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ORIGINAL ARTICLE
Year : 2016  |  Volume : 12  |  Issue : 1  |  Page : 137-141

Synthesis of sulfadimethoxine based surfactants and their evaluation as antitumor agents


1 Department of Petrochemicals, Egyptian Petroleum Research Institute, Cairo, Egypt
2 Department of Chemistry, Faculty of Science, Al-Azhar University, Cairo, Egypt

Date of Web Publication13-Apr-2016

Correspondence Address:
Manal Mohmed Khowdiary
Helwan, Cairo
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.172109

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 > Abstract 


Aim of the Study: Synthesized CO (II) and Pt (II) of sulfadimethoxine. These compounds were tested for potential antitumor activity against two of human tumor cell lines, colon carcinoma cell line [Hct116], and breast carcinoma cell line MCF7.
Materials and Methods: The structures of the resulting compounds have been investigated by elemental, FT-IR and H 1 NMR analyzes to insure the purity and confirmed the structures of them. The surface properties studies and octanol/water partition coefficients, Po/w were measured.
Results: The synthesized compounds exhibit biological activities with the lowest log Po/w and critical micelle concentration (CMC) values. In addition, in this article we provide an insight into this subject in order to increase the drug bioavailability. Inhibitory activity against colon carcinoma cells was detected for Pt and cobalt ion complex with IC50 = 4.5, 2.2 µg and against breast carcinoma cells IC50 = 18.2, 5.7 µg, respectively.
Summary: The main goal of cancer therapy is to attain the maximum therapeutic damage of tumor cells in combination with a minimum concentration of the drug. This can be achieved in principle via selective antitumor preparations, the cytostatic effects of which would be restricted within tumor tissue. While 100% selectivity may be impractical, the achievement of reasonably high selectivity seems to be a feasible aim. Platinum and cobalt complex surfactants in our research affect tumor tissue at a very low concentration at values lower than their CMC values; this indicate that the sulfadimethoxine complexes merit further investigation as potential antitumor drugs.

Keywords: Antitumor complexes, aromatic diamines, critical micelle concentration


How to cite this article:
Khowdiary MM, Mostafa NS. Synthesis of sulfadimethoxine based surfactants and their evaluation as antitumor agents. J Can Res Ther 2016;12:137-41

How to cite this URL:
Khowdiary MM, Mostafa NS. Synthesis of sulfadimethoxine based surfactants and their evaluation as antitumor agents. J Can Res Ther [serial online] 2016 [cited 2019 Dec 16];12:137-41. Available from: http://www.cancerjournal.net/text.asp?2016/12/1/137/172109




 > Introduction Top


Sulpha drugs are a group of compounds used for eliminating a wide range of infections in human and other animal systems.[1] Many chemotherapeutically important sulfa drugs such as sulfadiazine, sulfathiazole, sulfamerazine, and sulfonamides, possess SO NH moiety which is an important toxophoric function. Most drugs in the pyrimidine series fall into four categories: The barbiturates, the sulfonamides, the antimicrobials, and the antitumor agents. Interestingly, that sulfonamide drugs including pyrimidines such as sulfadimethoxine, sulfametoxydiazine, sulfasomidine, and sulfametomidine. The two groups are complementary rather than competitive, and sulfonamides remain the drugs of choice in well-defined areas such as some acute urinary tract infections,[2] or the numerous patients sensitive to penicillins.[3] Cancer chemotherapy with platinum drugs has been applied since the discovery of cisplatin's anti-proliferative properties.[4] However, in order to reduce the side effects, many efforts that initially focused on the evaluation of platinum-based drugs have shifted to seek other nonplatinum metal-based agents.[5],[6],[7],[8],[9]


 > Materials and Methods Top


Melting points are uncorrected and were determined on a Stuart melting point apparatus (Stuart Scientific, Redhill, UK). Elemental analysis (C, H, N) were performed on Perkin-Elmer 2400 analyzer (Perkin-Elmer, Norwalk, CT, USA) at the microanalytical laboratories of the Faculty of Science, Cairo University. All compounds were within ±0.4% of the theoretical values. The IR spectra (KBr) were measured on Shimadzu IR 110 spectrophotometer (Shimadzu, Koyoto, Japan),1 H-NMR spectra were obtained on a Bruker proton NMR-Avance 300 (300 MHz) (Bruker, Munuch, Germany), in DMSO-d6 as a solvent, using tetramethylsilane as internal standard. Mass spectra were run on HP Model MS-5988 (Hewlett Packard, Palo, Alto, California, USA). For synthesized of 4-amino-N-(2,6-dimethoxypyrimidin-4-yl) benzenesulfon-amide hydroselenite [(C12H14O4N4S) HSeO3] [SDHSeO3] (Ia). Stoichiometric amount of selenius acid (0.01 mol) were mixed with 4-amino-N-(2,6-dimethoxypyrimidin-4-yl) benzenesulfonamide (sulfadimethoxine) (0.01 mol) at room temperature in ethyl alcohol (20 ml) and then stirring until the precipitation is stopped. The white precipitate was filtered and washed with ethyl alcohol, then recrystallized by diethyl ether. And to synthesis of metal (II) hydrogen selenite dehydrate, selenius acid H2 SeO3 is reacted with basic metal carbonate such as Co (II), and Pt (II) carbonate which was prepared by mixing the aqueous solution of equimolar amount of metal chloride and sodium carbonate. The precipitate is washed until the absence of foreign ion. An aqueous solution of 2 g (0.016 mol) H2 SeO3 in 10 ml of water, was added to warm solution freshly prepared metal carbonate (0.08 mol) in 10 ml of water. The obtained solution is filtered and kept at room temperature for crystallization after 2 days. Cobalt (II) hydrogen selenite dehydrates is crystalline prisms of red color and platinum (II) hydrogen selenite dehydrate is crystalline prisms of yellow color. [RNH3]+2M [HSeO3]4 (Ib (Pt ion) Ic (Co ion)) complexes were prepared by using the same general procedure. Refluxing 2 mol of sulfonamide hydrogen selenite with 1 mol of cobalt or platinum hydrogen selenite in ethyl alcohol for 2 h. [Scheme 1] indicates the suggestion structure of the products. Evaluation methods of surface active properties like efficiency (PC20) were determined as the concentration (mol/L) capable of suppressing the surface tension by 20 dyne/cm.[10] The efficiency have been determined by extrapolating from γ =52 to the linear portion before critical micelle concentration (CMC) of the γ versus-log C plot,[11] at 25°C, effectiveness (γ CMC): The surface tension “γCMC” values at CMC were used to calculate the values of surface pressure (effectiveness) from the following expression: (γ CMC= γo–γCMC) where γo is the surface tension measured for the pure water at the appropriate temperature and γCMC is the surface tension at CMC. The effectiveness of adsorption is an important factor to determine such properties of surfactant as foaming, wetting, and emulsification, since tightly packed coherent interfacial films have very different interfacial properties than loosely packed, no coherent films.[12] For determination of CMC of the prepared surfactant, we used surface tension method.[13] In this method, the values of the surface tension obtained for various concentrations of aqueous solutions of the prepared surfactants were plotted versus the corresponding concentrations. Maximum surface excess Γmax the surface excess concentration is defined as the surface concentration at surface saturation; the maximum surface excess Γmax is a useful measure of the effectiveness of adsorption of the surfactant at the water-air interface, since it is the maximum value to which the adsorption can attain. where R = 8.314 J/mol/K, T is absolute temperature, (δγ/δ log C) is the slope of the. γ versus Log c plot at 25C°.[14] A substance which lowers the surface tension is thus present excess at or near the surface, that is, when the surface tension decreases with increasing the activity of the surfactant, Γ is positive. Minimum surface AREA (Amin) is the minimum area per molecule of the prepared compounds at the interface and was calculated from the following equation where N is Avogadro's number, and Γmax is the maximum surface excess. The standard free energies of micellization ΔG°mic and adsorption ΔG°ads, the process of micellization and adsorption are important for explanation of the effects of structural and environmental factors on the value of the CMC and for predicting the effects on it of new structural and environmental variations. Standard free energy of micellization ΔG°mic, and adsorption ΔG°ads have played an important role in such understanding. The standard free energy of micellization and adsorption are given by ΔG°mic = RTln CMC, ΔG°ads= ΔG°mic–6.023 × 10−1 γ CMCAmin. The interfacial activity (Iactiv.) which is expressed by the physicochemical parameter ΔGads/Amin, where ΔGads is the standard free energy of adsorption of the surfactant at the air/solution interface and Amin is the minimum cross-sectional area of the surfactant molecule. Methodology of octanol/water partition coefficients (Po/w) and solubility the volume ratio of octanol and water mixture is adjusted according to the expected value of Po/w (<). The concentration of the solute in the system should be <0.001 mol/L in any single phase. Very pure octanol and water must be used. The system, usually in a separator funnel or similar device, is shaken gently until the equilibrium is achieved. The system is then centrifuged to separate the two phases and break any emulsions. The two phases are then analyzed by an appropriate technique, Uv/v is, to determine solute concentrations. If possible, both phases are analyzed to achieve the mass balance. To evaluate the concentration of solute in two phases, different moles of solute were used in the range of 0.01–0.03 mM, holding constant the value of the wavelength (of that sample), the corresponding absorbance were investigated. The partition coefficient, P, of solute in two phases is described as PO/W= (concentration of solute in octanol phase/concentration of solute in aqueous phase).




 > Results Top


The results of surface parameters for the prepared cationic surfactants such as CMC of the prepared surfactants, Surfactants form aggregates of molecules or ions called micelles, formed when the concentration of the surfactant solute in the bulk of the solution exceeds a limiting value the so called CMC, which is a fundamental characteristic of each solute solvent system. If the properties of a surfactant solution are plotted as a function of the concentration of the surfactant, the properties usually vary linearly with the concentration up to CMC at which point there is a break in the curve as shown in [Figure 1]. The surface properties results included CMC, maximum surface excess (Γmax), minimum surface area (Amin) and Free energy of micellization (γ°mic) and adsorption (γ°ads) were calculated and listed in [Table 1].
Figure 1: Variation of surface tension for surfactants Ia-cagainst concentration

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Table 1: The critical micelle concentration (CMC) and surface parameters of prepared surfactants

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The results of the cytotoxic activity on human tumor cell lines were determined according to the dose values of drug exposure for cell lines to reduce survival to 50% (IC50). The experimental results recorded in [Table 2] and plots of surviving fraction versus concentration in µg in [Figure 2],[Figure 3],[Figure 4],[Figure 5].
Table 2: Cytotoxic activity of the Ia-c compounds on human cell line

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Figure 2: Inhibitory activity against colon carcinoma cells was detected for Pt ion complex with IC50 = 4.5 μg

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Figure 3: Inhibitory activity against colon carcinoma cells was detected for Co ion complex with IC50 = 2.2 μg

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Figure 4: Inhibitory activity against breast carcinoma cells was detected for Pt ion complex with IC50 = 18.2 μg

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Figure 5: Inhibitory activity against breast carcinoma cells was detected for Co ion complex with IC50=5.7 μg

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 > Discussion Top


The results in [Table 1] and [Figure 1] showed that on complexing the cationic surfactants with copper, tin or cobalt ions, high depression was observed in CMC values. That fact could be explained from the unique property of the metal complexes in water. That is the complexes retain its unity in their solutions, which increased their volume in the aqueous media and then repulsion occurs between the hydrophobic chain and water molecules. Effectiveness “γ CMC,” the most efficient one is that gives the greatest lowering of surface tension for a CMC. (Ic) Co complex were found to be the most efficient one [Table 1], because it achieved the maximum reduction of the surface tension at CMC [Figure 1]. Values of the efficiency “PC20” of the prepared surfactants are shown in [Table 1], the efficiency increase from parent to Pt to Co complex, this may be due to the entering of Co and Pt ion to the hydrophilic part of the amphiphile can increase the aggregation and adsorption ability of molecules at the interface. Maximum surface excess Γmax values, it is evident from [Table 1] increasing of (Γmax) for parent than Pt or Co complex molecules this due to in case of cobalt and platinium complex molecules From [Table 1] tended to adsorbed at the interface of hydrophobic part of the complex then form the micelles directly at low concentration. Minimum area per molecule Amin results given in [Table 1] indicate that the consequence decrease of Γmax occurred at the interface which logically accompanied with increasing in Amin values from Ia to Ic. The standard free energies of micellization γ°mic and energy of adsorption γ°ads results from [Table 1], values of γ°mic and γ°ads are always negative. But there is more increase in the negativity of ΔG°ads rather than those of micellization indicating the tendency of the molecules to be adsorbed at the interface. From [Table 1], the interfacial activity (Iactiv) of cobalt complex is the highest negative value, this actually normal result and expected from all previous surface parameters, that due to the cobalt complex has the highest surface activity of all tested compounds. Octanol/Water partition coefficients (Po/w) for prepared compounds, the partition coefficient, can provide an empiric handle in screening for some biological properties. For drug delivery, the lipophilic/hydrophilic balance has been shown to be a contributing factor for the rate and extent of drug absorption. Since biological membranes are lipoidal in nature, the rate of drug transfer for passively absorbed drugs is directly related to the lipophilicity of the molecule. The partition coefficient is commonly determined using an oil phase of octanol or chloroform and water. Drugs having value of Po/w much <1 are classified as lipophilic, whereas those with partition coefficients much <1 are indicative of a hydrophilic drug, the compounds of present study all their partition coefficient values negative values (−2.7, −3.7, −3,8) this means that they classified as hydrophilic drug. Although it appears that the partition coefficient may be the best predictor of absorption rate, the effect of dissolution rate, pKa, and solubility on absorption must not be neglected. Partition coefficient (oil/water) is a measure of a drug's lipophilicity and an indication of its ability to cross cell membranes. It is defined as the ratio of un-ionized drug distributed between the organic and aqueous Phases at equilibrium.

From the results of antitumor activity recorded in [Table 2] and [Figure 2],[Figure 3],[Figure 4],[Figure 5], the compounds tested exhibited high activity in vitro system on the tumor cell line investigated, IC have the highest cytotoxic effect on Hct116, the dose of it at which the survival reduction to 50% is (IC50=2.2 µg/ml)), as shown in [Figure 2], also Ib show good cytotoxic activity on Hct116(IC50=4.5 µg/ml), as shown in [Figure 3]. IC have the highest cytotoxic effect on MCF7, the dose of it at which the survival reduction to 50% is (IC50=5.7 µg/ml), as shown in [Figure 4], also Ib show good cytotoxic activity on Hct116(IC50=18.2 µg/ml), as shown in [Figure 5]. Ib exhibit good interaction by cell membrane due to its surface activity. The mechanisms, which could be suggested, interference with enzyme balance within the tumor, interference with the osmotic balance or increased cell membrane permeability. The antitumor potency of these cationic platinum based surfactants might be related to the increased charge density around the nitrogen atoms that might possibly disturb the osmotic balance between the tumor cells and the medium. Ic show cytotoxic activity against the colon tumor cell line under low concentration reduces the survival to 50%, this comes from the fact that cobalt complexes have the capacity to reduce the energy status in tumors as well as enhance the tumor hypoxia which also influences their antitumor activities. It may be also concluded that the level of cellular damage inflicted by these complexes depends on the nature of their axial ligands. There is an evidence that cobalt complexes cause significant changes in metabolism namely activation of lipid peroxidation, DNA damage, and reduction of the bioenergetic status tumor tissues. In general, high selectivity of action by redox - active cobalt complexes upon tumors is due to their specific reactivity. Finally, platinum and cobalt complex surfactants in our research affect the tumor tissue at very low concentration at values lower than their CMC values, which mean that there is a strong relation between very small values of CMC of these compounds and the reaching to IC50 values under very low concentration, that by increasing concentration of cationic surfactant causes increase the adsorption process on cell membrane until reaching the CMC, after this concentration the adsorption retarded slowly then stopped due to form micelles which prevent the mobility and suppress antitumor activity.



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 > References Top

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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
 
 
    Tables

  [Table 1], [Table 2]



 

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