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Synthesis of orotic acid derivatives and their effects on stem cell proliferation

  • Saeed Ali Syed , Amer Mahmood , Musaad Alfayez , Eric C. Hosten , Richard Betz , Abdulrahman M. Al-Obaid , Abdulrahman Ghadeer and Ahmed Bari EMAIL logo
Published/Copyright: June 20, 2020
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Open Chemistry
From the journal Open Chemistry Volume 18 Issue 1

Abstract

Orotic acid, a natural product, is involved in many biological processes. Human mesenchymal stem cells (hMSCs) have the potential of self-renewable and proliferation. They are commonly isolated from the bone marrow aspirates of large bones. The osteogenic potential of these stem cells has been extensively exploited by scientists in the past to evaluate the performance of synthetic scaffolds developed for tissue engineering. In this study, N-arylhydrazone derivatives of orotic acid have been synthesized, and their potential as stimulators of human mesenchymal stem cells has been evaluated. Some of the analogs exhibit well to moderate effect on the proliferation rate.

Graphical abstract

Orotic acid esters and several N-arylhydrazones derivatives were synthesized and evaluated for their stem cell proliferation potential with human stromal stem cells (hMSCs) which was never studied before. Some of the derivatives exhibit convincing upregulation of proliferation which is believed to be due to substitution on the aromatic ring.

Keywords: orotic hydrazide; arylhydrazone; mesenchymal stem cells; proliferation

1 Introduction

Heterocycles and heterocyclic derivatives continue to serve as versatile compounds for the synthesis of various natural products owing to the presence of various chromophores in them [1,2,3,4,5]. Pyrimidine carboxylic acid, commonly known as orotic acid, is found in many naturally occurring products such as milk whey and serves as an intermediate in the biosynthesis of pyrimidine, which is an essential component of DNA and RNA. Moreover, orotic acid can enhance the cardiac output and aid in the recovery from heart failure. It can also behave as a growth stimulant in mammals and may assist in the absorption of calcium, magnesium, and other essential nutrients. Orotic acid has also been reported to reduce bilirubin levels in infants and is also useful for the treatment of gout. Many orotic acid analogs exhibit remarkable antitumor and antimicrobial activities. Some of them also serve as enzyme inhibitors, thereby attracting the attention of chemists and molecular biologists [6,7,8,9].

Hydrazones constitute an important class of compounds in organic syntheses owing to the presence of the azomethine group in this molecule. Hydrazones and hydrazides are one of the most useful synthetic intermediates for the synthesis of various molecules and possible drug candidates [10]. Owing to their synthetic importance and their inherent biological activity, hydrazone derivatives have been the focus of interest for many synthetic chemists and biologists for many years. Their pharmacological profiles include antimicrobial, antiviral, anticancer, and antiinflammatory activities. The bioactivities of the hydrazide–hydrazone analogs are not only limited to the core moiety but are also dependent on the substituents on the terminal nitrogen atom. It has been long known that the introduction of aromatic substituents to the heterocyclic system results in more biologically potent molecules [11,12,13].

Human stromal (mesenchymal) stem cells (hMSCs) are multipotent stem cells that are capable of transforming into mesoderm-type cells such as osteoblasts and adipocytes. Hence, they are being introduced into clinical trials for tissue regeneration. Certain heterocyclic compounds have an immense potential to enhance stem cell proliferation, thereby allowing them to differentiate into other mature cell types. Thus, such compounds can assist in the stem cell therapy to aid in medical procedures such as heart and bone marrow transplants. Heterocyclic compounds have been designed and synthesized on a number of molecular platforms including substituted purines pyrimidines, quinazolines, pyrazines, pyrrolopyrimidine, pyrazolopyrimidine, pyridazines, and hydrazones, which lend an appropriate chemical concern to look into modulate complex cellular mechanism [14,15,16,17,18]. However, to the best of our knowledge, the effect of pyrimidine carboxylic acid on such processes has not yet been investigated.

In continuation to our interest in the hydrazone–hydrazide chemistry, herein, the preparation of N-arylhydrazone derivatives of the orotic acid and their potential in the hMSC proliferation have been described.

2 Materials and methods

2.1 Chemicals and instruments

All solvents and reagents were purchased from Aldrich Chemical Co. and were used as received. IR spectra were recorded on a PerkinElmer spectrum BX FT-IR spectrometer using KBr pellets. 1H and 13C NMR spectra were recorded on a Bruker instrument (500 and 125 MHz, respectively) in DMSO-d6. Mass spectra were obtained on a JEOL JMS-700 mass spectrometer, and the ionization method was electron ionization (70 eV). Melting points were measured with a Thermo Scientific 9100 apparatus and are uncorrected. Thin-layer chromatography (TLC) was performed with fluorescent silica gel HF254 plates (Merck) and visualized under UV 254 UV spectrometer on charring with the EtOH–H2SO4 (5:1) system. Merck silica gel 60 (230–400 mesh) was used for column chromatography.

2.1.1 General procedure for the synthesis of compounds 2 and 3

The synthesis was conducted according to the protocol given by Britikova [19]. Briefly, to a solution of 2 mmol orotic acid (1) in ethanol/butanol (50 mL), a catalytic amount of HCl was added. The resulting mixture was refluxed for 10 h with stirring, followed by in vacuo evaporation of the solvent. The solid obtained was washed several times with cold water; recrystallization in ethanol–water mixture and purification by column chromatography (10% ethylacetate–hexane) afforded compounds 2 and 3.

2.1.2 Structure identification of ethyl 2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxylate (3)

Yield: 71%, m.p.: 176. Brown crystals, IR (KBr) (v, cm–1): 1,715, 1,730 (C═O), 2,990 (NH), 3,335 (OH). 1H NMR (500.133 MHz, DMSO-d6): δ = 1.30 (t, 3H, CH3), 4.31 (m, 2H, CH2), 6.05 (s, 1H, CH), 11.14 (br s, 1H, NH), 11.39 (br s, 1H, NH). 13C NMR (125.76 MHz, DMSO-d6): δ = 15.21, 62.2, 103.50, 142.09, 151.20, 163.05, 164.55. MS (70 eV): m/z (Irel, %) 185 (71) [M + H]+, 112 (100): calculated for C7H8N2O4 (184.05): HRMS: 184.0499.

2.1.3 General procedure for the synthesis of arylhydrazones 5, 7, 8, 10, 11, and 12

Compound 4 was synthesized from the reaction of ethyl ester with hydrazine hydrate in refluxing ethanol. A mixture containing the orotic hydrazide 4 (1 mmol) and an appropriate aromatic aldehyde (1.1 mmol) with a catalytic amount of acetic acid was heated under reflux and stirring for 3 h in ethanol. After completion of the reaction, as indicated by TLC, the reaction mixture was poured into crushed ice. The solid separated was filtered under suction, washed with ice-cold water (50 mL), passed through a short column (1:1 ethylacetate–hexane), and subsequently dried to afford the pure products.

2.1.4 Structure identification of (E)-N-(4-methoxybenzylidene)-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carbohydrazide (5)

Yield: 64%, m.p.: 183°C. White solid, IR (KBr) (v = cm–1): 1,720, 1,723 (C═O), 3,019 (NH), 3,310 (OH). 1H NMR (500.133 MHz, DMSO-d6): δ = 3.82 (s, 3H, OCH3), 5.94 (s, 1H, CH), 7.70 (d, 2H, j = 8.5 Hz, arom), 7.83 (d, 2H, j = 9.0 Hz, arom), 8.33 (s, 1H, CH), 10.20 (br s, 1H, NH), 10.77 (br s, 1H, NH), 11.26 (br s, 1H, NH). 13C NMR (125.76 MHz, DMSO-d6): δ = 55.84, 100.79, 114.92, 125.37, 126.67, 129.57, 130.45, 150.38, 151.10, 151.30, 160.96, 164.51. MS (70 eV): m/z (Irel, %) 289 (39) [M + H]+, 267 (25), 133 (100): calculated for C13H12N4O4 (288.09): HRMS: 288.0819.

2.1.5 Structure identification of (E)-N′-(2,6-dichlorobenzylidene)-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carbohydrazide (7)

Yield: 69%, m.p.: 211°C. Light yellow solid, IR (KBr) (v = cm–1): 1,718, 1,723 (C═O), 3,029 (NH), 3,290 (OH). 1H NMR (500.133 MHz, DMSO-d6): δ = 6.16 (s, 1H, CH), 7.49–7.63 (m, 3H, arom), 7.99, 8.62 (s, 1H, CH), 11.03 (br s, 1H, NH), 11.37 (br s, 1H, NH), 12.38 (br s, 1H, NH). 13C NMR (125.76 MHz, DMSO-d6): δ = 101.29, 129.71 (2×), 130.18, 132.78, 133.11, 134.64, 137.63, 148.91, 157.08, 164.46, 167.07. MS (70 eV): m/z (Irel, %) 327 (39) [M + H]+, 292 (25), 170 (100): calculated for C12H8Cl2N4O3 (326.00): HRMS: 326.0736.

2.1.6 Structure identification of (E)-N-(4-nitrobenzylidene)-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carbohydrazide (8)

Yield: 69%, m.p.: 169°C. White solid, IR (KBr) (v = cm–1): 1,715, 1,723 (C═O), 3,039 (NH), 3,290 (OH). 1H NMR (500.133 MHz, DMSO-d6): δ = 5.94 (s, 1H, CH), 7.83 (s, 1H, arom), 8.34 (m, 3H, CH, 2× arom), 8.74 (s, 1H, arom), 10.12 (br s, 1H, NH), 10.72 (br s, 1H, NH), 11.26 (br s, 1H, NH). 13C NMR (125.76 MHz, DMSO-d6): δ = 103.0, 123.16, 131.16 (2×), 134.91 (2×), 144.20, 149.51, 151.33, 151.90, 164.16, 167.63. MS (70 eV): m/z (Irel, %) 304 (41) [M + H]+, 298 (78), 176 (100): calcd for C12H9N5O5 (303.06): HRMS: 303.0541.

2.1.7 Structure identification of (E)-N-(3,4-dichlorobenzylidene)-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carbohydrazide (10)

Yield: 55%, m.p.: 157°C. White solid, IR (KBr) (v = cm–1): 1,722, 1,723 (C═O), 3,031 (NH), 3,290 (OH). 1H NMR (500.133 MHz, DMSO-d6): δ = 5.99 (s, 1H, CH), 7.73 (m, 2H, arom), 7.99 (s, 2H, arom), 8.38 (s, 1H, CH), 11.03 (br s, 1H, NH), 11.27 (br s, 1H, NH), 12.33 (br s, 1H, NH). 13C NMR (125.76 MHz, DMSO-d6): δ = 101.17, 127.55, 129.44, 130.60, 132.27, 133.36, 134.74, 135.61, 147.78, 157.67, 164.48, 166.82. MS (70 eV): m/z (Irel, %) 289 (39) [M − Cl]+, 267 (25), 133 (100): calcd for C12H8Cl2N4O3 (326.00): HRMS: 326.0317.

2.1.8 Structure identification of (E)-N-(4-bromobenzylidene)-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carbohydrazide (11)

Yield: 59%, m.p.: 177°C. White solid, IR (KBr) (v = cm–1): 1,717, 1,725 (C═O), 3,050 (NH), 3,300 (OH). 1H NMR (500.133 MHz, DMSO-d6): δ = 6.11 (s, 1H, CH), 7.65 (d, 2H, j = 8.5 Hz, arom), 7.83 (d, 2H, j = 8.5 Hz, arom), 8.37 (s, 1H, CH), 8.71 (br s, 1H, NH), 10.25 (br s, 1H, NH), 11.25 (br s, 1H, NH). 13C NMR (125.76 MHz, DMSO-d6): δ = 99.83, 127.41, 129.73, 130.69, 131.86, 132.10 132.50, 145.33, 150.88, 151.20, 164.56, 162.07. MS (70 eV): m/z (Irel, %) 337 (30) [M + H]+, 211 (90), 157 (28): calculated for C12H9BrN4O3 (335.99): HRMS: 335.9701.

2.1.9 Structure identification of (E)-N-(4-chlorobenzylidene)-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carbohydrazide (12)

Yield: 63%, m.p.: 141°C. White solid, IR (KBr) (v = cm–1): 1,715, 1,730 (C═O), 2,990 (NH), 3,335 (OH). 1H NMR (500.133 MHz, DMSO-d6): δ = 6.10 (s, 1H, CH), 7.77 (d, 2H, j = 8.5 Hz, arom), 7.90 (d, 2H, j = 8.2 Hz, arom), 8.38 (s, 1H, CH), 8.71 (br s, 1H, NH), 10.13 (br s, 1H, NH), 11.26 (br s, 1H, NH). 13C NMR (125.76 MHz, DMSO-d6): δ = 101.04, 128.97 (2×), 129.53 (2×), 130.50, 133.09, 145.04, 149.20, 151.28, 161.05, 164.48. MS (70 eV): m/z (Irel, %) 276 (90) [M − OH]+, 247 (45), 110 (100): calculated for C12H9ClN4O3 (292.04): HRMS: 292.0390.

2.1.10 X-ray crystallographic studies of compounds 2, 3, and 4

Crystals of compound 2 (Scheme 1) were obtained by crystallization from ethanol–water (3:1) via slow solvent evaporation. The crystallographic data for compound 2 have been deposited at the Cambridge Crystallographic Data Center (deposit CCDC 1483501). Brown needles of compound 3 (Scheme 1) were obtained by crystallization from ethanol–water via slow solvent evaporation. The crystallographic data for compound 3 have been deposited at the Cambridge Crystallographic Data Center (deposit CCDC 150815). Yellow crystals of compound 4 (Scheme 1) were obtained by crystallization from hot ethanol via slow solvent evaporation. The compound crystallized with two molecules of water in the crystal lattice. The crystallographic data for compound 4 have been deposited at the Cambridge Crystallographic Data Center (deposit CCDC 1483500).

Scheme 1 Reaction scheme for the synthesis of compounds 2, 3, and 4.
Scheme 1

Reaction scheme for the synthesis of compounds 2, 3, and 4.

2.2 Cell culture

The experiments were conducted using the previously established hTERT-MSC-CL1 (hMSC) cell lines. Cells from passages between 24 and 28 were used and were cultured in T75 culture flask (BD FalconTM, NJ, USA). Cells were monitored with an inverted light microscope (Observer A1, Zeiss®, Gottingen, Germany). hMSCs were grown in DMEM (Gibco, Cat No. 41966052) supplemented with 10% FBS (Gibco, Cat No. 26140087), 1% pen/strep (10,000 units of penicillin and 10,000 g of streptomycin/mL; Gibco, Cat No. 15140122), and 1% NEAA (X100; Gibco, Cat No. 11140035). After the cells reached 80–90% confluences in the culture flasks, they were trypsinized and transferred into falcon tubes. They were counted in the Neubauer hemocytometer counting chamber (PAUL MARIENFELD GMBH & CO.KG.). The cells were seeded at a density of 0.01 × 106 cells per well in a 96-well tissue culture plate. The following day, diluted compounds were added to the cells at the desired concentration in triplicates. Two days later, the media was changed to normal growth media. The next day was designated as day 1 of proliferation (Figure 1).

2.2.1 alamarBlue cell viability assay

Cell viability was determined using the alamarBlue assay using the protocol recommended by the manufacturer (AbD Serotec, Raleigh, NC, USA). Briefly, 100 µL cells were cultured in 96-well plates in the appropriate medium. At specific time points, 10 µL alamarBlue substrate was added, and the plates were incubated in the dark at 37°C for 1 h. The readings were subsequently taken in the fluorescence mode (Ex 530 nm/Em 590 nm) using BioTek Synergy II microplate reader (BioTek Inc., Winooski, VT, US).

  1. Ethical approval: The conducted research is not related to either human or animal use.

3 Discussion

3.1 Synthesis of the target compounds

Owing to the low solubility in organic solvents, orotic acid has never been the choice as a starting material for synthetic chemists. Thus, very few reports are available on the synthesis of its analogs. To resolve this, orotic acid was esterified in butanol following a previously reported procedure. The product obtained (compound 2) was recrystallized in ethanol–water (3:1) at room temperature to obtain crystals suitable for X-ray crystallography (structure is shown in Figure 2). However, the cumbersome workup, low yield, and toxicity restrict the wide application of this compound.

Figure 1 Crystal structure of compound 2.
Figure 1

Crystal structure of compound 2.

Figure 2 Crystal structure of compound 3.
Figure 2

Crystal structure of compound 3.

Considering the limitations of the reported methods, the need for the development of new and efficient methods is highly desirable. Therefore, ethanol was used along with the catalytic amount of HCl to afford 3 in good yield (Scheme 1). The solid obtained (compound 3) was recrystallized in the ethanol–water mixture to afford crystals suitable for X-ray crystallographic studies (structure shown in Figure 2). The ethyl ester 3 was reacted with hydrazine hydrate in refluxing ethanol, yielding hydrazide 4 in 67% yield (Scheme 1). The same reaction was carried out with butyl ester of orotic acid, but the reaction time was longer, and the yield was significantly low. Starting material 4 (Figure 3) was then subjected through a series of acid-catalyzed condensation reaction with the various substituted aromatic aldehyde to afford the target compounds in excellent yields. All the compounds 2–12 (Schemes 1 and 2) were isolated as (E)-isomers, as confirmed by gated-decoupling (GD) measurements. In the 1H NMR spectra of the synthesized molecules, a signal of pyrimidine CH appeared at the characteristic position, and the aromatic protons also appeared in their respective regions. The IR spectra of all the synthesized compounds showed bands in the regions 3,050–3,350 (NH), 1,710–1,723 (C═O), and 1,600–1,680 (C═O), which are typical of an uracil ring. The mass and HRMS data are also in accord with the proposed structures of compounds 2–12.

Figure 3 Crystal structure of compound 4.
Figure 3

Crystal structure of compound 4.

Scheme 2 General synthesis of 5–12. Reagents and conditions: ethanol, AcOH, reflux 5 h.
Scheme 2

General synthesis of 5–12. Reagents and conditions: ethanol, AcOH, reflux 5 h.

3.2 Effect of the synthesized compounds on stem cell proliferation

All the synthesized compounds were tested on hMSCs, and the results are listed in Tables 1–3. Cells were treated for 48 h with the test compounds in triplicates at concentrations ranging from 5.0 to 50 µg/mL. Moreover, the cells were incubated for an additional 3 days to ensure the effect of these compounds on hMSCs. It was observed that only after 1 day of treatment of the cells with high concentrations (500 µM) of most of the compounds reduced the proliferation significantly (Table 1). However, compounds 5, 8, 9, 10, 11, and 12 were an exception, and these compounds increased the proliferation (Tables 1–3). In addition, these effects were more prominent at lower concentrations, at which these compounds (6, 9, 10, 11, and 12) imparted a significantly higher proliferation rate than the other compounds and compared to the control condition (DMSO). However, at lower concentrations, other compounds also showed significant upregulation such as 1, 2, and 3. Only compound 7 did not have any effect on proliferation on day 1. A similar trend was observed on day 2; all the compounds at the highest concentration (500 µM) retarded the proliferation, while compounds 5, 8, 9, 10, 11, and 12 (Scheme 2) still showed the significant higher proliferation rate. At lower concentrations (50 and 10 µM), all the compounds (except 7) showed significant upregulation of proliferation. The same trend was seen on day 5, indicating that these compounds 5, 8, 9, 10, 11, and 12 hold promising potential in the stem cell growth and possibly in differentiation (Tables 1–3). Other compounds exhibited a less significant effect on proliferation, suggesting that the substituents play a crucial role in stem cell proliferation. Therefore, the compounds showing some upregulation in stem cell proliferation can be considered as promising leads for further investigation.

Table 1

Proliferation data for day 1

Day-1
S. code500 µM250 µM50 µM10 µM
AvgStdvT testAvgStdvT testAvgStdvT testAvgStdvT test
DMSO1096.09.64371208.316.80282676.0137.17873791.3135.019752
11088.37.37110.33541620.310.01670.00003636.3111.39270.00324793.3116.67190.0006
21087.011.53260.35831167.398.33790.51592995.3245.29440.20284250.7177.58750.0235
31091.016.64330.67591389.387.83130.02483421.797.52090.00544329.5202.93960.0351
41604.78.62172.78431830.391.57150.00033470.739.00430.00204612.3207.16500.0045
55235.554.44720.00343579.595.45940.08652321.5217.08180.01612496.5102.53050.0029
61330.752.21430.00161567.764.73280.00073513.0281.33430.03264303.0241.83050.0512
71107.010.53570.25311154.772.00230.27712638.7307.33750.88644010.3200.17580.1913
83026.074.95330.76904577.5553.66460.06565290.5225.56710.00883899.0130.39940.7647
95269.5355.00000.04655590.5325.97620.01215171.0438.40620.03533823.51010.45560.8938
104924.0132.93610.00682223.5309.005660.11135593.562.93250.00082390.3103.36500.0003
114214.5152.02800.01955419.5870.44840.06286973.5833.67890.02855830.5132.22900.0026
126425.0425.67830.00924974.5225.56710.01387222.0450.00000.04305443.5344.36100.0253

Stdv = standard deviation, T test = statistical test.

Table 2

Proliferation data for day 2

Day-2
S. code500 µM250 µM50 µM10 µM
AvgStdvT testAvg.StdvT testAvgStdvT testAvgStdvT test
DMSO999.010.53571062.321.54842522.7213.01725044.3142.8157
11003.317.03920.72691186.052.43090.01953754.317.55940.00066972.7197.88970.0002
21005.38.73690.46781055.315.27530.67013194.3109.98790.00836445.7250.50420.0011
31006.09.53940.44171143.364.73280.10893750.3335.10050.00596089.0177.64290.0014
41620.081.06170.00021556.353.26660.00013547.7194.98030.00366578.7592.67560.0121
518510.7962.65480.011517558.71609.99200.056916434.71184.26450.707615428.01072.18420.1439
61243.752.91820.00141248.025.23890.00063685.7197.50020.00236331.7395.14600.0061
71011.74.04150.12381062.724.00690.98662455.0442.77650.82326224.7255.66450.0022
814936.01074.92460.839016152.71747.35640.245015853.3451.04800.830918328.74978.44620.5989
921324.03071.93600.028425056.71324.89110.000525675.5333.04730.002124465.51109.45050.0016
1017977.03877.97940.281220272.31341.15220.005121647.71984.55040.014522522.01091.77290.0036
1116545.71791.97140.285417391.01842.57670.084017395.71169.38200.242720079.33936.12820.2123
1221559.05771.33750.128720456.75338.34570.131822833.5642.76010.006623164.01938.88680.0096
Table 3

Proliferation data for day 5

Day-5
S. code500 µM250 µM50 µM10 µM
AvgStdvT testAvgStdvT testAvgStdvT testAvgStdvT test
DMSO1061.07.93731075.37.02385542.3519.216115918.5208.5965 
11068.04.00000.24421110.019.67230.04538124.3510.17280.003619337.794.50040.0001
21073.05.00000.09111095.73.78590.01167473.3854.26950.028717650.31565.92760.2361
31067.07.54980.39651105.011.00000.01708955.0623.71710.001918102.3312.34650.0034
41073.05.29150.09491121.310.96970.00367722.0186.96790.002416321.02234.76110.8250
518430.52257.79200.249422953.02134.04830.046524550.033.94110.000029229.52322.84580.0618
61061.76.50640.91581093.30.57740.01158896.0800.92950.003719469.32068.41780.1052
71050.74.04150.11491069.77.57190.39583934.3791.90550.042318398.01486.68390.1123
823158.02262.13000.023023921.0381.83770.002324148.51453.10440.030423016.01845.54870.8403
922249.5443.35600.005022765.5241.12340.002223440.0234.75950.001125126.5564.97830.0566
1019910.5311.83410.009418971.5932.673840.056020063.5982.17130.137925838.02129.80560.1841
1123420.52089.50050.037421173.0834.38600.015825119.01043.68960.011824440.01924.74470.3489
1220446.5400.92950.008820340.5449.01280.009321494.01170.96880.064527037.5999.14190.0354

4 Conclusion

We have found that some orotic hydrazide derivatives showed a significant proliferation of mesenchymal stem cells at a lower concentration, but no change was observed at higher concentrations. Therefore, this study opens a new era of stem cell proliferation, and the exploration of more potent molecules can be achieved through further modifications.

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Acknowledgment

The authors extend their appreciation to the Deanship of Scientific Research at King Saud University for funding this work through research group no RG-1440-009.

  1. Conflict of interest: The authors declare that they have no conflict of interest.

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Received: 2019-10-28
Revised: 2020-02-29
Accepted: 2020-03-09
Published Online: 2020-06-20

© 2020 Saeed Ali Syed et al., published by De Gruyter

This work is licensed under the Creative Commons Attribution 4.0 International License.

Articles in the same Issue

  1. Regular Articles
  2. Electrochemical antioxidant screening and evaluation based on guanine and chitosan immobilized MoS2 nanosheet modified glassy carbon electrode (guanine/CS/MoS2/GCE)
  3. Kinetic models of the extraction of vanillic acid from pumpkin seeds
  4. On the maximum ABC index of bipartite graphs without pendent vertices
  5. Estimation of the total antioxidant potential in the meat samples using thin-layer chromatography
  6. Molecular dynamics simulation of sI methane hydrate under compression and tension
  7. Spatial distribution and potential ecological risk assessment of some trace elements in sediments and grey mangrove (Avicennia marina) along the Arabian Gulf coast, Saudi Arabia
  8. Amino-functionalized graphene oxide for Cr(VI), Cu(II), Pb(II) and Cd(II) removal from industrial wastewater
  9. Chemical composition and in vitro activity of Origanum vulgare L., Satureja hortensis L., Thymus serpyllum L. and Thymus vulgaris L. essential oils towards oral isolates of Candida albicans and Candida glabrata
  10. Effect of excess Fluoride consumption on Urine-Serum Fluorides, Dental state and Thyroid Hormones among children in “Talab Sarai” Punjab Pakistan
  11. Design, Synthesis and Characterization of Novel Isoxazole Tagged Indole Hybrid Compounds
  12. Comparison of kinetic and enzymatic properties of intracellular phosphoserine aminotransferases from alkaliphilic and neutralophilic bacteria
  13. Green Organic Solvent-Free Oxidation of Alkylarenes with tert-Butyl Hydroperoxide Catalyzed by Water-Soluble Copper Complex
  14. Ducrosia ismaelis Asch. essential oil: chemical composition profile and anticancer, antimicrobial and antioxidant potential assessment
  15. DFT calculations as an efficient tool for prediction of Raman and infra-red spectra and activities of newly synthesized cathinones
  16. Influence of Chemical Osmosis on Solute Transport and Fluid Velocity in Clay Soils
  17. A New fatty acid and some triterpenoids from propolis of Nkambe (North-West Region, Cameroon) and evaluation of the antiradical scavenging activity of their extracts
  18. Antiplasmodial Activity of Stigmastane Steroids from Dryobalanops oblongifolia Stem Bark
  19. Rapid identification of direct-acting pancreatic protectants from Cyclocarya paliurus leaves tea by the method of serum pharmacochemistry combined with target cell extraction
  20. Immobilization of Pseudomonas aeruginosa static biomass on eggshell powder for on-line preconcentration and determination of Cr (VI)
  21. Assessment of methyl 2-({[(4,6-dimethoxypyrimidin-2-yl)carbamoyl] sulfamoyl}methyl)benzoate through biotic and abiotic degradation modes
  22. Stability of natural polyphenol fisetin in eye drops Stability of fisetin in eye drops
  23. Production of a bioflocculant by using activated sludge and its application in Pb(II) removal from aqueous solution
  24. Molecular Properties of Carbon Crystal Cubic Structures
  25. Synthesis and characterization of calcium carbonate whisker from yellow phosphorus slag
  26. Study on the interaction between catechin and cholesterol by the density functional theory
  27. Analysis of some pharmaceuticals in the presence of their synthetic impurities by applying hybrid micelle liquid chromatography
  28. Two mixed-ligand coordination polymers based on 2,5-thiophenedicarboxylic acid and flexible N-donor ligands: the protective effect on periodontitis via reducing the release of IL-1β and TNF-α
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  30. Development of ultrasound-assisted dispersive solid-phase microextraction based on mesoporous carbon coated with silica@iron oxide nanocomposite for preconcentration of Te and Tl in natural water systems
  31. N,N′-Bis[2-hydroxynaphthylidene]/[2-methoxybenzylidene]amino]oxamides and their divalent manganese complexes: Isolation, spectral characterization, morphology, antibacterial and cytotoxicity against leukemia cells
  32. Determination of the content of selected trace elements in Polish commercial fruit juices and health risk assessment
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  35. Anticancer, antioxidant, and acute toxicity studies of a Saudi polyherbal formulation, PHF5
  36. LaCoO3 perovskite-type catalysts in syngas conversion
  37. Comparative studies of two vegetal extracts from Stokesia laevis and Geranium pratense: polyphenol profile, cytotoxic effect and antiproliferative activity
  38. Fragmentation pattern of certain isatin–indole antiproliferative conjugates with application to identify their in vitro metabolic profiles in rat liver microsomes by liquid chromatography tandem mass spectrometry
  39. Investigation of polyphenol profile, antioxidant activity and hepatoprotective potential of Aconogonon alpinum (All.) Schur roots
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  46. Chirality of β2-agonists. An overview of pharmacological activity, stereoselective analysis, and synthesis
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https://doi.org/10.1515/chem-2020-0096
Keywords for this article
orotic hydrazide; arylhydrazone; mesenchymal stem cells; proliferation
Creative Commons
BY 4.0

Articles in the same Issue

  1. Regular Articles
  2. Electrochemical antioxidant screening and evaluation based on guanine and chitosan immobilized MoS2 nanosheet modified glassy carbon electrode (guanine/CS/MoS2/GCE)
  3. Kinetic models of the extraction of vanillic acid from pumpkin seeds
  4. On the maximum ABC index of bipartite graphs without pendent vertices
  5. Estimation of the total antioxidant potential in the meat samples using thin-layer chromatography
  6. Molecular dynamics simulation of sI methane hydrate under compression and tension
  7. Spatial distribution and potential ecological risk assessment of some trace elements in sediments and grey mangrove (Avicennia marina) along the Arabian Gulf coast, Saudi Arabia
  8. Amino-functionalized graphene oxide for Cr(VI), Cu(II), Pb(II) and Cd(II) removal from industrial wastewater
  9. Chemical composition and in vitro activity of Origanum vulgare L., Satureja hortensis L., Thymus serpyllum L. and Thymus vulgaris L. essential oils towards oral isolates of Candida albicans and Candida glabrata
  10. Effect of excess Fluoride consumption on Urine-Serum Fluorides, Dental state and Thyroid Hormones among children in “Talab Sarai” Punjab Pakistan
  11. Design, Synthesis and Characterization of Novel Isoxazole Tagged Indole Hybrid Compounds
  12. Comparison of kinetic and enzymatic properties of intracellular phosphoserine aminotransferases from alkaliphilic and neutralophilic bacteria
  13. Green Organic Solvent-Free Oxidation of Alkylarenes with tert-Butyl Hydroperoxide Catalyzed by Water-Soluble Copper Complex
  14. Ducrosia ismaelis Asch. essential oil: chemical composition profile and anticancer, antimicrobial and antioxidant potential assessment
  15. DFT calculations as an efficient tool for prediction of Raman and infra-red spectra and activities of newly synthesized cathinones
  16. Influence of Chemical Osmosis on Solute Transport and Fluid Velocity in Clay Soils
  17. A New fatty acid and some triterpenoids from propolis of Nkambe (North-West Region, Cameroon) and evaluation of the antiradical scavenging activity of their extracts
  18. Antiplasmodial Activity of Stigmastane Steroids from Dryobalanops oblongifolia Stem Bark
  19. Rapid identification of direct-acting pancreatic protectants from Cyclocarya paliurus leaves tea by the method of serum pharmacochemistry combined with target cell extraction
  20. Immobilization of Pseudomonas aeruginosa static biomass on eggshell powder for on-line preconcentration and determination of Cr (VI)
  21. Assessment of methyl 2-({[(4,6-dimethoxypyrimidin-2-yl)carbamoyl] sulfamoyl}methyl)benzoate through biotic and abiotic degradation modes
  22. Stability of natural polyphenol fisetin in eye drops Stability of fisetin in eye drops
  23. Production of a bioflocculant by using activated sludge and its application in Pb(II) removal from aqueous solution
  24. Molecular Properties of Carbon Crystal Cubic Structures
  25. Synthesis and characterization of calcium carbonate whisker from yellow phosphorus slag
  26. Study on the interaction between catechin and cholesterol by the density functional theory
  27. Analysis of some pharmaceuticals in the presence of their synthetic impurities by applying hybrid micelle liquid chromatography
  28. Two mixed-ligand coordination polymers based on 2,5-thiophenedicarboxylic acid and flexible N-donor ligands: the protective effect on periodontitis via reducing the release of IL-1β and TNF-α
  29. Incorporation of silver stearate nanoparticles in methacrylate polymeric monoliths for hemeprotein isolation
  30. Development of ultrasound-assisted dispersive solid-phase microextraction based on mesoporous carbon coated with silica@iron oxide nanocomposite for preconcentration of Te and Tl in natural water systems
  31. N,N′-Bis[2-hydroxynaphthylidene]/[2-methoxybenzylidene]amino]oxamides and their divalent manganese complexes: Isolation, spectral characterization, morphology, antibacterial and cytotoxicity against leukemia cells
  32. Determination of the content of selected trace elements in Polish commercial fruit juices and health risk assessment
  33. Diorganotin(iv) benzyldithiocarbamate complexes: synthesis, characterization, and thermal and cytotoxicity study
  34. Keratin 17 is induced in prurigo nodularis lesions
  35. Anticancer, antioxidant, and acute toxicity studies of a Saudi polyherbal formulation, PHF5
  36. LaCoO3 perovskite-type catalysts in syngas conversion
  37. Comparative studies of two vegetal extracts from Stokesia laevis and Geranium pratense: polyphenol profile, cytotoxic effect and antiproliferative activity
  38. Fragmentation pattern of certain isatin–indole antiproliferative conjugates with application to identify their in vitro metabolic profiles in rat liver microsomes by liquid chromatography tandem mass spectrometry
  39. Investigation of polyphenol profile, antioxidant activity and hepatoprotective potential of Aconogonon alpinum (All.) Schur roots
  40. Lead discovery of a guanidinyl tryptophan derivative on amyloid cascade inhibition
  41. Physicochemical evaluation of the fruit pulp of Opuntia spp growing in the Mediterranean area under hard climate conditions
  42. Electronic structural properties of amino/hydroxyl functionalized imidazolium-based bromide ionic liquids
  43. New Schiff bases of 2-(quinolin-8-yloxy)acetohydrazide and their Cu(ii), and Zn(ii) metal complexes: their in vitro antimicrobial potentials and in silico physicochemical and pharmacokinetics properties
  44. Treatment of adhesions after Achilles tendon injury using focused ultrasound with targeted bFGF plasmid-loaded cationic microbubbles
  45. Synthesis of orotic acid derivatives and their effects on stem cell proliferation
  46. Chirality of β2-agonists. An overview of pharmacological activity, stereoselective analysis, and synthesis
  47. Fe3O4@urea/HITh-SO3H as an efficient and reusable catalyst for the solvent-free synthesis of 7-aryl-8H-benzo[h]indeno[1,2-b]quinoline-8-one and indeno[2′,1′:5,6]pyrido[2,3-d]pyrimidine derivatives
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  49. Enhancement of thermal properties of bio-based microcapsules intended for textile applications
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  51. A green strategy for obtaining anthraquinones from Rheum tanguticum by subcritical water
  52. Cadmium (Cd) chloride affects the nutrient uptake and Cd-resistant bacterium reduces the adsorption of Cd in muskmelon plants
  53. Removal of H2S by vermicompost biofilter and analysis on bacterial community
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  55. A self-breaking supramolecular plugging system as lost circulation material in oilfield
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  62. New derivatives of a natural nordentatin
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  64. Study of the remediation effects of passivation materials on Pb-contaminated soil
  65. Saliva proteomic analysis reveals possible biomarkers of renal cell carcinoma
  66. Withania frutescens: Chemical characterization, analgesic, anti-inflammatory, and healing activities
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  75. Electrochemical evaluation of the antioxidant capacity of natural compounds on glassy carbon electrode modified with guanine-, polythionine-, and nitrogen-doped graphene
  76. A Dy(iii)–organic framework as a fluorescent probe for highly selective detection of picric acid and treatment activity on human lung cancer cells
  77. A Zn(ii)–organic cage with semirigid ligand for solvent-free cyanosilylation and inhibitory effect on ovarian cancer cell migration and invasion ability via regulating mi-RNA16 expression
  78. Polyphenol content and antioxidant activities of Prunus padus L. and Prunus serotina L. leaves: Electrochemical and spectrophotometric approach and their antimicrobial properties
  79. The combined use of GC, PDSC and FT-IR techniques to characterize fat extracted from commercial complete dry pet food for adult cats
  80. MALDI-TOF MS profiling in the discovery and identification of salivary proteomic patterns of temporomandibular joint disorders
  81. Concentrations of dioxins, furans and dioxin-like PCBs in natural animal feed additives
  82. Structure and some physicochemical and functional properties of water treated under ammonia with low-temperature low-pressure glow plasma of low frequency
  83. Mesoscale nanoparticles encapsulated with emodin for targeting antifibrosis in animal models
  84. Amine-functionalized magnetic activated carbon as an adsorbent for preconcentration and determination of acidic drugs in environmental water samples using HPLC-DAD
  85. Antioxidant activity as a response to cadmium pollution in three durum wheat genotypes differing in salt-tolerance
  86. A promising naphthoquinone [8-hydroxy-2-(2-thienylcarbonyl)naphtho[2,3-b]thiophene-4,9-dione] exerts anti-colorectal cancer activity through ferroptosis and inhibition of MAPK signaling pathway based on RNA sequencing
  87. Synthesis and efficacy of herbicidal ionic liquids with chlorsulfuron as the anion
  88. Effect of isovalent substitution on the crystal structure and properties of two-slab indates BaLa2−xSmxIn2O7
  89. Synthesis, spectral and thermo-kinetics explorations of Schiff-base derived metal complexes
  90. An improved reduction method for phase stability testing in the single-phase region
  91. Comparative analysis of chemical composition of some commercially important fishes with an emphasis on various Malaysian diets
  92. Development of a solventless stir bar sorptive extraction/thermal desorption large volume injection capillary gas chromatographic-mass spectrometric method for ultra-trace determination of pyrethroids pesticides in river and tap water samples
  93. A turbidity sensor development based on NL-PI observers: Experimental application to the control of a Sinaloa’s River Spirulina maxima cultivation
  94. Deep desulfurization of sintering flue gas in iron and steel works based on low-temperature oxidation
  95. Investigations of metallic elements and phenolics in Chinese medicinal plants
  96. Influence of site-classification approach on geochemical background values
  97. Effects of ageing on the surface characteristics and Cu(ii) adsorption behaviour of rice husk biochar in soil
  98. Adsorption and sugarcane-bagasse-derived activated carbon-based mitigation of 1-[2-(2-chloroethoxy)phenyl]sulfonyl-3-(4-methoxy-6-methyl-1,3,5-triazin-2-yl) urea-contaminated soils
  99. Antimicrobial and antifungal activities of bifunctional cooper(ii) complexes with non-steroidal anti-inflammatory drugs, flufenamic, mefenamic and tolfenamic acids and 1,10-phenanthroline
  100. Application of selenium and silicon to alleviate short-term drought stress in French marigold (Tagetes patula L.) as a model plant species
  101. Screening and analysis of xanthine oxidase inhibitors in jute leaves and their protective effects against hydrogen peroxide-induced oxidative stress in cells
  102. Synthesis and physicochemical studies of a series of mixed-ligand transition metal complexes and their molecular docking investigations against Coronavirus main protease
  103. A study of in vitro metabolism and cytotoxicity of mephedrone and methoxetamine in human and pig liver models using GC/MS and LC/MS analyses
  104. A new phenyl alkyl ester and a new combretin triterpene derivative from Combretum fragrans F. Hoffm (Combretaceae) and antiproliferative activity
  105. Erratum
  106. Erratum to: A one-step incubation ELISA kit for rapid determination of dibutyl phthalate in water, beverage and liquor
  107. Review Articles
  108. Sinoporphyrin sodium, a novel sensitizer for photodynamic and sonodynamic therapy
  109. Natural products isolated from Casimiroa
  110. Plant description, phytochemical constituents and bioactivities of Syzygium genus: A review
  111. Evaluation of elastomeric heat shielding materials as insulators for solid propellant rocket motors: A short review
  112. Special Issue on Applied Biochemistry and Biotechnology 2019
  113. An overview of Monascus fermentation processes for monacolin K production
  114. Study on online soft sensor method of total sugar content in chlorotetracycline fermentation tank
  115. Studies on the Anti-Gouty Arthritis and Anti-hyperuricemia Properties of Astilbin in Animal Models
  116. Effects of organic fertilizer on water use, photosynthetic characteristics, and fruit quality of pear jujube in northern Shaanxi
  117. Characteristics of the root exudate release system of typical plants in plateau lakeside wetland under phosphorus stress conditions
  118. Characterization of soil water by the means of hydrogen and oxygen isotope ratio at dry-wet season under different soil layers in the dry-hot valley of Jinsha River
  119. Composition and diurnal variation of floral scent emission in Rosa rugosa Thunb. and Tulipa gesneriana L.
  120. Preparation of a novel ginkgolide B niosomal composite drug
  121. The degradation, biodegradability and toxicity evaluation of sulfamethazine antibiotics by gamma radiation
  122. Special issue on Monitoring, Risk Assessment and Sustainable Management for the Exposure to Environmental Toxins
  123. Insight into the cadmium and zinc binding potential of humic acids derived from composts by EEM spectra combined with PARAFAC analysis
  124. Source apportionment of soil contamination based on multivariate receptor and robust geostatistics in a typical rural–urban area, Wuhan city, middle China
  125. Special Issue on 13th JCC 2018
  126. The Role of H2C2O4 and Na2CO3 as Precipitating Agents on The Physichochemical Properties and Photocatalytic Activity of Bismuth Oxide
  127. Preparation of magnetite-silica–cetyltrimethylammonium for phenol removal based on adsolubilization
  128. Topical Issue on Agriculture
  129. Size-dependent growth kinetics of struvite crystals in wastewater with calcium ions
  130. The effect of silica-calcite sedimentary rock contained in the chicken broiler diet on the overall quality of chicken muscles
  131. Physicochemical properties of selected herbicidal products containing nicosulfuron as an active ingredient
  132. Lycopene in tomatoes and tomato products
  133. Fluorescence in the assessment of the share of a key component in the mixing of feed
  134. Sulfur application alleviates chromium stress in maize and wheat
  135. Effectiveness of removal of sulphur compounds from the air after 3 years of biofiltration with a mixture of compost soil, peat, coconut fibre and oak bark
  136. Special Issue on the 4th Green Chemistry 2018
  137. Study and fire test of banana fibre reinforced composites with flame retardance properties
  138. Special Issue on the International conference CosCI 2018
  139. Disintegration, In vitro Dissolution, and Drug Release Kinetics Profiles of k-Carrageenan-based Nutraceutical Hard-shell Capsules Containing Salicylamide
  140. Synthesis of amorphous aluminosilicate from impure Indonesian kaolin
  141. Special Issue on the International Conf on Science, Applied Science, Teaching and Education 2019
  142. Functionalization of Congo red dye as a light harvester on solar cell
  143. The effect of nitrite food preservatives added to se’i meat on the expression of wild-type p53 protein
  144. Biocompatibility and osteoconductivity of scaffold porous composite collagen–hydroxyapatite based coral for bone regeneration
  145. Special Issue on the Joint Science Congress of Materials and Polymers (ISCMP 2019)
  146. Effect of natural boron mineral use on the essential oil ratio and components of Musk Sage (Salvia sclarea L.)
  147. A theoretical and experimental study of the adsorptive removal of hexavalent chromium ions using graphene oxide as an adsorbent
  148. A study on the bacterial adhesion of Streptococcus mutans in various dental ceramics: In vitro study
  149. Corrosion study of copper in aqueous sulfuric acid solution in the presence of (2E,5E)-2,5-dibenzylidenecyclopentanone and (2E,5E)-bis[(4-dimethylamino)benzylidene]cyclopentanone: Experimental and theoretical study
  150. Special Issue on Chemistry Today for Tomorrow 2019
  151. Diabetes mellitus type 2: Exploratory data analysis based on clinical reading
  152. Multivariate analysis for the classification of copper–lead and copper–zinc glasses
  153. Special Issue on Advances in Chemistry and Polymers
  154. The spatial and temporal distribution of cationic and anionic radicals in early embryo implantation
  155. Special Issue on 3rd IC3PE 2020
  156. Magnetic iron oxide/clay nanocomposites for adsorption and catalytic oxidation in water treatment applications
  157. Special Issue on IC3PE 2018/2019 Conference
  158. Exergy analysis of conventional and hydrothermal liquefaction–esterification processes of microalgae for biodiesel production
  159. Advancing biodiesel production from microalgae Spirulina sp. by a simultaneous extraction–transesterification process using palm oil as a co-solvent of methanol
  160. Topical Issue on Applications of Mathematics in Chemistry
  161. Omega and the related counting polynomials of some chemical structures
  162. M-polynomial and topological indices of zigzag edge coronoid fused by starphene
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