Arnika Das1,2, Sujeet Kumar1, Leentje Persoons3, Dirk Daelemans3, Dominique Schols3, Hakan Alici4, Hakan Tahtaci5, Subhas S Karki1,2. 1. Department of Pharmaceutical Chemistry, KLE College of Pharmacy, Bengaluru, 560010, Karnataka, India. 2. Dr Prabhakar B Kore Basic Science Research Centre, Off-Campus, KLE College of Pharmacy, A Constituent Unit of KLE Academy of Higher Education and Research-Belagavi, Bengaluru, 560010, Karnataka, India. 3. Rega Institute for Medical Research, Department of Microbiology, Immunology and Transplantation, Laboratory of Virology and Chemotherapy, KU Leuven, B-3000, Leuven, Belgium. 4. Department of Physics, Faculty of Arts and Sciences, Zonguldak Bulent Ecevit University, 67100, Zonguldak, Turkey. 5. Department of Chemistry, Faculty of Science, Karabuk University, 78050, Karabuk, Turkey.
Abstract
Series of (E)-1-benzyl-4-((4-styrylphenoxy)methyl)-1H-1,2,3-triazoles 7a-x were obtained by Wittig reaction between 4-((1-benzyl-1H-1,2,3-triazol-4-yl)methoxy)benzaldehydes 5a-d and benzyl triphenylphosphonium halides 6a-f in benzene. The structures of the synthesized compounds were confirmed by FTIR, NMR (1H and 13C NMR) spectroscopy, and mass spectrometry. All synthesized compounds were screened for their cytotoxic activity against human cancer cell lines including pancreatic carcinoma, colorectal carcinoma, lung carcinoma, and leukemias such as acute lymphoblastic, chronic myeloid, and non-Hodgkinson lymphoma cell lines. In vitro cytotoxicity data showed that compounds 7c, 7e, 7h, 7j, 7k, 7r, and 7w were moderately cytotoxic (11.6-19.3 μM) against the selected cancer cell lines. These cytotoxicity findings were supported using molecular docking studies of the compounds against 1TUB receptor. The drug-likeness properties of the compounds evaluated by in silico ADME analyses. Resveratrol linked 1,2,3-triazoles were more sensitive towards human carcinoma cell lines but least sensitive towards leukemia and lymphoma cell lines.
Series of pan class="Gene">(E)-1-benzyl-4-((4-styrylphenoxy)methyl)-1H-n>n class="Chemical">1,2,3-triazoles 7a-x were obtained by Wittig reaction between 4-((1-benzyl-1H-1,2,3-triazol-4-yl)methoxy)benzaldehydes5a-d and benzyl triphenylphosphonium halides6a-f in benzene. The structures of the synthesized compounds were confirmed by FTIR, NMR (1H and 13C NMR) spectroscopy, and mass spectrometry. All synthesized compounds were screened for their cytotoxic activity against humancancer cell lines including pancreatic carcinoma, colorectal carcinoma, lung carcinoma, and leukemias such as acute lymphoblastic, chronic myeloid, and non-Hodgkinson lymphoma cell lines. In vitro cytotoxicity data showed that compounds 7c, 7e, 7h, 7j, 7k, 7r, and 7w were moderately cytotoxic (11.6-19.3 μM) against the selected cancer cell lines. These cytotoxicity findings were supported using molecular docking studies of the compounds against 1TUB receptor. The drug-likeness properties of the compounds evaluated by in silico ADME analyses. Resveratrol linked 1,2,3-triazoles were more sensitive towards humancarcinoma cell lines but least sensitive towards leukemia and lymphoma cell lines.
pan class="Disease">Cancer is a group of diseases responsible for one in six n>n class="Disease">deaths worldwide. To overcome this threat, effective methods such as immunotherapy, chemotherapy, surgery, and radiotherapy are needed. Each method has its advantages and disadvantages. Chemotherapeutic agents used to kill or inhibit the growth of cancer cells often have serious side effects, whereas radiotherapy and surgery are limited [1]. To fill this void, there is always a need for better alternatives. It is a daunting task to develop a new anticancer compound with improved pharmaceutical properties. The role of heterocyclic chemistry is commendable in this regard. Low toxicity, high regeneration, and better receptor binding make nitrogen (N) -containing heterocycle the first choice between synthons in the drug discovery process [2].
Three pan class="Chemical">nitrogens and two n>n class="Chemical">carbon atoms of triazole contain a five heterocyclic compound ring, a 1,2,3-triazole ring exhibits a variety of biological functions, including antiviral, anti-inflammatory, antimicrobial and anti-tubercular. In addition, 1,4-disubstituted1,2,3-triazoles show significant anticancer activity [3, 4, 5]. Recently Kaushik et al, developed and synthesized amide linked 1,4-disubstituted1,2,3-triazoles (I) as an anticancer agents [6]. Murugavel et al, have been linked to the production of thiophen containing 1,2,3-triazole (II) and pyridine moiety as a potential for topoisomerase IIα inhibiting anticancer agents [7]. A series of connected chalcone 1,2,3 triazoles (III) was synthesized using a green chemical method and tested as anticancer agents [8].
pan class="Chemical">Stilbene based compounds have attracted biologin>n class="Chemical">sts and chemists because they are widely available in nature. They have a variety of biological functions [9, 10]. Hydroxylated stilbenes have been found in medicinal plants but plain stilbene is not found in nature. Trans-3,5,4′-trihydroxy stilbene (resveratrol) (IV) is found in grapes and plays a role in preventing coronary heart disease associated with the use of red wine [11, 12, 13]. This resveratrol exhibits the activity of many biological agents, such as chemopreventive [14] antioxidant [15] antineoplastic [16] and antiestrogenic [17]. Various extracts/structures of stilbenes show anticancer activity [18, 19, 20, 21].
In recent times, the molecular hybridization approach is a widely used techniques in drug discovery, which forms new molecular entities by incorporating pan class="Chemical">stilbenes by linker through the methylene with n>n class="Chemical">1,2,3-triazoles. These integrated or cohesive systems may have advanced biological properties related to specific substances. As the continuation of our work in small nitrogenous heterocyclic compounds, a series of E stilbene linked to 1,4-disubstituted-1,2,3-triazole derivatives (7a-x) were synthesized, identified, and in vitro cytotoxicity is performed in this paper (see Figure 1).
Figure 1
Pharmacologically hybridized/linked 1,2,3-triazole derivatives such as amide linked 1,4-disubstituted 1,2,3-triazoles I, thiophen containing 1,2,3-triazole pyridine II, chalcone linked 1,2,3-triazole III, resveratrol IV and resveratrol linked 1,2,3-triazoles 7a-x.
Pharmacologically hybridized/linked pan class="Chemical">1,2,3-triazole derivatives such as n>n class="Chemical">amide linked 1,4-disubstituted1,2,3-triazoles I, thiophen containing 1,2,3-triazole pyridine II, chalcone linked 1,2,3-triazole III, resveratrol IV and resveratrol linked 1,2,3-triazoles7a-x.
Furthermore, in pan class="Chemical">silico ADME properties were investigated to determine the drug-likeness properties of the synthesized compounds using the Swissn>n class="Chemical">ADME webserver [22, 23]. We also conducted docking simulations both to support the in vitro cytotoxicity studies of the compounds and to identify their binding sites on the 1TUB receptor (tubulin-docetaxel complex) [24].
Experimental
General information and instrumentation
Reagents and solvents were tested for purity before use. Melting points (m.p.) were measured by open capillary pan class="Gene">tube method in liquid n>n class="Chemical">paraffin (heavy) and are uncorrected. FTIR spectra were recorded using infrared (IR) grade potassium bromide (KBr) by diffuse reflectance technique on a JASCO 460 + instrument. The 1H NMR spectra were recorded in deuterated dimethyl sulfoxide (DMSO-d6) and chloroform (CDCl3) in the range of 400–500 MHz (MHz) on Bruker (Ultraspec AMX 400) and JEOL RESONANCE instruments. Chemical shift (δ) values in ppm were expressed using tetramethylsilane (TMS) as the reference. Compound purity was determined by an Agilent 1100 HPLC coupled to an Agilent mass spectrometry detector (MSD) with electrospray ionization in positive mode. 4-(Prop-2-ynyloxy)benzaldehyde (3) and aryl azides (4a-d) were prepared as per literature [25] and 4-((1-arylmethyl-1H-1,2,3-triazol-4-yl)methoxy)benzaldehydes (5a-d) were synthesized as per the literature [26]. Various aryltriphenylphosphonium chlorides (6a-f) were prepared as per the literature [27].
All n class="Disease">tumor cell lines were acquired from the American Type Culture Collection (ATCC, Manassas, VA, USA), except for the DND-41 cell line, which was purchased from Deutsche Sammlung von Mikroorganismen und Zellkulturen (DSMZ Leibniz-Institut, Braunschweig, Germany). All cell lines were cultured as recommended by the suppliers. Media were purchased from GIBCO Life Technologies, USA, and supplemented with 10% fetal bovine serum (HyClone, GE Healthcare Life Sciences, USA). For real-time monitoring, adherent cell lines n>n class="CellLine">HCT-116, NCI–H460, and Capan-1 were seeded at a density between 500 and 1500 cells per well in 384-well clear-bottomed tissue culture plates (Greiner). After overnight incubation, cells were treated with the test compounds at seven different concentrations ranging from 100 to 6.4 × 10−3 μM. Suspension cell lines K-562, Z-138, and DND-41 were seeded at densities ranging from 2500 to 5000 cells per well in 384-well clear-bottomed tissue culture plates containing the test compounds at the same seven concentration points. The plates were incubated and monitored at 37 °C for 72 h in the IncuCyte® system (Essen BioScience Inc., Ann Arbor, MI, USA) for real-time imaging. Images were taken every 3 h, with one field imaged per well under 10× magnification. Cell growth was then quantified based on percent cellular confluence as analyzed by the IncuCyte® image analysis software and used to determine the IC50 values.
Methodology for in silico studies
The 3D structures of all compounds were prepared using Avogadro v1.2.0 [28] and their energies were minimized with the MMFF94s force field. The pan class="Chemical">ADME properties, pharmacokinetic properties, and drug-likenesses of the compounds were then investigated with the Swissn>n class="Chemical">ADME webserver [22, 23]. Finally, docking simulations of all compounds were performed with the crystal structure of a tubulin heterodimer (PDB ID: 1TUB) [24]. All ligands and the target were prepared using PyRx software [29] and the docking experiments were subsequently carried out using AutoDock Vina software [30] with the Lamarckian genetic algorithm (LGA) [31, 32]. The visualizations of docking simulation results were conducted using the Discovery studio [33].
Results and discussion
Chemistry
Series of pan class="Gene">(E)-1-benzyl-4-((4-styrylphenoxy)methyl)-1H-n>n class="Chemical">1,2,3-triazoles (7a-x) were obtained by Wittig reaction (Figure 2) [34] between the respective 4-((1-benzyl-1H-1,2,3-triazol-4-yl)methoxy) benzaldehydes (5a-d) and benzyltriphenylphosphonium halides (chlorides and bromide) (6a-f). Compounds 5a-d were obtained via copper (Cu)-catalyzed regioselective 1,3-dipolar cycloaddition of 4-(prop-2-ynyloxy)benzaldehyde (3) with benzyl azides (4a-d), while the reaction between 4-hydroxybenzaldehyde (1) and propargyl bromide (2) led to compound 3. Schemes 1a-c represent the synthetic routes and Table 1 contains the structures of 7a-x. Structural confirmation was performed with Fourier transform infrared (FTIR), nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry.
Figure 2
Mechanism of synthesis for 7a-x.
Scheme 1
a. Synthesis of 4-(prop-2-yn-1-yloxy)benzaldehyde (3). b. Synthesis of 4-((1-benzyl-1H-1,2,3-triazol-4-yl)methoxy)benzaldehydes (5a-d). c. Synthesis of (E)-1-benzyl-4-((4-styrylphenoxy)methyl)-1H-1,2,3-triazoles (7a-x).
Mechanism of synthesis for pan class="Chemical">7a-x.
a. Synthesis of pan class="Chemical">4-(prop-2-yn-1-yloxy)benzaldehyde (3). b. Synthesis of n>n class="Chemical">4-((1-benzyl-1H-1,2,3-triazol-4-yl)methoxy)benzaldehydes (5a-d). c. Synthesis of (E)-1-benzyl-4-((4-styrylphenoxy)methyl)-1H-1,2,3-triazoles (7a-x).
Synthesized pan class="Chemical">stilbene linked n>n class="Chemical">1,2,3-triazole analogues (7a-x).
The FTIR spectra of compounds pan class="Chemical">7a-x showed stretching peaks in the ranges of 3010–3101 (-CH, ar.), 2734–2964 (-CH, ali.), 1513–1634 (>C=N-), 1507–1516 (>C=C<), and 1176–1266 (-O-) cm−1 for the groups given in parentheses. Methylene (–n>n class="Chemical">CH2–) bending peaks appeared in the range of 1427–1492 cm−1. Compounds 7d, 7e, 7j, 7k, 7m-r, 7v, and 7w showed methyl (-CH3) bending peaks in the range of 1336–1395 cm−1, while the nitro (-NO2) stretching in 7f-l, 7r, and 7x appeared between 1514 and 1592 cm−1.
1HNMR spectra showed pan class="Chemical">singlet triazole ring protons in the range of 8.20–8.38 δ ppm. The aromatic protons appeared between 6.93 and 8.25 δ ppm while two doublet peaks appeared in the range of 7.06–7.50 δ ppm for -CH=CH of styryl moiety [35, 36]. Peaks at 5.40–5.80 and 5.13–5.20 δ ppm represent -N–n>n class="Chemical">CH2– and –OCH2-, respectively. The –CH3 protons of 7d, 7j, 7m-r, and 7v appeared between 2.27 and 2.29 δ ppm along with -O-CH3 protons of 7e, 7k, 7q, and 7w at 3.76 δ ppm. The nature of the carbon in 7a-x was ascertained by the respective 13C NMR spectral data. Absence of the –C≡CH proton of 3 at 1.56 δ ppm and presence of additional -N–CH2– protons at 5.52 δ ppm along with singlet triazole-H at 7.59 δ ppm in 5a confirmed the reaction between 3 and 4a. Table 1 contains details of compounds 7a-x such as molecular weight, molecular formula, yield, percentage purity, and physical constant.
Biological study
In vitro cellular pan class="Disease">cytotoxicity evaluations of derivatives n>n class="Chemical">7a-x were performed using six different humancancer cell lines (Capan-1, HCT-116, NCI–H460, DND-41, K-562, and Z-138) in 384-well micro-titer plates [37]. The tubulin inhibitor docetaxel [38] and the pan-kinase inhibitor staurosporine (STS) [39] were used as reference compounds and dimethyl sulfoxide (DMSO) as a solvent. The cytotoxicity data summarized in Table 2 represent 50% inhibitory concentrations (IC50).
Table 2
In-vitro cytotoxicity data of synthesized stilbene linked 1,2,3-triazoles 7a-x (μM).
Compound
Capan-1
HCT-116
NCI–H460
DND-41
K-562
Z-138
Pancreatic adeno-carcinoma
Colorectal carcinoma
Lung carcinoma
Acute lymphoblastic leukemia
Chronic myeloid leukemia
Non-Hodgkin lymphoma
7a
46.7
29.1
34.3
61.4
39.9
>100
7b
30.7
46.7
31.7
>100
>100
>100
7c
96.4
36.1
>100
>100
19.3
>100
7d
>100
>100
81.7
>100
>100
60.3
7e
55.3
13.5
35.1
>100
>100
>100
7f
45.3
62.4
40.7
>100
>100
>100
7g
>100
26.1
78.5
82.1
>100
>100
7h
40.2
12.2
11.6
>100
>100
>100
7i
62.3
21.3
31.3
>100
>100
>100
7j
62.3
>100
98.3
>100
>100
>100
7k
50.2
12.6
95.4
>100
>100
>100
7l
70.3
76.7
44.3
>100
>100
>100
7m
45.9
>100
41.7
>100
>100
>100
7n
73.4
>100
>100
>100
>100
>100
7o
51.8
>100
47.3
81.2
>100
>100
7p
52.4
87.4
60.8
>100
>100
>100
7q
34.6
30.5
37.1
>100
>100
>100
7r
39.5
21.3
16.2
>100
>100
>100
7s
80.6
33
61.1
>100
>100
>100
7t
67.3
71.5
91.9
>100
>100
>100
7u
41.3
36.5
33.8
>100
>100
>100
7v
>100
57.3
>100
>100
>100
>100
7w
48.9
36
12.4
>100
>100
>100
7x
>100
55.8
72.5
>100
>100
>100
Docetaxel
0.0063
0.0008
0.0001
0.0019
0.0034
0.0019
STS
0.0046
0.0003
0.0032
0.0064
0.0298
0.0003
In-vitro pan class="Disease">cytotoxicity data of synthesized n>n class="Chemical">stilbene linked 1,2,3-triazoles7a-x (μM).
Irrespective of the substituents on the aromatic ring system, compounds pan class="Chemical">7a-x were found to be poorly cytotoxic towards acute n>n class="Disease">lymphoma (DND-41), chronic myeloid leukemia (K-562), Non Hodgin lymphoma (Z-138) and moderate cytotoxic against pancreatic adeno carcinoma (Capan-1), colorectal carcinoma (HCT-116), lung carcinoma (NCI–H460). In general, among the tested derivatives, 7a and 7c showed some cytotoxic chronic myeloid leukemia (K-562) cells. Most of the compounds displayed some sort of cytotoxic activity 31–96 μM against pancreatic adeno carcinoma (Capan-1) cells except compounds 7d, 7g, 7v and 7x. For colorectal carcinoma cells (HCT-116), the cytotoxic activity exhibited by many compounds of the series ranging from 12-87 μM. Among this series, 7e, 7h and 7k were the most potent with IC50 at 12–13 μM, many compounds such as 7a, 7g, 7i, 7q and 7r were cytotoxic in the range of 20–30 μM. For lung carcinoma (NCI–H460) cells, 12–16 μM cytotoxicity activity showed by compounds 7h, 7r and 7w, whereas remaining compounds exhibited the activity ˃30 μM. In case of acute lymphoblastc leukemia (DND-41), very limited compounds namely 7a, 7g and 7o displayed some cytotoxic activity 60–80 μM, remaining all compounds did not display any cytotoxic activity. Even for the chronic myeloid leukemia (K-562) cells also not showed any activity by the synthesized compounds except 7a and 7c with 40 and 19 μM. Similarly, for Non Hodgin lymphoma (Z-138), one compound that is 7d showed some cytotoxic activity with IC50 60μM, and remaining compounds in the series failed to display activity. By looking at the cytotoxicity results from Table 2, the most of the compounds tested in the series were cytotoxic only against carcinoma cells but not active or cytotoxic to leukemia and lymphoma but none of the tested compounds was not potent as compared to both the drug standards. The compounds shown in Figure 3 are the most active members of the series.
Figure 3
Biologically active stilbene linked 1,2,3-triazole derivatives.
Table 3 shows the physicochemical properties, pan class="Chemical">ADME parameters, and violations of drug-likeness rules of the synthesized compounds. Calculated physicochemical and lipophilicity parameters are used by various filters to evaluate the drug-likeness of synthesized compounds and, in this paper, we evaluated the drug-likeness properties of the compounds with the most significant filtering approaches in the literature. The filters used here and their rules are as follows:
Table 3
Physicochemical and pharmacokinetic properties of stilbene linked 1,2,3-triazoles.
Lipinski (Pfizer) filter [40]: MW ≤ 500; MLOGP ≤4.15; HBA ≤10; pan class="Gene">HBD ≤5
Ghose filter [41]: 160 ≤ MW ≤ 480; -0.4 ≤ WLOGP ≤5.6; 40 ≤ MR ≤ 130; 20 ≤ atoms ≤70Veber (GSK) filter [42]: RB ≤ 10; TPSA ≤140Egan (Pharmacia) filter [43]: WLOGP ≤5.88; TPSA ≤131.6Muegge (Bayer) filter [44]: 200 ≤ MW ≤ 600, -2 ≤ XLOGP ≤5; TPSA ≤157; HBA ≤10; pan class="Gene">HBD ≤5; RB ≤ 15; number of rings ≤7; number of n>n class="Chemical">carbons >4; number of heteroatoms >1.
Physicochemical and pharmacokinetic properties of pan class="Chemical">stilbene linked n>n class="Chemical">1,2,3-triazoles.
Molecular weight: MW, topological polar surface area: tPSA, Molar Refractivity: MR, fraction of pan class="Gene">sp3 n>n class="Chemical">carbon atoms: Fsp3, HBD: hydrogen bonds donor, HBA: hydrogen bond acceptor, RB: rotatable bonds, LogP values: indicator of Lipophilicity, ESOL: aqueous solubility parameter, Log Kp: skin permeation, F: Bioavailability Score.
The filters generally assume that an orally active drug should not violate the above criteria more than once. When Table 3 is examined, it can be said that all newly synthesized compounds and the reference drug pan class="Chemical">STS meet these criteria. However, the other reference drug, n>n class="Chemical">docetaxel, is observed to violate all filters more than once, except the Muegge filter.
pan class="Gene">Fsp3 is another newly introduced parameter [45] to interpret the drug-likeness properties of molecules. According to Table 3, the n>n class="Gene">Fsp3 values of all compounds are lower than those of docetaxel and STS. Furthermore, we observed that the ESOL values of all synthesized compounds belonged to the moderately water-soluble class. Compounds 7c, 7j, 7o, 7p, 7s, 7t, 7u, 7v, 7w, and 7x have values greater than -6; thus, they are in the poorly soluble class. On the other hand, other newly synthesized compounds and reference drugs are in the moderately soluble class. Log Kp in the table is the skin permeation parameter suggested by Potts et al. [46], and a low negative log Kp value of a compound corresponds to higher absorption into human skin. Accordingly, all newly synthesized compounds have higher levels of skin absorption than the reference drugs. In the table, the bioavailability score (F) of the compounds signifies the probability that a compound will have oral bioavailability in rats [47]. The newly synthesized compounds and STS have higher F scores than docetaxel.
We also conducted molecular docking simulations to help elucidate the antipan class="Disease">cancer activities of the synthesized compounds. In the docking simulations, we utilized the crystal structure of the tubulin-docetaxel complex [24] (PDB ID: 1TUB) as the target. The binding affinity values obtained as a result of the docking studies are shown in Table 3. As is seen there, compounds 7h and 7r, which show good cytotoxicity in vitro, have the highest binding energy values. It was also observed that the reference drug STS had a higher binding affinity than the other reference drug, docetaxel, which is also the co-ligand of 1TUB. In this context, to identify the binding regions of 7h, 7r, STS, and docetaxel, we display the two-dimensional (2D) interaction diagrams and 3D interactions between these compounds and 1TUB in Figures 4, 5, 6, and 7.
Figure 4
The 2D and 3D representations of interactions between compound 7h and 1TUB receptor.
Figure 5
The 2D and 3D representations of interactions between compound 7r and 1TUB receptor.
Figure 6
The 2D and 3D representations of interactions between docetaxel (co-ligand) and 1TUB receptor.
Figure 7
The 2D and 3D representations of interactions between STS and 1TUB receptor.
The 2D and 3D representations of interactions between compound 7h and 1pan class="Gene">TUB receptor.
The 2D and 3D representations of interactions between compound 7r and 1pan class="Gene">TUB receptor.
The 2D and 3D representations of interactions between pan class="Chemical">docetaxel (co-ligand) and 1n>n class="Gene">TUB receptor.
The 2D and 3D representations of interactions between pan class="Chemical">STS and 1n>n class="Gene">TUB receptor.
As seen in Figures 4, 5, 6, and 7, compound 7h has a total of 4 pan class="Chemical">hydrogen bond interactions, including 3 conventional n>n class="Chemical">hydrogen bonds (coHB) and 1 carbon hydrogen bond (caHB). Compound 7h also has 3 electrostatic interactions (2 pi-anion (PA), 1 pi-cation (PC)), 5 hydrophobic interactions (1 pi-pi T-shaped (PT), 3 pi-alkyl (PAl)), and 1 halogen interaction. On the other hand, compound 7r has 2 hydrogen bonds (1 coHB, 1 pi-donor hydrogen bond (pdHB)), 3 electrostatic interactions (1 PC, 2 PA), and 9 hydrophobic interactions (2 PT, 6 PAl, 1 Alkyl (Al)).
For reference compounds pan class="Chemical">docetaxel and n>n class="Chemical">STS, it can be said that docetaxel has 3 hydrogen bonds (3 coHB, 1 caHB), 1 electrostatic interaction (1 PC), and 8 hydrophobic interactions (1 PT, 2 PAl, 5 Al), whereas STS has 2 hydrogen bonds (3 coHB, 1 caHB), 2 electrostatic interactions (1 PC), and 6 hydrophobic interactions (2 PAl, 4 pi-pi stacked (PSt)). In this case, the PSt interactions of STS may have caused STS to show higher affinity for 1TUB than docetaxel.
Conclusions
24 derivatives of n class="Chemical">resveratrol linked n>n class="Chemical">1,2,3-triazole (7a-x) were synthesized, characterized by 1H, 13C NMR, Mass Spectrometry and FTIR. All the compounds tested for their cytotoxic study against three carcinoma, two leukemia and one lymphoma human cancer cell lines. Most of the compounds tested in the series were cytotoxic towards all three types of carcinoma cells but were not cytotoxic to leukemia and lymphoma. In the docking simulations, we docked all the compounds with protein 1TUB. Compounds 7h and 7r, which showed good cytotoxicity in vitro, have the highest binding energy values. We identified according to docking results that compound 7h has four hydrogen bond, three electrostatic interactions, five hydrophobic interactions, and one halogen interaction while another compound 7r has two hydrogen bonds, three electrostatic interactions, and nine hydrophobic interactions. Therefore, resveratrol linked 1,2,3-triazoles were more sensitive towards humancarcinoma cell lines but least sensitive towards leukemia and lymphoma cell lines. Hence, further optimization is required to obtain an effective lead molecule against cancer.
Declarations
Author contribution statement
A. Das: Performed the experiments; Contributed reagents, materials, analysis tools or data.D. Daelemans: Performed the experiments.L. Persoons: Performed the experiments.D. Schols: Analyzed and interpreted the data; Contributed reagents, materials, analysis tools or data; Wrote the paper.S. S Karki: Conceived and designed the experiments; Analyzed and interpreted the data; Wrote the paper.S. Kumar: Contributed reagents, materials, analysis tools or data; Wrote the paper.H. Alici: Conceived and designed the experiments; Performed the experiments; Contributed reagents, materials, analysis tools or data.H. Tahtaci: Analyzed and interpreted the data; Wrote the paper.
Funding statement
This work was supported by Federal funds from the Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and pan class="Species">Human Services, under Contract No. 75N93019D00005.
Data availability statement
Data will be made available on request.
Declaration of interests statement
The authors declare no conflict of interest.
Additional information
No additional information is available for this paper.
Authors: Marcus D Hanwell; Donald E Curtis; David C Lonie; Tim Vandermeersch; Eva Zurek; Geoffrey R Hutchison Journal: J Cheminform Date: 2012-08-13 Impact factor: 5.514
Figure 1
Figure 2
Scheme 1
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7