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