Utilization of Cyanoacetohydrazide and Oxadiazolyl Acetonitrile in the Synthesis of Some New Cytotoxic Heterocyclic Compounds
Abstract
:1. Introduction
2. Results and Discussion
2.1. Chemistry
2.2. Pharmacological Activity
2.2.1. Antitumor Activity Using in Vitro Ehrlich Ascites Assay
Comp. No. | In Vitro Cytotoxicity | IC50 (μg/mL) a | ||
---|---|---|---|---|
HePG2 | HCT-116 | PC3 | MCF-7 | |
4 | 50.3 ± 4.22 | 64.7 ± 4.11 | 48.1 ± 3.64 | 58.4 ± 3.67 |
6 | 70.7 ± 4.65 | 72.6 ± 4.51 | 86.0 ± 4.63 | 80.4 ± 4.75 |
8 | 10.3 ± 0.81 | 8.1 ± 0.35 | 7.4 ± 0.34 | 5.6 ± 0.30 |
9 | 13.2 ± 1.31 | 14.8 ± 1.53 | 9.1 ± 0.86 | 10.5 ± 1.04 |
10 | 18.4 ± 1.06 | 20.0 ± 1.96 | 13.7 ± 1.37 | 12.3 ± 1.08 |
11 | 23.4 ± 1.46 | 30.3 ± 2.64 | 26.2 ± 1.60 | 28.7 ± 1.83 |
12 | 16.5 ± 1.35 | 16.9 ± 1.14 | 15.7 ± 1.56 | 19.7 ± 1.76 |
17 | 34.1 ± 2.30 | 37.5 ± 2.67 | 17.5 ± 1.42 | 23.1 ± 1.51 |
18 | 46.0 ± 3.61 | 40.7 ± 2.63 | 33.3 ± 2.07 | 29.4 ± 2.00 |
19 | 60.3 ± 3.97 | 68.3 ± 3.88 | 35.3 ± 2.94 | 41.5 ± 2.43 |
20 | 83.2 ± 4.83 | >100 | 70.9 ± 4.75 | 63.1 ± 3.89 |
21 | 11.8 ± 1.12 | 10.5 ± 0.89 | 8.9 ± 0.45 | 9.1 ± 0.87 |
5-fu | 7.9 ± 0.28 | 5.2 ± 0.14 | 8.3 ± 0.25 | 5.5 ± 0.21 |
Compounds | Conc. (µg/mL) | HePG-2 | HCT-116 | PC3 | MCF-7 |
---|---|---|---|---|---|
5-FU | 100 µg/mL | 8.6 | 7.2 | 8.1 | 7.7 |
50 µg/mL | 17.1 | 12.0 | 15.8 | 14.3 | |
25 µg/mL | 24.0 | 19.3 | 22.5 | 21.5 | |
12.5 µg/mL | 33.1 | 30.6 | 36.7 | 34.6 | |
6.25 µg/mL | 56.8 | 48.9 | 55.2 | 47.4 | |
3.125 µg/mL | 70.6 | 60.5 | 74.1 | 58.3 | |
1.56 µg/mL | 88.7 | 73.4 | 92.5 | 76.9 | |
4 | 100 µg/mL | 37.9 | 42.7 | 36.1 | 41.1 |
50 µg/mL | 48.8 | 55.5 | 48.4 | 52.9 | |
25 µg/mL | 63.0 | 67.2 | 62.5 | 64.6 | |
12.5 µg/mL | 75.6 | 81.3 | 74.2 | 78.2 | |
6.25 µg/mL | 93.1 | 94.9 | 95.6 | 99.3 | |
3.125 µg/mL | 100 | 100 | 100 | 100 | |
1.56 µg/mL | 100 | 100 | 100 | 100 | |
6 | 100 µg/mL | 44.5 | 45.7 | 49.3 | 46.8 |
50 µg/mL | 57.2 | 56.6 | 60.6 | 61.2 | |
25 µg/mL | 70.4 | 71.3 | 78.1 | 73.3 | |
12.5 µg/mL | 82.9 | 83.4 | 91.7 | 86.9 | |
6.25 µg/mL | 98.8 | 96.5 | 100 | 100 | |
3.125 µg/mL | 100 | 100 | 100 | 100 | |
1.56 µg/mL | 100 | 100 | 100 | 100 | |
8 | 100 µg/mL | 13.0 | 8.3 | 8.4 | 7.0 |
50 µg/mL | 18.2 | 17.9 | 14.3 | 12.3 | |
25 µg/mL | 25.8 | 25.1 | 22.5 | 19.5 | |
12.5 µg/mL | 36.9 | 33.7 | 31.9 | 31.9 | |
6.25 µg/mL | 68.5 | 56.8 | 52.6 | 50.6 | |
3.125 µg/mL | 75.6 | 71.4 | 70.8 | 62.2 | |
1.56 µg/mL | 97.4 | 89.3 | 91.1 | 74.4 | |
9 | 100 µg/mL | 18.4 | 16.2 | 8.1 | 13.1 |
50 µg/mL | 26.3 | 25.3 | 17.6 | 18.9 | |
25 µg/mL | 35.1 | 36.4 | 26.8 | 27.4 | |
12.5 µg/mL | 43.7 | 48.1 | 37.2 | 38.2 | |
6.25 µg/mL | 61.0 | 67.5 | 55.5 | 66.7 | |
3.125 µg/mL | 84.2 | 88.7 | 78.1 | 76.1 | |
1.56 µg/mL | 100 | 100 | 96.0 | 98.5 | |
10 | 100 µg/mL | 23.1 | 20.1 | 19.0 | 15.1 |
50 µg/mL | 30.0 | 32.4 | 26.4 | 24.2 | |
25 µg/mL | 41.5 | 42.8 | 35.9 | 35.1 | |
12.5 µg/mL | 53.8 | 55.5 | 43.2 | 42.8 | |
6.25 µg/mL | 67.3 | 71.2 | 65.3 | 59.9 | |
3.125 µg/mL | 89.7 | 95.3 | 83.6 | 81.7 | |
1.56 µg/mL | 100 | 100 | 100 | 100 | |
11 | 100 µg/mL | 24.8 | 29.1 | 26.6 | 25.9 |
50 µg/mL | 35.7 | 39.7 | 37.3 | 38.8 | |
25 µg/mL | 47.4 | 52.5 | 49.2 | 50.1 | |
12.5 µg/mL | 58.1 | 63.8 | 60.5 | 65.9 | |
6.25 µg/mL | 72.3 | 77.9 | 74.1 | 78.6 | |
3.125 µg/mL | 91.8 | 96.2 | 97.2 | 96.7 | |
1.56 µg/mL | 100 | 100 | 100 | 100 |
Compounds | Conc. (µg/mL) | HePG-2 | HCT-116 | PC3 | MCF-7 |
---|---|---|---|---|---|
12 | 100 µg/mL | 19.9 | 18.3 | 21.0 | 22.9 |
50 µg/mL | 27.2 | 26.8 | 29.2 | 31.2 | |
25 µg/mL | 36.1 | 39.5 | 38.3 | 43.8 | |
12.5 µg/mL | 51.3 | 50.4 | 47.5 | 54.2 | |
6.25 µg/mL | 71.4 | 72.6 | 65.4 | 71.3 | |
3.125 µg/mL | 89.5 | 90.7 | 86.7 | 88.5 | |
1.56 µg/mL | 100 | 100 | 100 | 100 | |
17 | 100 µg/mL | 29.1 | 31.5 | 19.7 | 24.2 |
50 µg/mL | 42.2 | 45.2 | 27.5 | 35.5 | |
25 µg/mL | 51.9 | 55.8 | 39.1 | 46.1 | |
12.5 µg/mL | 71.3 | 69.7 | 51.6 | 57.3 | |
6.25 µg/mL | 84.5 | 81.3 | 73.4 | 72.6 | |
3.125 µg/mL | 100 | 99.4 | 92.4 | 96.8 | |
1.56 µg/mL | 100 | 100 | 100 | 100 | |
18 | 100 µg/mL | 35.9 | 33.6 | 31.1 | 28.6 |
50 µg/mL | 48.1 | 45.5 | 42.5 | 39.5 | |
25 µg/mL | 60.5 | 57.1 | 53.2 | 51.3 | |
12.5 µg/mL | 72.8 | 70.0 | 65.4 | 62.9 | |
6.25 µg/mL | 89.2 | 91.2 | 78.0 | 77.8 | |
3.125 µg/mL | 100 | 100 | 99.3 | 96.4 | |
1.56 µg/mL | 100 | 100 | 100 | 100 | |
19 | 100 µg/mL | 38.7 | 43.7 | 29.5 | 31.9 |
50 µg/mL | 53.2 | 56.5 | 42.8 | 46.0 | |
25 µg/mL | 70.3 | 69.1 | 53.1 | 59.2 | |
12.5 µg/mL | 89.1 | 84.2 | 72.2 | 71.3 | |
6.25 µg/mL | 100 | 98.3 | 84.6 | 93.5 | |
3.125 µg/mL | 100 | 100 | 100 | 100 | |
1.56 µg/mL | 100 | 100 | 100 | 100 | |
20 | 100 µg/mL | 48.1 | 53.7 | 45.0 | 39.8 |
50 µg/mL | 61.3 | 72.5 | 56.2 | 54.6 | |
25 µg/mL | 73.4 | 85.4 | 71.6 | 70.3 | |
12.5 µg/mL | 86.7 | 98.9 | 82.1 | 94.1 | |
6.25 µg/mL | 99.8 | 100 | 98.4 | 100 | |
3.125 µg/mL | 100 | 100 | 100 | 100 | |
1.56 µg/mL | 100 | 100 | 100 | 100 | |
21 | 100 µg/mL | 15.7 | 13.1 | 7.7 | 8.4 |
50 µg/mL | 22.1 | 19.2 | 16.1 | 17.3 | |
25 µg/mL | 27.4 | 27.6 | 24.5 | 26.5 | |
12.5 µg/mL | 42.9 | 38.5 | 38.2 | 37.0 | |
6.25 µg/mL | 65.8 | 66.8 | 55.3 | 55.4 | |
3.125 µg/mL | 83.2 | 75.7 | 78.1 | 78.8 | |
1.56 µg/mL | 99.0 | 97.1 | 94.4 | 95.9 |
2.2.2. Antioxidant Activity Using 2,2′-Azino-bis(3-ethylbenzthiazoline-6-sulfonic Acid (ABTS) Inhibition
Comp. No. | Antioxidant Activity Absorbance | (ABTS Method) Inhibition (%) | Bleomycin Dependent DNA Damage |
---|---|---|---|
4 | 0.261 | 48.4 | 0.116 |
6 | 0.271 | 46.4 | 0.129 |
8 | 0.060 | 88.1 | 0.069 |
9 | 0.127 | 74.9 | 0.077 |
10 | 0.143 | 71.7 | 0.088 |
11 | 0.204 | 59.7 | 0.094 |
12 | 0.162 | 68.0 | 0.081 |
17 | 0.201 | 60.3 | 0.104 |
18 | 0.230 | 54.5 | 0.074 |
19 | 0.257 | 49.2 | 0.122 |
20 | 0.268 | 47.0 | 0.143 |
21 | 0.071 | 86.0 | 0.074 |
Control of ABTS | 0.506 | 0 | - |
Ascorbic acid | 0.056 | 88.9 | 0.072 |
2.2.3. Bleomycin-Dependent Deoxyribonucleic Acid (DNA) Damage
2.2.4. Structure Activity Relationship
- Compound 8 showed very strong activities against the four cell lines, which may be due to the presence of two NH and C≡N groups.
- Compound 9 showed very strong activities against the PC-3 and MCF-7 cell lines, and strong activity against the HePG2 and HCT-116 cell lines which may be due to the presence of NH and the oxadiazole moiety.
- Compounds 10 and 12 showed strong activity against the four cell lines, which may be due to the presence of two NH groups and the sulfur atom, which has a vacant orbital that can accept electrons.
- Compound 17 showed strong and moderate activity due to the presence of NH and OH groups.
- Compound 21 showed very strong activities against the HCT-116, PC-3 and MCF-7 cell lines, and strong activity against the HePG2 cell line which may be due to the presence of NH of the tetrazine moiety and C≡N group with α-H and β-NH.
- Compounds 4, 6, 11, 18, 19 and 20 showed either weak or moderate activities because of the absence of C≡N as in compounds 4, 6 or the absence of α-H as in compounds 11, 18, 19 and 20.
3. Materials and Methods
3.1. General Information
3.2. Synthesis
3.2.1. Ethyl 2-(8-(4-Chloro-3-methylphenyl)-3-thioxo-1,2,4,6,7-pentaazaspiro[4,5]deca-1,7-diene-6-yl)acetate (2)
3.2.2. 2-(3-(4-Chloro-3-methylphenyl)-6-oxo-5,6-dihydropyridazin-1(4H)-yl)-N′-(2-oxoindolin-3-ylidene)-acetohydrazide (4)
3.2.3. 6-(4-Chloro-3-methylphenyl)-2-(2-(3,5-dimethyl-1H-pyrazol-1-yl)-2-oxoethyl)-4,5-dihydropyridazin-3(2H)-one (5)
3.2.4. General Procedure for the Synthesis of Compounds 6 and 7
3.2.5. General Procedure for Synthesizing Compounds 8 and 9
3.2.6. Another Method for Synthesizing Compound 8
3.2.7. Another Method for Synthesizing Compound (9)
3.2.8. General Procedure for Synthesizing Compounds 10–13
3.2.9. General Procedure for Synthesizing Compounds 14 and 15
3.2.10. 2-(3-(4-Chloro-3-methylphenyl)-6-oxo-5,6-dihydropyridazin-1(4H)-yl)-N-(3-cyano-4,6-dimethyl-2-oxopyridin-1(2H)-yl)acetamide (16)
3.2.11. General Procedure for Synthesizing Compounds 17 and 18
3.2.12. General Procedure for Synthesizing Compounds 19 and 20
3.2.13. 2-(6-((3-(4-Chloro-3-methylphenyl)-6-oxo-5,6-dihydropyridazin-1(4H)-yl) methyl)-1,2-dihydro-1,2,4,5-tetrazin-3-yl)acetonitrile (21)
3.2.14. 2-(5-((3-(4-Chloro-3-methylphenyl)-6-oxo-5,6-dihydropyridazin-1(4H)-yl)methyl)-4H-benzo[g]- [1,3,4,6]-thiatriazocin-2-yl)acetonitrile (22)
3.3. Pharmacological Activity
3.3.1. Cytotoxicity Assay
MTT Assay
3.3.2. Antioxidant Assay
ABTS Method
Bleomycin—Dependent DNA Damage Assay
4. Conclusions
Supplementary Materials
Acknowledgments
Author Contributions
Conflicts of Interest
References
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- Sample Availability: Not available.
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Shaker, S.A.; Marzouk, M.I. Utilization of Cyanoacetohydrazide and Oxadiazolyl Acetonitrile in the Synthesis of Some New Cytotoxic Heterocyclic Compounds. Molecules 2016, 21, 155. https://doi.org/10.3390/molecules21020155
Shaker SA, Marzouk MI. Utilization of Cyanoacetohydrazide and Oxadiazolyl Acetonitrile in the Synthesis of Some New Cytotoxic Heterocyclic Compounds. Molecules. 2016; 21(2):155. https://doi.org/10.3390/molecules21020155
Chicago/Turabian StyleShaker, Soheir A., and Magda I. Marzouk. 2016. "Utilization of Cyanoacetohydrazide and Oxadiazolyl Acetonitrile in the Synthesis of Some New Cytotoxic Heterocyclic Compounds" Molecules 21, no. 2: 155. https://doi.org/10.3390/molecules21020155
APA StyleShaker, S. A., & Marzouk, M. I. (2016). Utilization of Cyanoacetohydrazide and Oxadiazolyl Acetonitrile in the Synthesis of Some New Cytotoxic Heterocyclic Compounds. Molecules, 21(2), 155. https://doi.org/10.3390/molecules21020155