From our DFT calculations of Ibuprofen drug (IBF) and other related molecules such as 2-Phenylpropanoic acid (2-PPA) and 3-Phenylpropanoic acid (3-PPA), it has been found that the ionization potential energies of their anions are decreased strongly, with respect to their values in the molecular forms, rendering them as spontaneous electron donor which can compensate the electron deficiency for the positive cancer cells. Time dependent calculations show good coincidence with the experimental absorption spectra. Some complexes of IBF are prepared with Cu ++ and Zn ++ ions. The ratio between the M ++ and the ligand (IBF) is 1:2 which has been verified by atomic absorption spectra and elemental analyses. Their spectral studies have been performed in different solvents of different polarities. The metabolite products of IBF have been studied from DFT calculations point of view and it has been concluded that the consistency of the ionization constants and the electron affinities of them with those of the nucleic acid bases prevents the electron transfer between them therefore they are safe for the human body from cancer diseases.
Cancer is a leading cause of death in both more and less economically developed countries due to tobacco use, obesity, physical inactivity, and infections [
All melting points of the studied compounds have been determined on a Gallen-Kamp melting point apparatus.
The elemental analyses (C, H, N) were determined using Elementer Analyses system (GmbH, Donaustr-7, D-63452) Hanau, (Germany).
The electronic absorption spectra of the studied compounds had been scanned by uv-2011 PC, uv-vis scanning spectrophotometer (Shimadzu) using 1 cm matched silica cells.
The atomic absorption spectra of the complexes were studied by using an atomic absorption spectrophotometer (Buck Scientific Model 210 GVP).
All materials supplied to our experimental work were bought from the different companies without further purification. Ibuprofen (IBF) was bought from Sigma Aldrich and 2-Phenylpropanoic acid (2-PPA) was bought from Alfa Aesar as well as 3-Phenylpropanoic acid (3-PPA).
Ibuprofen (2.06 g, 0.01 moles) was allowed to be dissolved in a solution of potassium bicarbonate (1.10 g, 0.011 mole) in 80 ml of water. During stirring the solution, CuSO4・5H2O was added slowly (1.25 g, 0.005 mole) in 10 ml of water. The mixture was allowed to be stirred for 30 minutes. The aquamarine precipitated and was collected, washed with water followed by ethanol, and then recrystallized from ether. The product was air-dried, [
2.0 Mmoles (0.412 g) of ibuprofen react with 2.0 mmoles (0.112 g) of KOH dissolved in 20 mL of distilled water, to give the potassium salt of the ligand. Then 1.0 mmole (0.2195 g) of Zn(CH3COO)2・2H2O (aqueous solution) was added during stirring. The white needle precipitated and collected by filtration, washed several times with distilled water and acetone, then dried in vacuum, [
From elemental analysis,
The absolute intensity of band absorption can be calculated and it has been shown that Einstein transition probabilities coefficients, [
Compound | Melting point range ˚C |
---|---|
IBF | 74 - 76 |
3-PPA | 44 - 48 |
Cu(IBF)2 | 250 - 252 |
Zn(IBF)2・2H2O | 78 - 82 |
Compound | % Theoretical | % Experimental | ||
---|---|---|---|---|
C | H | C | H | |
Cu(IBF)2 | 65.87 | 7.23 | 63.74 | 6.55 |
Zn(IBF)2・2H2O | 60.10 | 7.48 | 60.40 | 7.44 |
Compound | % Theoretical | % Experimental |
---|---|---|
M+2 | M+2 | |
Cu(IBF)2 | 13.40 | 12.95 |
Zn(IBF)2・2H2O | 12.77 | 12.1 |
ground state I, and the excited state f, are given as follows:
where:
e = The charge of the electron
h = Planck’s constant
C = The velocity of light, 3 ´ 1010 cm・sec−1
Gf = Degeneracy of the state
Dif = Dipole strength
Substituting the numerical values and assuming that degeneracy of the state is singlet, then:
Mulliken related the quantity Bif to the Oscillator strength, F, which is the measure of the intensity.
Also the Oscillator strength can be related to the absolute intensity as follows:
where: m = The mass of electron
N = The Avogadro’s number
e = Molar extinction coefficient
if a molecule or an atom is in an excited state then, in the absence of an external electromagnetic field, on the average, after a time of
excited state to the ground state, it will emit a photon.
where
Computational studies on the isolated molecules in the gas phase were performed by the aid of GAUSSIAN 03 package. Minimum energy structures have been achieved using semi-empirical AM1 method. DFT/6-31**G calculations were performed on the minimum energy structures using the closed shell Hartree-Fock, Becke’s three parameters density functional theory, DFT, [
With respect to DFT calculations, it has been carried out as B3LYP/6-31**G and the energy of the DFT theory can be represented as a function of the electron density as follows:
where
where Ci is the eigenvectors for each eigenfunction Ψi and
where
Ibuprofen, 2 (4-isobutylphenylpropanoic acid (IBF), is a non-steroidal anti-inflammatory drug (NSAID) which can be used for relieving pain, antipyretic and anti-inflammatory. About 60% of patients improve with any given NSAID and it is advised that if one does not work that another can be used. Ibuprofen may be considered as weak anti-inflammatory than other NSAIDs. IBF molecule has two conformers R and S as shown in the following
are mirror images of each other. These mirror images are non-super-imposable, which are mirror images but not identical. This mirror image property occurs in molecules that have asymmetric carbon atom. The two optical isomers of ibuprofen are identified by the prefixes R− (Levo Rotatory) and S+ (Dextro Rotatory). DFT calculations have been performed according to El-Shahawy, [
From the previous
From the previous
Regarding the HOMO of IBF molecule even in the R and S-forms, it is ψm in each singlet configuration eigenfunctions of the excited states. From the previous
From the previous
Form of IBF | TE au | ΔE | IP eV | Ea | Dip. Mom. D |
---|---|---|---|---|---|
S-IBF | −656.5408 | 0.0010397 au | 6.6837 | 0.8879 | 2.2182 |
R-IBF | −656.5419 | 0.0282917 eV | 6.6766 | 0.9048 | 1.4383 |
Compound | TE au | Ip eV | Ea eV | Dip. Mom. D |
---|---|---|---|---|
S-IBF | −656.5408 | 6.6837 | 0.8879 | 2.2182 |
R-IBF | −656.5419 | 6.6766 | 0.9048 | 1.4383 |
2-PPA | −499.3220 | 7.0146 | 0.9633 | 1.9947 |
3-PPA | −499.3209 | 6.8812 | 0.8768 | 1.8931 |
Cu(IBF)2 | −2952.01917046 | 6.53509 | 1.38397 | 1.6296 |
Zn(IBF)2 | −3090.86733452 | 6.494817 | 2.479230 | 1.4591 |
N.B. 2-PA is 2-phenyl propanioc acid and 3-PA is 3-phenyl propanioc acid. Ip is the ionization potential, Ea is the electron affinity and Dip. Mom. Is dipole moment.
Excited State Singlet-A | Eigenvectors | Transition | ΔE eV | λcalc. nm | f | λexp. nm |
---|---|---|---|---|---|---|
Excited State 1 | ||||||
54 → 57 56 → 57 56 → 59 56 → 60 | −0.22953 0.60334 0.11187 0.10821 | ψm−2 → ψm+1 ψm → ψm+1 ψm→ ψm+3 ψm→ ψm+4 | 5.0675 | 245 nm | 0.0843 | 263 nm |
Excited State 2 | ||||||
54 → 57 55 → 57 55 → 60 55 → 61 56 → 58 56 → 59 | −0.14064 −0.45550 0.10498 −0.10824 0.47239 0.10670 | ψm−2 → ψm+1 ψm−1 → ψm+1 ψm−1 → ψm+4 ψm−1 → ψm+5 ψm → ψm+2 ψm→ ψm+3 | 5.1952 | 238.65 nm | 0.0016 | 231 nm |
Excited State 3 | ||||||
54 → 57 54 → 59 54 → 60 56 → 57 56 → 58 | 0.56731 0.15448 0.13998 0.26587 0.12041 | ψm−2 → ψm+1 ψm−2 → ψm+3 ψm−2 → ψm+4 ψm → ψm+1 ψm → ψm+2 | 5.3933 | 229.89 | 0.0177 |
Excited State Singlet-A | Eigenvectors | Transition | ΔE eV | λcalc. nm | F | λexp. nm |
---|---|---|---|---|---|---|
Excited State 1 | ||||||
54 → 57 54 → 61 56 → 57 56 → 58 56 → 61 | 0.29826 −0.11518 0.55621 −0.17879 −0.11978 | ψm−2 → ψm+1 ψm−2 → ψm+5 ψm → ψm+1 ψm → ψm+2 ψm → ψm+5 | 4.9819 | 245 nm | 0.0658 | 263 nm |
Excited State 2 | ||||||
54 → 57 55 → 57 55 → 58 55 → 61 56 → 58 56 → 59 56 → 61 | 0.12731 0.42453 0.10408 0.15894 0.41711 −0.25061 −0.14454 | ψm−2 → ψm+1 ψm−1 → ψm+1 ψm−1 → ψm+2 ψm−1 → ψm+5 ψm → ψm+5 ψm → ψm+3 ψm → ψm+5 | 5.2043 | 238.24 | 0.0104 | 231 nm |
Excited State 3 | ||||||
54 → 57 54 → 58 54 → 61 56 → 57 | 0.52994 −0.12594 −0.17235 −0.34971 | ψm−2 → ψm+1 ψm−2 → ψm+2 ψm−2 → ψm+5 ψm → ψm+1 | 5.4852 | 226.03 | 0.0497 |
Solvent | maxλ | Aif 10−7 S−1 | Bif 10−7 S・g−1 | Dif 1018 | fif 102 | εmax | τ ns |
---|---|---|---|---|---|---|---|
Ethanol | 230.05 | 2.45 | 3.00 | 4.14 | 1.95 | 830.78 | 40.82 |
263.51 | 0.455 | 1.67 | 1.15 | 0.476 | 254.41 | 219.78 | |
Methanol | 230.89 | 2.13 | 5.28 | 3.64 | 1.71 | 827.39 | 46.95 |
263.68 | 0.457 | 1.68 | 1.16 | 0.478 | 264.90 | 218.82 | |
Isopropanol | 230.76 | 2.29 | 5.66 | 3.90 | 1.84 | 855.45 | 43.67 |
263.68 | 0.479 | 1.76 | 1.22 | 0.501 | 273.23 | 208.77 | |
Cyclohexane | 231.60 | 2.00 | 4.99 | 3.44 | 1.61 | 822.45 | 50.00 |
263.42 | 0.490 | 1.80 | 1.24 | 0.512 | 277.23 | 204.08 | |
Chloroform | 264.20 | 0.523 | 1.94 | 1.34 | 0.549 | 299.51 | 191.21 |
[
The ultraviolet spectra of 2-Phenylpropanoic acid
The first calculated electronic transition from the ground state to the first singlet state lies at 236 nm which is not far from the experimental maximum wavelength at 259 nm,
Solvent | λmax nm | Aif × 10−7 S−1 | Bif × 10−7 S・g−1 | Dif × 1018 | Ff × 102 | εmax (mole・L−1・cm−1) | τ ns |
---|---|---|---|---|---|---|---|
Ethanol | 228.23 | 2.16 | 5.16 | 3.56 | 1.69 | 728.83 | 46.37 |
256.93 | 0.354 | 1.21 | 0.834 | 0.352 | 181.25 | 282.46 | |
Methanol | 227.71 | 1.70 | 4.03 | 2.78 | 1.32 | 675.83 | 58.97 |
256.93 | 0.316 | 1.08 | 0.744 | 0.31.4 | 161.75 | 316.46 | |
Isopropanol | 228.55 | 1.71 | 4.11 | 2.84 | 1.35 | 728.01 | 58.39 |
256.98 | 0.316 | 1.08 | 0.442 | 0.314 | 167.77 | 316.46 | |
Cyclohexane | 229.40 | 1.42 | 3.46 | 2.38 | 1.13 | 682.04 | 70.24 |
256.76 | 0.354 | 1.21 | 0.832 | 0.352 | 183.75 | 282.46 | |
Bidistilled water | 227.71 | 1.95 | 4.63 | 3.19 | 1.52 | 708.69 | 51.24 |
257.24 | 0.363 | 1.24 | 0.856 | 0.361 | 201.10 | 275.48 | |
Mineral water | 227.19 | 1.93 | 4.56 | 3.15 | 1.50 | 714.14 | 51.69 |
257.11 | 0.37 3 | 1.27 | 0.879 | 0.0371 | 198.51 | 268.10 | |
Chloroform | 258.23 | 0.397 | 1.37 | 94.7 | 0.0398 | 186.17 | 251.89 |
Excited State Singlet-A | Eigenvectors | Transition | ΔE eV | λcalc. nm | F | λexp. nm |
---|---|---|---|---|---|---|
Excited State 1 | ||||||
38 → 41 38 → 44 40 → 41 40 → 42 40 → 44 | 0.38938 0.15307 0.49968 0.12154 0.13478 | ψm−2 → ψm+1 ψm−2 → ψm+4 ψm → ψm+1 ψm → ψm+2 ψm → ψm+4 | 5.0799 | 244 | 0.0310 | 257 |
Excited State 2 | ||||||
38 → 41 39 → 41 39 → 42 39 → 44 40 → 42 40 → 43 40 → 44 | 0.14958 0.49872 −0.12444 −0.13935 −0.35902 −0.23889 0.10196 | ψm−2 → ψm+1 ψm−1 → ψm+1 ψm−1 → ψm+2 ψm−1 → ψm+4 ψm → ψm+2 ψm → ψm+3 ψm → ψm+4 | 5.3127 | 233 | 0.0010 | 228 |
Excited State 3 | ||||||
38 → 41 38 → 44 39 → 41 40 → 41 | 0.46682 0.15992 −0.15381 −0.41663 | ψm−2 → ψm+1 ψm−2 → ψm+4 ψm−1 → ψm+1 ψm → ψm+1 | 5.6450 | 220 | 0.0391 |
Solvent | λmax nm | Aif × 10−5 S−1 | Bif × 10−6 S・g−1 | Dif × 1020 | F × 104 | εmax (mole・L−1・cm−1) | Τ ns |
---|---|---|---|---|---|---|---|
Ethanol | 215.66 | 10.7 | 2.17 | 14.9 | 4.52 | 45.18 | 930.65 |
259.03 | 2.82 | 0.985 | 6.79 | 2.85 | 17.43 | 3549.21 | |
Methanol | 215.66 | 13.5 | 2.72 | 18.8 | 9.45 | 43.92 | 740.85 |
259.05 | 2.93 | 1.02 | 7.06 | 2.96 | 17.72 | 3414.77 | |
Isopropanol | 215.10 | 12.9 | 2.58 | 17.8 | 8.98 | 45.14 | 775.76 |
258.90 | 2.67 | 0.933 | 6.44 | 2.70 | 15.87 | 3739.84 | |
Cyclohexane | 219.94 | 35.5 | 0.760 | 5.24 | 2.59 | 25.37 | 2814.22 |
259.25 | 2.23 | 0.781 | 5.39 | 2.26 | 13.92 | 4486.45 | |
Bidistilled water | 258.25 | 3.42 | 1.19 | 8.17 | 3.44 | 19.97 | 2922.26 |
Mineral water | 258.47 | 2.86 | 0.994 | 6.85 | 2.88 | 17.99 | 3493.48 |
Chloroform | 260.09 | 3.24 | 1.15 | 7.91 | 3.30 | 20.06 | 3086.17 |
The blue or green colors (aquamarine) of the copper complexes as in the Cu(ligand)2 complex are due to the of absorption band in the region 600 - 900 nm in the spectra. For Cu(IBF)2 complex spectra,
From
From the minimum energy structure of Zn-complex,
Excited State Singlet-A | Eigenvectors | Transition | ΔE eV | λcalc. nm | F | λexp. nm |
---|---|---|---|---|---|---|
Excited State 1 | ||||||
38 → 41 38 → 42 38 → 44 | 0.65683 −0.16373 −0.10939 | ψm−2 → ψm+1 ψm−2 → ψm+2 ψm−2 → ψm+4 | 5.2628 | 236 | 0.0001 | 259 |
Excited State 2 | ||||||
39 → 41 39 → 42 39 → 44 40 → 41 40 → 44 | −0.15524 −0.31449 0.16121 0.50780 0.30508 | ψm−1 → ψm+1 ψm−1 → ψm+2 ψm−1 → ψm+4 ψm → ψm+1 ψm → ψm+4 | 5.3097 | 234 | 0.0107 | 215 |
Excited State 3 | ||||||
39 → 41 39 → 42 40 → 41 40 → 42 40 → 44 | 0.13112 0.24926 0.46741 −0.24198 −0.37012 | ψm−1 → ψm+1 ψm−1 → ψm+2 ψm → ψm+1 ψm → ψm+2 ψm → ψm+4 | 5.5265 | 224 | 0.0044 |
Solvent | λmax nm | Aif × 10−6 S−1 | Bif × 10−8 S・g−1 | Dif × 1018 | fif × 103 | εmax (mole・L−1・cm−1) | τ ns |
---|---|---|---|---|---|---|---|
Ethanol | 285.98 | 157 | 7.37 | 50.8 | 193 | 2414.24 | 6.37 |
694.42 | 0.486 | 0.328 | 2.26 | 3.53 | 206.27 | 2057.61 | |
Methanol | 275.02 | 107 | 4.48 | 30.9 | 122 | 2527.24 | 9.35 |
693.64 | 0.384 | 0.258 | 1.78 | 2.78 | 154.24 | 2604.17 | |
Isopropanol | 291.04 | 142 | 7.04 | 48.6 | 181 | 2265.86 | 7.04 |
699.87 | 0.556 | 0.383 | 2.64 | 4.10 | 238.56 | 1798.56 | |
Chloroform | 275.58 | 88.7 | 3.73 | 25.8 | 101 | 2305.71 | 11.27 |
695.78 | 0.515 | 0.349 | 2.41 | 3.76 | 214.75 | 1941.75 | |
Cyclohexane | 272.74 | 127 | 5.19 | 35.8 | 143 | 2187.01 | 7.87 |
703.37 | 0.376 | 0.263 | 1.81 | 2.80 | 169.81 | 2659.57 |
Solvent | λmax nm | Aif × 10−7 S−1 | Bif × 10−7 S・g−1 | Dif × 1018 | Ff × 103 | εmax (mole・L−1・cm−1) | τ ns |
---|---|---|---|---|---|---|---|
Ethanol | 227.67 | 2.17 | 5.16 | 3.56 | 0.170 | 2325.29 | 46.08 |
263.60 | 0.528 | 1.95 | 1.34 | 5.53 | 281.74 | 189.39 | |
Methanol | 227.99 | 2.95 | 7.03 | 4.85 | 0.231 | 2372.86 | 33.90 |
263.90 | 0.542 | 2.00 | 1.38 | 5.68 | 313.70 | 184.50 | |
Isopropanol | 230.07 | 2.17 | 5.32 | 3.67 | 0.173 | 1592.12 | 46.08 |
263.21 | 0.509 | 1.87 | 1.29 | 5.31 | 288.61 | 196.46 | |
Chloroform | 262.82 | 0.522 | 1.91 | 1.32 | 5.43 | 311.87 | 191.57 |
Cyclohexane | 228.94 | 4.95 | 11.9 | 8.23 | 0.390 | 2505.71 | 20.20 |
262.95 | 0.911 | 3.33 | 2.30 | 9.49 | 421.21 | 109.77 | |
Bidistilled water | 229.20 | 5.44 | 13.2 | 9.08 | 0.430 | 2547.47 | 18.38 |
262.64 | 0.587 | 2.16 | 1.49 | 6.14 | 352.47 | 170.36 |
To deepen the denotation of cancer, it is mutual electron transfer between the nucleic acid bases and electron donor or electron acceptor, i.e. free radicals, drugs even some food like grills and fries. Losing an electron from the nucleic acid bases inside the nucleus produces carcinogenic cell in which the nucleus acts as electron donor to any electron acceptor such as in case of Paracetamol metabolite in the liver, NABQI,
After administration of Ibuprofen drug, it passes via human stomach of pH ~ 2 and in full stomach of pH ~ 4 - 5 saving the molecular form of the drug AH. After the drug arrival to gastrointestine of pH ~8 - 9, therefore the anionic form A− of Ibuprofen drug exists side by side with the molecular form AH in intestine. The ionization constant of Ibuprofen dsrug pKa = s4.85, using the relation:
Therefore the ratio between anions A− and molecules AH being equal to 1 approximately. The pH value of human blood equals to 7.4 and its pKa = 5.2, hence the ratio between anions A− and molecules AH is still nearly equal to 1. Therefore Ibuprofen drug exists in the intestine and in the blood as the anionic form A− and the molecular form AH. The existence of free molecule of the drug AH together with the anion A− in the intestine establishes equilibrium between them. This mixture is spontaneous electron donor to the carcinogenic cells rendering them being in normal state.
The ionization energy, Ip, of Ibuprofen drug molecule by DFT method in the stomach being equal to, 6.6804 eV, and decreases when the drug arrives to the small intestine at which the pH value lies between 8 - 9 and the value of the ionization potential decreases to 0.9015 eV, table. Therefore the Ibuprofen drug behaves as spontaneous electron donor in the small intestine. In the same way, the electron affinity of Ibuprofen drug molecule in the stomach is equal to 0.81634 eV, table, which decreases in the small intestine to be −1.4392 eV. This means that Ibuprofen drug anion hasn’t the ability to receive an electron from the IBF molecules. Spontaneous electron donor to nucleic acid bases must fulfill the following condition:
where Ip is the ionization potential energy of the anion and Ea(NAB) is the electron affinity of nucleic acid bases.
From comparison point of view with respect to the nucleic acid bases it has been found the following values of the electronic total energy, ionization energy and electron affinity in the following
From
Since Ibuprofen in the small intestine has very low ionization energy, 0.9015 eV and the electron affinity values of nucleic acid bases are higher than that of IBF anion; therefore IBF anions in the presence of IBF molecules can act as spontaneous electron donor to compensate the electron deficiency of the carcinogenic cells in the intestine. The presence of the mixture of A− and AH in the blood gives the chance to inhibit different types of cancers such as protostate, lung and breast cancers [
From the previous
The metabolic activation may be via chiral inversion not only leads to higher therapeutic potency; from another hand it may also cause a great risk of acute kidney failure in patients with renal disorder. The side effect of Ibuprofen includes gastrointestinal disturbance and central nervous system (CNS) depression. All of these adverse effects are found to be mild, [
Compound | TE au | Ip eV | Ea eV |
---|---|---|---|
Adenine | −467.17488 | 6.4061 | +1.2672 |
Guanine | −542.37704 | 6.1879 | +1.2828 |
Cytosine | −394.82291 | 6.5819 | +1.4768 |
Uracil | −414.70313 | 7.3316 | +1.8626 |
S-Ibuprofen in the Stomach | −656.5408 | 6.6837 | +0.8879 |
S-Ibuprofen in the small intestine | −655.9788 | 0.9015 | −1.4392 |
TE is the total energy, Ip is the ionization energy, Ea is the electron affinity.
Anion | TE au | Ip eV | Ea eV | Dip. Mom. D |
---|---|---|---|---|
IBF | −655.9788 | 0.9015 | −1.4392 | 17.4635 |
2-PPA | −498.7676 | 0.8966 | −2.0580 | 10.6771 |
3-PPA | −498.7635 | 0.6289 | −1.7385 | 15.5631 |
Compound | TE | Ip | Ea | ||
---|---|---|---|---|---|
S-IBF | −656.54088 | 6.6804 | 0.8163 | ||
1HIBF | −731.73070 | 6.8831 | 1.0591 | ||
2HIBF | −731.73523 | 6.5980 | 0.8376 | ||
3HIBF | −731.72320 | 6.8916 | 1.0803 | ||
CIBF | −805.74479 | 6.8097 | 1.0071 | ||
CPPA | −687.83361 | 7.5253 | 2.0444 | ||
From comparative point of view, the Ip’s and Ea’s of the metabolite products of IBF,
From the different values of Ip’s of nucleic acid bases,
prevents the electron transfer between them [
1) It is good for the health to take Ibuprofen drug regularly to avoid cancers of gastrointestine, protostate, breast and lung.
2) 2PPA and 3-PPA are better as anticancer than Ibuprofen drug.
3) Ibuprofen metal ion complexes are not anti-cancers like anions of IBF, 2-PPA and 3-PPa.
Anwar El- Shahawy,Hana Gashlan,Safaa Qusti,Ghada Ezzat,Hossam Emara, (2016) DFT-Quantum Spectroscopic Studies and Anti-Cancer Effect of Ibuprofen Drug and Some Analogues. Computational Chemistry,04,33-50. doi: 10.4236/cc.2016.42004