (s, 1H, H-5 of MGF). The other three PAbCDs also had the same conclusions like the DETA-bCD. The results see supplementary data (Fig. S5). 2D NMR spectroscopy provided an effective way for studying inter-and intra-molecular interaction. In the case of two protons located closely enough in real space, a NOE cross-correlation between the relevant protons in NOESY or ROESY spectra can be produced. Spatial contacts are within 0.4 nm with the presence of NOE cross-peaks between protons of the two species [30]. The length of amino side chains should play a key role in the complex. This could be supported by the ROESY, which indicated the

formation of self-inclusion of amino arms on CD in the cases of DETA or TETA-bCD, but not in those of NH2-bCD and EN-bCD. 2D ROESY of the inclusion complexes of MGF with PAbCDs were analyzed in order to understand the conformation. The ROESY spectrum of the MGF/TETA-bCD complex (Fig. 7) showed obvious correlation of the H-5, and H-8 protons of MGF with the H-3, 5 protons of DETA-bCD. The results indicated that the A ring of MGF penetrated the wide cavity of TETA-bCD. The inclusion mode of MGF/TETA-bCD could be ascribed to both non-covalent and covalent interactions between the host and guest as depicted in Fig. 8. The entry of the amine chain distorts the shape of the CD cavity, making the inclusion of MGF more tightly. It is possible to explain why the Ks value increases as the amine chain grows. The DETAbCDs also had the same conclusions like the TETA-bCD. The results see supplementary data (Fig. S6). Similar inclusion modes could also be derived for other PAbCDs except that no inclusion of amino side chains in CD cavities existed for NH2-bCD and EN-bCD owing to its too short amino side chain (see supplemental data Fig. S7). 3.3. X-ray powder diffraction XRD is usually used to investigate the crystalline structure and lattice information of the complexation between host and guest. As indicated in Fig. 3, broad peaks confirmed the amorphous pattern of TETA-bCD (3-A). MGF displayed a series of intense peaks, indicating its crystalline form (3-B). Whereas the inclusion complexes noted an amorphous halo pattern from the diffractogram, in which the sharp diffraction peaks of MGF completely disappeared (3-D). It was a simple hybrid pattern for their 1:1 physical mixture, while most of the characteristic peaks of the MGF are present in the diffraction pattern (3-C). These results further proved that MGF had been incorporated into the cavity of CDs and presented as the amorphous or disordered structure. The other three PAbCDs also had the same results as the TETA-bCD (Fig. S2).

Fig. 3. X-ray powder diffraction patterns of TETA-bCD (A), MGF (B), physical mixture (C), MGF/TETA-bCD (D).

J. Liang et al. / Journal of Molecular Structure 1193 (2019) 207e214

3.4. Scanning electron microscopy The morphological changes in the powdered form of the modified CDs and isolated drugs, their inclusion complexes and physical mixtures were acquired via scanning electron microscopy (SEM) [27]. From the SEM analysis in Fig. 4 that NH2-bCD (a) appeared as irregular-shaped crystals with nubby morphology while MGF (b) was a three-dimensional crystal with irregular shape. The physical mixture (c) showed the characteristic of MGF and the three-dimensional shape crystals of NH2-bCD coincidently and individually. In contrast, there was an enormous change in the shape and morphology of particles in MGF/NH2-bCD inclusion complex (d), showing a strong coupling in the solid-state. The other three PAbCDs also had the same conclusions as the NH2-bCD (Fig. S3).

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Table 3 Water solubility of MGN and four inclusion complexes. Compound

MGF MGF/NH2-bCD complex MGF/EN-bCD complex MGF/DETA-bCD complex MGF/TETA-bCD complex

Water Solubility Solubility (mg/mL)

Fold increase

0.111 13.4 45.3 70.6 84.2

1.0 120 408 636 758

3.5. Thermal gravimetric analysis Thermal gravimetric analysis (TGA), among the miscellaneous thermoanalytical methods, is commonly used to look for the signature of inclusion complex formation by determining if there is an existence of change in guest's phase transition temperatures [28]. Thermogravimetric analysis on the MGF/NH2-bCD complexes allowed us to deeply study their thermal properties. Fig. 5 was a systematic analysis of the TGA curves, indicating that MGF lost weight significantly at ca. 270  C. Nevertheless, the NH2-bCD and MGF/NH2-bCD complexes were decomposed at ca. 195  C and 225  C, respectively indicated from the TGA curves in Fig. 5d and c. Thus, MGF was warped into the cavity of CDs according to the empirical results. The other three PAbCDs also had the same conclusions as the NH2-bCD (Fig. S4). 3.6. Water solubility

Fig. 4. Scanning electron microphotographs of NH2-bCD (a), MGF (b), physical mixture of MGF and NH2-bCD (c), and MGF/NH2-bCD complex (d).

The absorbance of MGF/PAbCDs in a saturated aqueous solution was measured by the UVevis spectrum. The water solubility of the four complexes was calculated from the standard curve of MGF (Fig. S8). The results show that the water solubility of this MGF (Table 3), compared with that of native MGF, was markedly increased to approximately 8.8, 16.8, 32.4 and 49.1 mg/mL by the solubilizing effects of NH2-bCD, EN-bCD, DETA-bCD, and TETA-bCD, respectively. This confirmed the reliability of the obtained more satisfactory water solubility of MGF/CDs complexes, which would be beneficial for the utilization of this compound as medicine products. 3.7. In vitro cytotoxicity studies

Fig. 5. Thermal gravimetric analysis curve of MGF (a), MGF/NH2-bCD physical mixture (b), MGF/NH2-bCD complex (c), NH2-bCD (d).

The cytotoxicity of MGF and its inclusion complexes with modified CDs was evaluated in vitro against human cancer cell lines HCT116, HepG2, SY5Y and HEK293T by MTT assay using cisplatin (DPP) and adriamycin as a positive drug. Table 4 lists all the IC50 values, representing the concentration of a drug required for 50% reduction of cellular growth. The in vitro cytotoxicity of MGF in the form of inclusion complexes with PAbCDs was better than that of native MGF and PAbCDs, particularly for MGF/NH2-bCD inclusion complex, which was even superior to that of DPP. The in vitro cytotoxicity of MGF in the form of inclusion complexes with PAbCDs was all greater than that of native MGF and PAbCDs. PAbCDs and their inclusion complexes have significant inhibitory effects on HCT116 cells. This may be related to CD in the large intestine or rectal lysis. For the amino-rich TETA-CD, the IC50 value is the largest. The IC50 value of NH2-bCD is the smallest. It indicates that the release of MGF in the cancer cell is related to the binding constant. If the binding constant is great, the bioavailability of MGF with PAbCD will be low. Furthermore, by incorporation with PAbCD, MGF is significantly less cytotoxic to normal human kidney cell HEK293T than native MGF, suggesting a safer MGF drug formulation. These changes might come from greater cellular uptakes of

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Fig. 6. 1H NMR spectra of (a) DETA-bCD (in D2O), (b) MGF (in DMSO‑d6) and (c) their inclusion complex (in D2O).

Fig. 7. ROESY spectrum of the MGF/TETA-bCD complex in D2O.

drugs with the assistance of PAbCDs according to previous work [31]. On the other hand, the IC50 values also indicated that the uptake of drugs with the amino group into the cells was easy [32]. 4. Conclusions In this study, the inclusion complexes of MGF and PAbCDs were prepared. The inclusion complexation behaviour and properties of

complexes were investigated. The results showed that the formation of complex make a beneficial improvement of water solubility and cytotoxicity compared with native MGF. These results point to a new approach to pharmaceutical formulation of MGF as a potential anticancer drug. In the future, PAbCDs will have a great application prospect in formulation applications. PAbCDs would greatly enhance the bioavailability of poorly water-soluble drugs with its superior water solubility. MGF will also better serve the human

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Fig. 8. Possible inclusion mode of MGN/TETA-bCD inclusion complex.

Table 4 In vitro cytotoxic activities of MGN and its inclusion complex. Samples

NH2-bCD EN-bCD DETA-bCD TETA-bCD DPP Adriamycin MGF MGF/NH2-bCD complex MGF/EN-bCD complex MGF/DETA-bCD complex MGF/TETA-bCD complex

IC50(mM) HCT116

HepG2

SY5Y

HEK293T

>100 >100 >100 >100 8.13 0.26 25.33 3.24 14.17 16.95 28.42

>100 >100 >100 >100 2.14 6.35 18.45 16.62 23.67 24.1 26.07

>100 >100 >100 >100 13.38 5.45 18.31 26.91 26.81 37.35 37.72

>100 >100 >100 >100 2.17 1.81 15.67 >100 >100 >100 >100

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