A series of perimidine derivatives (L1–5) were prepared and characterized by IR, 1H·NMR, mass spectroscopy, UV-Vis, XRD, thermal, and SEM analysis. Five VO(II) complexes were synthesized and investigated by most previous tools besides the theoretical usage. A neutral tetradentate mode of bonding is the general approach for all binding ligands towards bi-vanadyl atoms. A square-pyramidal is the configuration proposed for all complexes. XRD analysis introduces the nanocrystalline nature of the ligand while the amorphous appearance of its metal ion complexes. The rocky shape is the observable surface morphology from SEM images. Thermal analysis verifies the presence of water of crystallization with all coordination spheres. The optimization process was accomplished using the Gaussian 09 software by different methods. The most stable configurations were extracted and displayed. Essential parameters were computed based on frontier energy gaps with all compounds. QSAR parameters were also obtained to give another side of view about the biological approach with the priority of the L3 ligand. Applying AutoDockTools 4.2 program over all perimidine derivatives introduces efficiency against 4c3p protein of breast cancer. Antitumor activity was screened for all compounds by a comparative view over breast, colon, and liver carcinoma cell lines. IC50 values represent promising efficiency of the L4-VO(II) complex against breast, colon, and liver carcinoma cell lines. The binding efficiency of ligands towards CT-DNA was tested. Binding constant (
Vanadium was widely used as a therapeutic agent in the late eighteenth century, treating a variety of ailments including anemia, tuberculosis, rheumatism, and diabetes [
Chemicals essential for preparation of perimidine derivatives such as 1,8-diaminonaphthalene, ethylbenzoyl acetate, 4-methoxyaniline, aniline, 4-chloroaniline, 3-chloroaniline, 4-nitroaniline, NaNO2, NaOH, HCl, and dioxane were purchased from Fluka and used without previous treatments. Also, VOSO4·xH2O salt used for the complexation process was commercially available from Sigma-Aldrich. All handled solvents were from Merck and used without previous purification.
Ligands
Synthesis of perimidine compounds
1H·NMR of L1 ligand (as example).
Mass spectra of L1 and L4 ligands.
(a) Structures of perimidine ligands (L1–5). (b) Optimized structures of five perimidine ligands.
New VO(II) complex series was synthesized by using variable derivatives from perimidine ligands. Equimolar (3 mmol) values were used from the perimidine ligand and dissolved fully in dioxane; after that, it was mixed with VOSO4·xH2O which dissolves in the dioxane/H2O mixture. The weighted molar ratio value from vanadyl salt was calculated attributing to its anhydrous weight. After ≈5 h reflux, 0.5
The binding attitudes of perimidine derivatives towards calf thymus DNA (CT-DNA) will be studied by using the spectroscopy method. CT-DNA (50 mg) was dissolved by stirring overnight in double deionized water (pH = 7.0) and must be kept at 4°C. Bi-distilled water was used to prepare the buffer (5.0 mM tris(hydroxymethyl)-aminomethane and 50 mM NaCl, pH = 7.2). Tris-HCl buffer was prepared in deionized water. DNA buffering solution gave absorbance ratio at 260/280 nm by 1.8–1.9, and this indicates the absence of protein from DNA [
The evaluation of cytotoxicity of candidate anticancer drugs will be performed using the most effective, available SRB method. All molecules and their derivatives will be tested for their toxicity on different cancer cell lines. In an attempt to evaluate the impact, the samples were prepared with different concentrations: 0.01, 0.1, 1, 10, and 100
The cytotoxic effect of the composites and ligands will be tested against different cancer cell lines (HepG2, MCF-7, and HCT116) as donor cancer cell lines by means of the SRB cytotoxicity test. To avoid the contamination, the RPMI media of the cells were supplemented with 100
The element contents (carbon, hydrogen, and nitrogen) were determined at the Micro-Analytical Unit of Cairo University. Vanadium, sulfate, and chloride contents were evaluated by known standard methods [
Applying the Jenway 4010 conductivity meter, the molar conductivity of freshly prepared 1.0 × 10−3 mol/cm3 in DMSO solutions was estimated.
X-ray diffraction manners were recorded on the Rigaku diffractometer using Cu/K
IR spectra were obtained using the JASCO FT/IR-4100 spectrophotometer from 400 to 4000 cm−1 in the KBr disc, while 1H·NMR spectra were recorded in deuterated dimethyl sulfoxide using the Varian Gemini 300 NMR spectrometer.
Mass spectra were recorded on GCMS-QP1000 EX (Shimadzu) and GCMS 5988-A.
ESR spectra of VO(II)-powdered complexes were obtained on the Bruker EMX spectrometer working in the X-band (9.60 GHz) with 100 kHz modulation frequency. The microwave power was set at 1 mW, and modulation amplitude was set at 4 Gauss. The low field signal was obtained after 4 scans with a 10-fold increase in the receiver gain. A powder spectrum was obtained in a 2 mm quartz capillary at ordinary temperature.
Electronic spectra for all compounds were recorded using the UV2 Unicam UV/Vis spectrophotometer in the DMSO solvent. Magnetic susceptibility values for VO(II) complexes were conducted by the Johnson Matthey magnetic susceptibility balance at room temperature.
The Shimadzu thermogravimetric analyzer (20–900°C) at 10°C·min−1 heating rate under nitrogen was used for thermal analysis. Theoretical treatments (modeling and docking) were accomplished by known standard programs.
Antitumor activity was conducted at the Regional Center for Mycology and Biotechnology.
Implementing the Gaussian 09 software [
New perimidine compounds were treated for the optimization process to give the best structural forms. HyperChem (v8.1) software is the tool used for such a purpose. The preoptimization process was executed by molecular mechanics force field (MM+) accompanied by semiempirical AM1 for the soft adjustment procedure. This process was accomplished without fixing any parameter till the equilibrium state for geometric structures. A system for minimizing energy was employed the Polak–Ribiere conjugated gradient algorithm. The QSAR process leads to computing essential parameters including the partition coefficient (log
Applying AutoDockTools 4.2 by using Gasteiger partial charges which added over the elements of pyrimidine ligands, the simulation procedure was executed to give a view on the biological behavior of compounds. Rotatable bonds were cleared, and nonpolar hydrogen atoms were conjoined. Interaction occurred between inhibitors (ligands) and protein receptors (4c3p, 3bch, and 4zdr) for breast, colon, and liver cancer proteins. The docking process was accomplished after addition of fundamental hydrogen atoms, Kollman united atom-type charges, and salvation parameters [
Essential analytical and physical data for ligands and their VO(II) complexes are summarized in Table
Significant analytical and physical data of perimidine compounds and their VO(II) complexes.
Compounds (formula weight) (calcd./found) | Color | Elemental analysis (%) calcd. (found) | ||||
---|---|---|---|---|---|---|
C | H | N | SO4/Cl | V | ||
( |
Dark brown | 76.91 (76.90) | 4.65 (4.66) | 14.35 (14.35) | — | — |
( |
Dark brown | 40.88 (40.88) | 2.74 (2.73) | 7.63 (7.65) | 26.16 (26.16) | 13.87 (13.88) |
( |
Dark brown | 74.27 (74.27) | 4.79 (4.79) | 13.32 (13.31) | — | — |
( |
Dark green | 39.91 (39.90) | 3.09 (3.10) | 7.16 (7.17) | 24.55 (24.54) | 13.02 (13.03) |
( |
Dark brown | 68.96 (68.95) | 3.93 (3.93) | 16.08 (16.09) | — | — |
( |
Dark green | 38.52 (38.52) | 2.46 (2.46) | 8.99 (8.97) | 24.65 (24.66) | 13.07 (13.05) |
( |
Dark brown | 70.67 (70.66) | 4.03 (4.02) | 13.19 (13.18) | 8.34 (8.35) | — |
( |
Dark green | 39.05 (39.05) | 2.49 (2.48) | 7.29 (7.28) | 24.99 (25.02)/4.61 (4.63) | 13.25 (13.26) |
( |
Dark brown | 70.67 (70.68) | 4.03 (4.05) | 13.19 (13.18) | 8.34 (8.35) | — |
( |
Dark brown | 37.30 (37.31) | 2.88 (2.88) | 6.96 (6.95) | 23.87 (23.88)/4.40 (4.41) | 12.66 (12.67) |
The assignments of all characteristic bands for five perimidine ligands and their VO(II) complexes are summarized in Table
Significant IR spectral bands (cm−1) of perimidine compounds and their VO(II) complexes.
Compounds |
|
|
|
|
|
|
|
|
|
|
---|---|---|---|---|---|---|---|---|---|---|
( |
3155 | 1473 | 1618 | 1518 | — | — | — | — | — | — |
( |
3110, 3350 | 1470 | 1596 | 1514 | 1420 | 1142 | 765, 670 | 966 | 588 | 476 |
( |
3177 | 1470 | 1597 | 1508 | —- | — | — | — | — | — |
( |
3100, 3372 | 1447 | 1592 | 1502 | 1411 | 1146 | 765, 697 | 1074 | 572 | 515 |
( |
3150 | 1473 | 1620 | 1538 | — | — | — | — | — | — |
( |
3105, 3382 | 1447 | 1616 | 1517 | 1411 | 1179 | 743, 697 | 966 | 600 | 508 |
( |
3160 | 1474 | 1614 | 1518 | — | — | — | — | — | — |
( |
3100, 3420 | 1471 | 1624 | 1510 | 1434 | 1150 | 755, 637 | 985 | 610 | 550 |
( |
3150 | 1473 | 1620 | 1518 | — | — | — | — | — | — |
( |
3054, 3384 | 1446 | 1616 | 1512 | 1368 | 1140 | 754, 689 | 1074 | 589 | 508 |
Electronic transition bands and magnetic moment values are aggregated in Table
Electronic transitions of perimidine compounds and their VO(II) complexes.
Compounds |
|
d-d transition bands (cm−1) | Intraligand and charge transfer (cm−1) |
---|---|---|---|
( |
— | — | 31,746; 26,316; 23,923; 18,868 |
( |
1.66 | 15,290; 12800 | 35,714; 29,412; 25,641; 24,272; 17,857 |
( |
— | — | 38,168; 28,249; 23,810; 19,048 |
( |
1.68 | 15,393; 12750 | 37,037; 30,769; 26,316; 23,256; 17,544 |
( |
— | — | 36,364; 30,303; 26,316; 23,810; 19,157 |
( |
1.66 | 15,873; 12830 | 37,037; 28,571; 26,667; 18,182 |
( |
— | — | 31,746; 25,974; 18,587 |
( |
1.67 | 15,385; 12,800 | 35,714; 30,303; 25,974; 24,390; 17,857 |
( |
— | — | 31,250; 26,316; 24,390; 18,182 |
( |
1.65 | 15,873; 12780 | 35,714; 30,769; 25,000; 23,256; 18,868 |
Geometry optimization of VO(II)-perimidine complexes (a–e, respectively).
ESR spectra (Figure
ESR spectrum of L1 + VO(II)complex.
Spin Hamiltonian parameters of all VO(II) complexes (A and
Complex |
|
|
|
|
|
|
|
|
|
|
2
|
2
|
|
|
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
( |
1.93 | 1.96 | 1.95 | 167 | 115.57 | 66 | 99.67 | 1.71 | 117.52 | 0.796 | −0.843 | −1.981 | 1.959 | 0.9357 |
( |
1.94 | 1.97 | 1.96 | 170 | 114.12 | 71 | 104.00 | 1.93 | 115.19 | 0.861 | −0.724 | −1.512 | 1.490 | 0.9435 |
( |
1.92 | 1.96 | 1.95 | 168 | 114.28 | 69 | 105.67 | 1.95 | 115.19 | 0.865 | −0.961 | −1.985 | 1.964 | 0.9243 |
( |
1.94 | 1.98 | 1.97 | 171 | 113.45 | 73 | 105.67 | 2.79 | 114.00 | 0.895 | −0.727 | −1.055 | 1.033 | 0.9395 |
( |
1.93 | 1.97 | 1.96 | 171 | 112.86 | 72 | 105.00 | 2.24 | 115.19 | 0.869 | −0.841 | −1.515 | 1.494 | 0.9318 |
The hyperfine conjunction disciplinarians were calculated by taking A// and A⊥ as negative, which gave positive values of
Dipolar term values can be determined by
If
The
Thus,
X-ray diffraction patterns were executed over 10° < 2
X-ray diffraction pattern of high crystalline ligand.
The degradation behaviors of all perimidine compounds and their VO(II) complexes were tested. The proposed degradation insights corresponding to all decomposition stages are tabulated (Table
Estimated TG data of perimidine compounds and all VO(II) complexes.
Compound | Steps | Temp. range (°C) | Decomposed | Weight loss; calcd. (found %) |
---|---|---|---|---|
L1 | 1st | 45.1–120.5 | -[C6H6 + N2] | 27.18 (27.16) |
2nd | 122.2–410.1 | -[C6H5 + CO] | 26.92 (26.95) | |
3rd | 410.3–670.2 | -[C8H7N2] | 33.59 (33.54) | |
Residue | 4C | 12.31 (12.35) | ||
[(VO)2 (SO4)2 (L1)]H2O | 1st | 80.3–120.3 | -[H2O + SO4] | 15.53 (15.55) |
2nd | 120.6–391.7 | -[SO4 + C6H6 + N2] | 27.53 (27.55) | |
3rd | 391.9–798.8 | -[C19H12N2] | 36.53 (36.50) | |
Residue | V2O3 | 20.41 (20.40) | ||
L2 | 1st | 65.6–156.1 | -[C6H5OCH3] | 25.72 (25.71) |
2nd | 156.6–299.9 | -[C6H5 + CO + N2] | 31.66 (31.69) | |
3rd | 301.0–663.2 | -[C9H7N2] | 34.05 (33.89) | |
Residue | 3C | 8.57 (8.71) | ||
[(VO)2 (SO4)2 (L2)]2H2O | 1st | 42.1–135.1 | -[2H2O + 2SO4] | 29.16 (29.16) |
2nd | 136.1–270.1 | -[C6H5OCH3 + N2] | 17.40 (17.29) | |
3rd | 271.0–485.4 | -[C6H5] | 9.85 (9.94) | |
4th | 485.6–797.9 | -[C13H7N2] | 24.43 (24.45) | |
Residue | V2O3 | 19.15 (19.16) | ||
L3 | 1st | 63.66–230.51 | -[C6H6 + NO2] | 28.50 (27.90) |
2nd | 231.21–410.11 | -[C7H5 + CO + N2] | 33.33 (33.31) | |
3rd | 410.52–650.64 | -[C11H6N2] | 38.16 (38.79) | |
[(VO)2 (SO4)2 (L3)]H2O | 1st | 79.2–140.6 | -[H2O + SO4] | 14.63 (14.62) |
2nd | 141.9–278.9 | -[SO4 + C6H5 + CO] | 25.81 (25.78) | |
3rd | 279.1–479.5 | -[NO2 + C6H6 + N2] | 19.52 (19.53) | |
4th | 480.11–798.8 | -[C12H6N2] | 22.86 (22.90) | |
Residue | V2O2 | 17.18 (17.17) | ||
L4 | 1st | 64.65–145.46 | -[C6H5Cl + CO + N2] | 39.68 (39.68) |
2nd | 145.68–326.78 | -[C6H5 + N2] | 24.74 (24.75) | |
3rd | 330.12–680.23 | -[C12H7] | 35.58 (35.57) | |
[(VO)2 (SO4)2 (L4)]H2O | 1st | 69.1–256.1 | -[H2O + C6H5Cl + SO4] | 29.48 (29.65) |
2nd | 256.9–484.1 | -[SO4 + CON2 + C6H5] | 29.80 (29.81) | |
3rd | 484.6–789.4 | -[C10H7N2] | 20.18 (19.98) | |
Residue | V2O2 + 2C | 20.54 (20.56) | ||
L5 | 1st | 62.3–169.6 | -[C6H5 + N2] | 24.74 (24.71) |
2nd | 160.1–371.9 | -[C6H5Cl + CO + N2] | 39.68 (39.59) | |
3rd | 372.6–666.8 | -[C9H7] | 27.10 (27.19) | |
Residue | 3C | 8.48 (8.51) | ||
[(VO)2 (SO4)2 (L5)]3H2O | 1st | 42.1–266.3 | -[3H2O + C6H5Cl] | 20.70 (20.71) |
2nd | 266.38–482.5 | -[2SO4 + CON2 + C6H5] | 40.41 (40.61) | |
3rd | 482.9–793.5 | -[C8H7N2] | 16.29 (16.36) | |
Residue | V2O2 + 4C | 22.60 (22.32) |
Appling the spectrophotometric titration method, the binding mod of perimidine derivatives towards CT-DNA was investigated. Electronic absorption of freshly prepared solutions was obtained at 25°C over 200–800 nm range, with a reference solution for each concentration. Scanned solutions include fixed ligand concentration (2 × 10−5 M) with a regular increase of DNA added. The effective binding constant for the interaction of the organic derivatives with DNA was obtained based on observable changes in absorption at 418, 420, 420, 385, and 410 nm for LH, LOMe, LNO2, L4, and L5, respectively. A regular increase of DNA amount added to the ligand solution leads to the bathochromic effect for the significant ligand band assigned for transition inside interacting groups. This band is minimized gradually as appeared clearly with the aggregated spectra for each derivative. This minimization is followed by appearance of the slightly shifted peak (1-2 nm) from the free ligand peak, which assigns for the binding complex and suffers a gradual increase in absorbance. This is considered as a sufficient indicator of coupled DNA helix stabilization, after the interaction process. Such an investigation suggests the coupling for binding sites through electrostatic attraction or occluded in major and minor grooves inside DNA. Also, the bathochromic effect can be investigated and explained based on two bases: broad surface area of perimidine molecules and the presence of planar aromatic chromophore, which facilitate well binding towards CT-DNA. This groove binding leads to structural reorganization of CT-DNA. This requires a partial disassembling or deterioration of double helix at the exterior phosphate, which leads to formation of cavity suitable for entering compounds [
Hammett’s relation between the effect of p-substituent (
Applying the Gaussian 09 software, the optimization process was executed over all new compounds till reaching the best configuration. A known standard method was used for this purpose. Essential parameters will be extracted from the energy levels of frontiers (HOMO and LUMO). The energy gap between
(a) Frontier molecular orbitals of HOMO(1)and LUMO(2) pictures of perimidine ligands. (b) Frontier molecular orbitals of HOMO(1) and LUMO(2) pictures of VO(II)-perimidine complexes (A–E, respectively).
Energy parameters (eV) using the DFT/B3LYP method of optimized structures.
Compound |
|
|
( |
|
|
|
|
|
|
ϭ |
---|---|---|---|---|---|---|---|---|---|---|
L1 | −0.17417 | −0.07574 | −0.0984 | 0.09843 | 0.124955 | −0.12496 | 0.049215 | 0.024608 | 0.158628 | 20.31900843 |
L1 + VO(II) | −0.20433 | −0.19545 | −0.0089 | 0.00888 | 0.19989 | −0.19989 | 0.00444 | 0.00222 | 4.499551 | 225.2252252 |
L2 | −0.17142 | −0.07426 | −0.0972 | 0.09716 | 0.12284 | −0.12284 | 0.04858 | 0.02429 | 0.155307 | 20.58460272 |
L2 + VO(II) | −0.20163 | −0.19237 | −0.0093 | 0.00926 | 0.197 | −0.197 | 0.00463 | 0.002315 | 4.191037 | 215.9827214 |
L3 | −0.21252 | −0.05654 | −0.156 | 0.15598 | 0.13453 | −0.13453 | 0.07799 | 0.038995 | 0.11603 | 12.82215669 |
L3 + VO(II) | −0.21881 | −0.21008 | −0.0087 | 0.00873 | 0.214445 | −0.21445 | 0.004365 | 0.002183 | 5.267658 | 229.0950745 |
L4 | −0.25291 | −0.05654 | −0.1964 | 0.19637 | 0.154725 | −0.15473 | 0.098185 | 0.049093 | 0.121912 | 10.18485512 |
L4 + VO(II) | −0.20433 | −0.19545 | −0.0089 | 0.00888 | 0.19989 | −0.19989 | 0.00444 | 0.00222 | 4.499551 | 225.2252252 |
L5 | −0.17808 | −0.0842 | −0.0939 | 0.09388 | 0.13114 | −0.13114 | 0.04694 | 0.02347 | 0.183188 | 21.30379207 |
L5 + VO(II) | −0.19719 | −0.16607 | −0.0311 | 0.03112 | 0.18163 | −0.18163 | 0.01556 | 0.00778 | 1.060073 | 64.26735219 |
Whenever, the extracted data assigning for VO(II) complexes introduce the following observations: (i) frontier energy gaps are completely minimized from original perimidines leading to red shift inside electronic transitions. Such a behavior may clarify the effect of metal atoms (vanadyl) in stabilizing the compounds. This reduction is preferable in biological attitude of compounds [
Hammett’s relation between the effect of p-substituent (
Considerable bond lengths, charges, dipole moment (
Compound | O19 | N11 | N15 | N16 | C18–O19 | C12–N11 | C14–N15 | N15–N16 | V1 | V2 |
|
|
|
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
L1 | −0.415473 | −0.555221 | −0.349927 | −0.275635 | 1.224561 | 1.384229 | 1.287795 | 1.366391 | — | — | 5.1769 | 567.81 | 0.0316 |
L1 + VO(II) | −0.410181 | −0.282766 | −0.316313 | −0.248429 | — | — | — | — | 0.933201 | 0.929331 | 11.5667 | 16513.7 | 0.003 |
L2 | −0.410237 | −0.555363 | −0.348134 | −0.275746 | — | — | — | — | — | — | 6.4963 | 576.26 | 0.0403 |
L2 + VO(II) | −0.420038 | −0.397120 | −0.322648 | −0.250261 | — | — | — | — | 0.927552 | 0.915069 | 3.5504 | 31387.7 | 0.0008 |
L3 | −0.416751 | −0.044378 | −0.050930 | 0.113237 | 1.317259 | 2.076019 | 1.772715 | 1.281712 | — | — | 5.3595 | 7613.39 | 0.002 |
L3 + VO(II) | −0.414856 | −0.387699 | −0.320321 | −0.254947 | 0.955124 | 0.952544 | 16.6899 | 17266.3 | 0.0032 | ||||
L4 | −0.313357 | −0.358945 | −0.031267 | −0.294059 | 1.223609 | 1.404653 | 1.286454 | 1.367672 | — | — | 4.4684 | 315.92 | 0.4055 |
L4 + VO(II) | −0.410181 | −0.282766 | −0.316313 | −0.248429 | — | — | — | — | 0.933201 | 0.929331 | 11.5667 | 16513.7 | 0.003 |
L5 | −0.354631 | −0.480428 | −0.209492 | −0.312115 | 1.224058 | 1.384450 | 1.286411 | 1.367122 | — | — | 3.9661 | 600.17 | 0.043 |
L5 + VO(II) | −0.405024 | −0.408894 | −0.304735 | −0.210573 | — | — | — | — | 0.905245 | 0.730601 | 8.9706 | 20988.6 | 0.002 |
Using the HyperChem (v8.1) program, essential QSAR parameters are calculated and tabulated (Table
QSAR computation for optimized structures of perimidine compounds.
Function | L1 | L2 | L3 | L4 | L5 |
---|---|---|---|---|---|
Surface area (approx.) (Å2) | 425.73 | 488.36 | 496.79 | 464.04 | 465.53 |
Surface area (grid) (Å2) | 623.02 | 661.15 | 661.91 | 644.29 | 642.82 |
Volume (Å3) | 1060.57 | 1138.87 | 1134.04 | 1105.99 | 1105.72 |
Hydration energy (kcal/mol) | −8.29 | −9.97 | −17.83 | −8.00 | −8.02 |
Log P | 2.53 | 1.53 | −1.64 | 2.31 | 2.31 |
Reactivity (Å3) | 132.87 | 139.25 | 138.92 | 137.59 | 137.59 |
Polarizability (Å3) | 45.32 | 47.80 | 47.62 | 47.25 | 47.25 |
Mass (amu) | 390.44 | 420.47 | 436.45 | 424.89 | 424.89 |
Simulation technique is a new revolution process served in different applications. Drug design is a complicated process that needs significant facilities to establish a view about the expected efficiency of proposed drugs. In last decades, the docking computation process between the proposed drug (inhibitor) and the infected cell proteins is the concern in drug industrial research. AutoDockTools 4.2 software was used for this approach. 4c3p, 3bch, and 4zdr are the BDP files for breast, colon, and liver cancer cell proteins which are used for the docking process with five perimidine derivatives. The extracted energies over PDB files (a format using the Gaussian 09 software) are presented in Table
Docking energy values (kcal/mol) of perimidine compounds (HL) and protein receptors complexes.
Ligands | p |
Receptor | Est. free energy of binding | Est. inhibition constant ( |
vdW + bond + desolving energy | Electrostatic energy | Total intercooled energy | Frequency | Interacting surface |
---|---|---|---|---|---|---|---|---|---|
L1 | 10.96 | 4c3p | −7.92 | 1.57 | −9.29 | −0.06 | −9.34 | 30% | 859.778 |
3bch | +355.37 | — | +349.42 | +0.06 | +349.48 | 10% | 665.36 | ||
4zdr | −4.72 | 345.45 | −5.97 | −0.05 | −6.02 | 20% | 723.695 | ||
L2 | 10.96 | 4c3p | −7.75 | 2.09 | −9.13 | −0.13 | −9.26 | 10% | 983.377 |
3bch | +490.76 | — | +473.39 | +0.00 | +473.39 | 10% | 662.71 | ||
4zdr | −4.32 | 686.85 | −5.97 | −0.02 | −5.99 | 20% | 758.018 | ||
L3 | 10.95 | 4c3p | +647.56 | — | +644.74 | +0.01 | +644.75 | 10% | 718.318 |
3bch | +709.10 | — | +699.61 | −0.05 | +699.56 | 10% | 661.43 | ||
4zdr | −4.66 | 385.21 | −6.46 | +0.07 | −6.39 | 10% | 621.389 | ||
L4 | 10.96 | 4c3p | −7.28 | 4.62 | −8.57 | −0.03 | −8.60 | 20% | 929.747 |
3bch | +552.25 | — | +549.59 | −0.03 | +549.56 | 30% | 710.605 | ||
4zdr | −4.67 | 376.04 | −6.13 | −0.19 | −6.32 | 20% | 595.541 | ||
L5 | 10.95 | 4c3p | −8.41 | 683.74 | −9.81 | −0.00 | −9.81 | 20% | 925.161 |
3bch | +663.87 | — | +661.94 | +0.01 | +661.95 | 10% | 703.598 | ||
4zdr | −4.84 | 284.49 | −6.39 | +0.04 | −6.35 | 10% | 690.838 |
Interacting protein-inhibitor complexes (a) L1, (b) L2, (c) L3, (d) L4, and (e) L5 with 4zdr receptor (a–e, respectively).
Interacting complexes hp plot for (a) L1, (b) L2, (c) L3, (d) L4, and (e) L5 with 4zdr receptor (a–e, respectively).
The results obtained by screening all prepared compounds for comparison confirmed that the complexes exhibit more cytotoxicity against HepG2, MCF-7, and HCT116
IC50 of some tested compounds against liver (HepG2), breast (MCF-7), and colon (HCT116) cancer cell lines.
Cell type | IC50 ( | ||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|
L1 | VO(II)-L1 | L2 | VO(II)-L2 | L3 | VO(II)-L3 | L4 | VO(II)-L4 | L5 | VO(II)-L5 | Doxorubicin | |
MCF-7 | 19.68 | 23.06 | 25.92 | 93.92 | 15.50 | >100 | 24.96 | 3.42 | 11.44 | >100 | 0.60 |
HepG2 | 19.79 | 19.94 | 27.23 | 55.67 | 11.01 | >100 | 28.25 | 1.27 | 9.91 | >100 | 0.34 |
HCT116 | 19.15 | 22.93 | 13.27 | 95.17 | 15.53 | >100 | 26.24 | 1.66 | 23.30 | >100 | 0.39 |
Dose response curves of perimidine ligands against MCF-7 (a), HCT116 (b), and HepG2 (c) cancer cells.
This paper presents new VO(II) complexes derived from a series of perimidine ligands. This study focuses on the effect of substituents on the chemistry and applicability of complexes. All the new compounds were well characterized by all possible tools. The complexes were found in a nanoscale comfortably. The different theoretical implementations gave a view about the biological feature of the investigated compounds in a comparative way. The docking process displays the high interaction of organic derivatives against breast cancer, while the experimental investigation displays the priority of the L4-VO(II) complex against all carcinomas tested. The binding efficiency of ligands towards CT-DNA was tested. Binding constant (
The data used to support the findings of this study are available from the corresponding author upon request.
The authors declare that they have no conflicts of interest regarding the publication of this paper.
The authors extend their appreciation to the Deanship of Scientific Research at King Khalid University for funding this work through General Research project under grant number (G.R.P-124-38).
Figure S1: 1H·NMR spectra of L4 and L5 perimidine ligands. Figure S2: mass spectra of L3 and L4 ligands. Figure S3: X-ray patterns of four perimidine ligands. Figure S4: SEM images of perimidine ligands and their VO(II) complexes. Figure S5: interacting protein-inhibitor complexes for L1, L2, L3, L4, and L5 with 4c3p (1) and 3bch (2) receptors (A–E, respectively). Figure S6: interacting hp plot: LH, LOMe, LNO2, LClP, and LClM with 4c3p(1) and 3bch(2) receptors (A–E, respectively). Figure S7: 2D plot forms: L1, L2, L3, L4, and L5 with 4c3p (1), 3bch (2), and 4zdr (3) receptors (A–E, respectively). Figure S8: dose response curves of perimidine-VO(II) complexes against MCF-7, HCT116, and HepG2 cancer cells.