Synthesis and Bioactivity Assessment of Novel Spiro Pyrazole-Oxindole Congeners Exhibiting Potent and Selective in vitro Anticancer Effects
Abstract
1. Introduction
2. Results and Discussion
2.1. Chemistry
2.2. Biological Activity
2.2.1. Antimicrobial Activity
2.2.2. Antioxidant Activity
2.2.3. Evaluation of In Vitro Anti-Proliferative Activity
2.2.4. Apoptosis Induction in MCF-7and HCT-116 Cancer Cells
2.2.5. Effect of the Newly Synthesized Compounds on Key Pro- and Antiapoptotic Markers
3. Materials and Methods
3.1. Chemicals and Supplies
3.2. Chemical and Physical Characterization of Synthesized Spiro Pyrazole-Oxindole Congeners
3.3. Synthesis
3.3.1. General Procedure for the Preparation of 3-hydroxy-3-(2-(aryl)-2-oxoethyl)indolin-2-ones 5a–c, 6a–c and 7a–i
3.3.2. General Procedure for the Preparation of 3-(2-(aryl)-2-oxo-ethylidene)indolin-2-ones 8a–c, 9a–c and 10a–i
3.3.3. General Procedure for the Synthesis of 2’,4’-dihydrospiro(indoline-3,3’-pyrazol)-2-one Derivatives 11a–c, 12a–c and 13a–i
3.3.4. General Procedure for the Synthesis of 2’-phenyl-2’,4’-dihydrospiro(indoline-3,3’-pyrazol)-2-ones 14a–i
3.3.5. General Procedure for Synthesis of Quinoline-4-carboxylic acids 15a, b
3.4. Biological Assays
3.4.1. Antimicrobial Evaluation
3.4.2. Antioxidant Evaluation
3.4.3. Anticancer Evaluation
Cell Culture
MTT Cytotoxicity Assay
3.5. Apoptosis Assay
Author Contributions
Funding
Conflicts of Interest
References
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Sample Availability: Samples of the synthesized spiro pyrazole-oxindole compounds are available from the authors upon request and MTA formulation. |
Compd. No b | Inhibition Zone (mm) | ||||||
---|---|---|---|---|---|---|---|
Gram-Positive | Gram-Negative | Yeast | Fungi | ||||
S. aureus (ATCC 6538) | B. subtilis (ATCC 6633) | P. aeruginosa (ATCC 27853) | E. coli (DSMZ 1058) | C. albicans (ATCC 10231) | S. cerevisiae (ATCC 9080) | A. niger (NRRL A-326) | |
11a | - | 12 | 8 | - | 20 | 16 | - |
11b | - | 12 | 12 | - | 18 | 18 | - |
11c | - | 10 | 10 | - | 20 | 25 | - |
12a | 8 | 16 | 18 | - | 12 | 10 | - |
12b | 10 | 18 | 24 | - | 10 | 10 | 8 |
12c | 10 | 18 | 20 | - | 10 | 10 | - |
13a | - | - | - | - | 18 | 20 | - |
15a | 8 | 16 | 24 | - | 12 | - | 10 |
15b | 8 | 10 | - | - | 8 | - | - |
Amoxicillin | 25.6 | 28.4 | - | - | - | - | - |
Ciprofloxacin | - | - | 30.2 | 25.8 | - | - | - |
Amphotericin B | - | - | - | - | 24.8 | 23.5 | 26.7 |
Compd. No | Scavenging Activity (%) a at Different Time (min) | |||
---|---|---|---|---|
15 | 30 | 45 | 60 | |
11a | 6.86 ± 1.17 | 10.26 ± 1.37 | 17.73 ± 1.28 | 26.87 ± 1.56 |
11b | 9.60 ± 1.77 | 14.28 ± 1.52 | 20.44 ± 1.65 | 30.76 ± 2.04 |
11c | 40.65 ± 1.28 | 40.65 ± 1.81 | 40.65 ± 1.67 | 40.65 ± 1.35 |
12a | 56.43 ± 1.08 | 67.09 ± 1.45 | 76.92 ± 1.51 | 81.41 ± 1.37 |
12b | 17.29 ± 1.53 | 23.46 ± 1.64 | 30.56 ± 1.49 | 40.65 ± 1.46 |
12c | 9.76 ± 1.76 | 10.24 ± 1.26 | 11.39 ± 1.53 | 13.97 ± 1.55 |
13a | 41.14 ±1.25 | 45.77 ± 1.36 | 56.55 ± 1.99 | 64.08 ± 2.01 |
13b | 43.52± 1.98 | 47.05 ± 1.81 | 56.33 ± 1.29 | 65.55 ± 1.55 |
13c | 13.97± 1.36 | 20.97 ± 1.26 | 23.96 ± 1.51 | 35.13 ± 1.61 |
13d | 19.32± 1.24 | 31.32 ± 1.81 | 25.92 ± 1.24 | 39.70 ± 1.99 |
13e | 9.10 ± 1.38 | 26.15 ± 1.26 | 36.70 ± 1.62 | 48.13 ± 1.82 |
13f | 17.90 ± 1.62 | 28.28 ± 1.61 | 34.28 ± 1.27 | 40.74 ± 1.54 |
13g | 25.95 ± 1.85 | 44.00 ± 1.46 | 49.25 ± 1.77 | 53.67 ± 1.81 |
13h | 15.22 ± 1.98 | 16.31 ± 1.96 | 20.58 ± 1.48 | 35.71 ± 1.91 |
14i | 45.88 ± 1.05 | 54.32 ± 1.08 | 60.60 ± 1.64 | 69.18 ± 1.65 |
14a | 41.09 ± 2.05 | 51.52 ± 1.91 | 53.98 ± 2.06 | 59.22 ± 2.14 |
14b | 42.36 ± 1.45 | 58.08 ± 1.28 | 60.27 ± 1.66 | 65.96 ± 1.64 |
14c | 14.85 ± 1.36 | 22.56 ± 1.79 | 26.29 ± 1.23 | 39.48 ± 1.61 |
14d | 39.91 ± 1.75 | 41.82 ± 1.49 | 44.96 ± 1.37 | 55.44 ± 1.33 |
14e | 17.89 ± 1.23 | 28.18 ± 1.27 | 30.87 ± 1.98 | 34.89 ± 1.72 |
14f | 9.05 ± 1.63 | 10.15 ± 1.83 | 16.19 ± 1.21 | 22.93 ± 1.62 |
14g | 8.39 ± 1.14 | 11.87 ± 1.23 | 14.08 ± 2.01 | 26.55 ± 2.13 |
14h | 57.93 ± 1.36 | 67.35 ± 1.35 | 72.00 ± 1.82 | 85.99 ± 2.17 |
14i | 39.91 ± 1.87 | 41.82 ± 1.09 | 44.96 ± 1.66 | 55.44 ± 1.55 |
15a | 9.36 ± 1.25 | 14.15 ± 1.61 | 20.39 ± 1.92 | 24.77 ± 2.05 |
15b | 23.60 ± 1.36 | 32.73 ± 1.13 | 39.23 ± 1.29 | 47.48 |
Negative control | 0 | 0 | 0 | 0 |
Ascorbic acid | 94.37 ± 1.74 | 97.45 ± 1.32 | 98.78 ± 0.94 | 99.67 ± 0.28 |
Compd. No. | Growth Inhibition (%) | Growth Inhibition (%) | |||||||
---|---|---|---|---|---|---|---|---|---|
HCT-116 | HepG-2 | MCF-7 | BJ-1 | Compd. No. | HCT-116 | HepG-2 | MCF-7 | BJ-1 | |
11a | 96.2 | - | 94.3 | 6.2 | 13g | 92.4 | 81.9 | 91.6 | 13.0 |
11b | 94.9 | - | 92.3 | 10.1 | 13h | 91.3 | 79.5 | 93.4 | 14.1 |
11c | 30.2 | - | 0 | 45.2 | 13i | 97.7 | 96.8 | 97.8 | 69.4 |
12a | 96.7 | - | 93.6 | 9.1 | 14a | 91.2 | - | 90.4 | 14.2 |
12b | 95.1 | - | 97.4 | 5.0 | 14b | 84.6 | - | 80.3 | 8.1 |
12c | 12.4 | - | 6.3 | 62.3 | 14c | 91.8 | - | 92.3 | 13.6 |
13a | 96.9 | 89.3 | 96.4 | 11.6 | 14d | 96.2 | - | 94 | 9.5 |
13b | 94.5 | 81.4 | 95.4 | 10.4 | 14e | 35.1 | - | 85.3 | 16.6 |
13c | 97.9 | 90.9 | 97.8 | 5.1 | 14f | 91.4 | - | 89.3 | 14.5 |
13d | 94.6 | 82.7 | 96.4 | 7.0 | 14g | 92.1 | - | 90.6 | 16.0 |
13e | 90.4 | 79.8 | 96.4 | 10.3 | 14h | 96.2 | - | 94 | 86.5 |
13f | 86.5 | 72.8 | 79.7 | 16.4 | 14i | 35.1 | - | 52.3 | 78.6 |
Doxorubicin | 100 | 100 | 96.8 | 0 | 100 | 100 | 96.8 | 0 |
Compd. No. | IC50ug/ml | ||
---|---|---|---|
HCT-116 | HepG-2 | MCF-7 | |
11a | 5.7 | - | 21.1 |
11b | 16.4 | - | 19.4 |
12a | 5.8 | - | 20.2 |
12b | 7.9 | - | 16.7 |
13a | 31.3 | 60.6 | 32.4 |
13b | 21.3 | 48.0 | 24.0 |
13c | 14.7 | 27.0 | 24.1 |
13d | 26.9 | 60.9 | 25.4 |
13e | 35.4 | 67.1 | 31.9 |
13f | 28.4 | 83.6 | 32.1 |
13g | 35.3 | 72.2 | 43.0 |
13h | 20.5 | 19.2 | 5.8 |
14a | 36.2 | - | 32.3 |
14b | 40.1 | - | 36.3 |
14c | 40.5 | - | 32.5 |
14d | 30.7 | - | 31.6 |
14e | - | - | 54.0 |
14f | 35.8 | - | 31.2 |
14g | 38.0 | - | 37.4 |
Doxorubicin | 26.1 | 21.6 | 37.6 |
Compounds | Caspase-3 Activity % | Bcl-2 (ng/50 mg Protein) | p53 (Pg/50 mg Protein) | Bax (pg/50 mg Protein) |
---|---|---|---|---|
Control (MCF-7) | 10.2 ± 2.84 | 25.13 ± 3.45 | 4.18 ± 0.58 | 39.56 ± 4.56 |
11a | 16.67 ± 0.67 | 12.3 ± 2.26 | 14.45 ± 0.82 | 122.34 ± 3.45 |
11b | 16.19 ± 0.79 | 16.18 ± 0.78 | 5.85 ± 0.75 | 109.35 ± 4.05 |
12a | 14.18 ± 0.74 | 13.09 ± 2.27 | 13.31 ± 1.08 | 113.09 ± 1.98 |
12b | 47.25 ± 1.89 | 12.87 ± 1.84 | 29.58 ± 2.53 | 167.07 ± 4.83 |
13c | 39.07 ± 4.97 | 44.5 ± 4.56 | 7.34 ± 1.5 | 88.34 ± 3.79 |
Compounds | Caspase-3 Activity % | Bcl-2 (ng/50 mg Protein) | p53 (pg/50 mg Protein) | Bax (pg/50 mg Protein) |
---|---|---|---|---|
Control (HCT-116) | 13.60 ± 2.45 | 23.56 ± 3.56 | 1.68 ± 0.06 | 118.54 ± 0.83 |
11a | 19.12 ± 0.89 | 8.2 ± 1.26 | 16.2 ± 0.56 | 159.26 ± 0.96 |
11b | 14.04 ± 0.54 | 7.25 ± 1.45 | 3.25 ± 0.15 | 119.14 ± 1.65 |
12a | 17.43 ± 0.58 | 21.13 ± 1.45 | 23.11 ± 1.22 | 124.56 ± 0.95 |
12b | 33.12 ± 1.37 | 18.87 ± 1.84 | 48.07 ± 1.94 | 191.07 ± 1.95 |
13c | 47.32 ± 6.32 | 57.45 ± 6.45 | 2.34 ± 0.95 | 123.45 ±7.45 |
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Abo-Salem, H.M.; Nassrallah, A.; Soliman, A.A.F.; Ebied, M.S.; Elawady, M.E.; Abdelhamid, S.A.; El-Sawy, E.R.; Al-Sheikh, Y.A.; Aboul-Soud, M.A.M. Synthesis and Bioactivity Assessment of Novel Spiro Pyrazole-Oxindole Congeners Exhibiting Potent and Selective in vitro Anticancer Effects. Molecules 2020, 25, 1124. https://doi.org/10.3390/molecules25051124
Abo-Salem HM, Nassrallah A, Soliman AAF, Ebied MS, Elawady ME, Abdelhamid SA, El-Sawy ER, Al-Sheikh YA, Aboul-Soud MAM. Synthesis and Bioactivity Assessment of Novel Spiro Pyrazole-Oxindole Congeners Exhibiting Potent and Selective in vitro Anticancer Effects. Molecules. 2020; 25(5):1124. https://doi.org/10.3390/molecules25051124
Chicago/Turabian StyleAbo-Salem, Heba M., Amr Nassrallah, Ahmed A.F. Soliman, Manal S. Ebied, Mohamed E. Elawady, Sayeda A. Abdelhamid, Eslam R. El-Sawy, Yazeed A. Al-Sheikh, and Mourad A. M. Aboul-Soud. 2020. "Synthesis and Bioactivity Assessment of Novel Spiro Pyrazole-Oxindole Congeners Exhibiting Potent and Selective in vitro Anticancer Effects" Molecules 25, no. 5: 1124. https://doi.org/10.3390/molecules25051124
APA StyleAbo-Salem, H. M., Nassrallah, A., Soliman, A. A. F., Ebied, M. S., Elawady, M. E., Abdelhamid, S. A., El-Sawy, E. R., Al-Sheikh, Y. A., & Aboul-Soud, M. A. M. (2020). Synthesis and Bioactivity Assessment of Novel Spiro Pyrazole-Oxindole Congeners Exhibiting Potent and Selective in vitro Anticancer Effects. Molecules, 25(5), 1124. https://doi.org/10.3390/molecules25051124