Acylation of Oleanolic Acid Oximes Effectively Improves Cytotoxic Activity in In Vitro Studies
Abstract
:1. Introduction
2. Materials and Methods
2.1. Materials
2.2. Synthesis of A-Ring Oleanolic Acid Derivatives 2–4, 5a–5g, 6a–6g, and 7a–7g
2.2.1. Synthesis of Oximes 2–4
2.2.2. Acylation of Oximes 2–4 with Carboxylic Acids
2.3. SAR Analysis
2.4. Cytotoxic Activity of A-Ring Oleanolic Acid Derivatives
2.4.1. MTT Assay
2.4.2. Apoptosis
2.5. Physicochemical Properties, Pharmacokinetics, and ADMETox Activity
3. Results
3.1. Synthesis of Cytotoxic Agents
3.2. SAR Analysis
3.3. Cytotoxic Activity of Acylated Oximes
3.3.1. In Vivo Assay
3.3.2. Selectivity Index
3.3.3. The Apoptosis Assay
3.4. Physicochemical Properties, Pharmacokinetics, and ADMETox Activity
4. Discussion
4.1. Synthesis
4.2. SAR Analysis
4.3. Biological Tests
4.4. ADMETox Analysis
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
List of Abbreviation (In Alphabetical Order)
References
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Comp. No. | Compound Structure | IC50 [μM] (±s) | ||||||
---|---|---|---|---|---|---|---|---|
R1 | R2 | R3 | HeLa | KB | MCF-7 | A-549 | HDF | |
1 (OA) | --- | H2 | OH | 11.82 * (0.19) | 14.93 * (0.12) | 13.95 * (0.11) | 8.79 (0.28) | 17.89 (0.33) |
2 | H | H2 | OMe | 13.23 * (0.70) | 12.40 * (0.80) | 15.30 * (1.60) | 13.00 (0.07) | 21.14 (0.39) |
5a | CH3- | 11.08 (0.16) | 11.39 (0.26) | 10.53 (1.19) | 10.60 (0.04) | 29.04 (0.01) | ||
5b | Cl-CH2- | 19.84 (0.06) | 18.44 (0.71) | 18.03 (0.03) | 19.79 (0.09) | 37.02 (0.16) | ||
5c | CH3-CH2- | 38.06 (0.11) | 38.75 (0.28) | 38.12 (0.33) | 36.17 (0.62) | 39.92 (0.21) | ||
5d | C6H5- | 84.92 (0.11) | 83.18 (0.37) | 83.29 (0.01) | 73.94 (0.99) | 113.02 (0.54) | ||
5e | 3′-NO2-C6H4- | 20.14 (0.51) | 23.91 (0.19) | 21.84 (0.74) | 21.08 (0.31) | 37.96 (0.37) | ||
5f | 4′-NO2-C6H4- | 62.02 (0.63) | 60.74 (0.48) | 61.36 (0.41) | 69.93 (0.19) | 132.19 (0.03) | ||
5g | 3′,5′-di-NO2-C6H3- | 4.19 (0.09) | 4.61 (0.33) | 5.18 (0.59) | 4.82 (0.61) | 6.22 (0.39) | ||
3 | H | O2 | OMe | 125.17 (0.80) | 60.27 (0.40) | 48.42 (0.40) | 63.02 (0.03) | 60.95 (0.12) |
6a | CH3- | 27.45 (0.94) | 27.91 (0.02) | 28.03 (0.002) | 28.16 (0.18) | 49.05 (0.08) | ||
6b | Cl-CH2- | 61.03 (0.38) | 60.99 (0.25) | 64.12 (0.08) | 61.77 (0.18) | 88.01 (0.40) | ||
6c | CH3-CH2- | 24.02 (0.07) | 24.82 (0.19) | 23.02 (0.94) | 24.16 (0.31) | 49.04 (0.27) | ||
6d | C6H5- | 28.43 (0.13) | 27.21 (0.07) | 27.50 (0.07) | 27.83 (0.08) | 41.99 (0.02) | ||
6e | 3′-NO2-C6H4- | 71.18 (0.94) | 70.01 (0.16) | 74.98 (0.71) | 74.03 (0.02) | 97.03 (0.13) | ||
6f | 4′-NO2-C6H4- | 28.30 (0.44) | 26.29 (0.04) | 26.01 (0.71) | 28.11 (0.62) | 37.17 (0.01) | ||
6g | 3′,5′-di-NO2-C6H3- | 6.11 (0.39) | 8.98 (0.12) | 6.62 (0.19) | 5.39 (0.05) | 7.27 (0.21) | ||
4 | H | 8.72 (0.20) | 8.72 (0.70) | 7.42 (0.60) | 7.29 (0.19) | 13.92 (0.06) | ||
7a | CH3- | 82.19 (0.38) | 81.49 (0.30) | 81.03 (0.18) | 84.92 (0.03) | 116.03 (0.81) | ||
7b | Cl-CH2- | 19.24 (0.14) | 19.83 (0.79) | 15.63 (0.12) | 19.34 (0.22) | 39.05 (0.39) | ||
7c | CH3-CH2- | H2 | OMor | 142.59 (0.56) | 149.74 (0.04) | 152.88 (0.14) | 147.81 (0.19) | 179.41 (0.05) |
7d | C6H5- | 45.27 (0.15) | 45.92 (0.41) | 41.74 (0.09) | 46.82 (0.27) | 66.17 (0.02) | ||
7e | 3′-NO2-C6H4- | 12.05 (0.07) | 13.88 (0.14) | 10.18 (0.17) | 13.82 (0.14) | 28.02 (0.16) | ||
7f | 4′-NO2-C6H4- | 60.04 (0.22) | 61.52 (0.11) | 57.16 (0.38) | 62.94 (0.77) | 85.13 (0.02) | ||
7g | 3′,5′-di-NO2-C6H3- | 6.24 (0.02) | 6.01 (0.39) | 7.27 (0.05) | 6.52 (0.38) | 9.16 (0.03) |
Comp. No. | Compound structure | Selectivity Index | |||||
---|---|---|---|---|---|---|---|
R1 | R2 | R3 | HeLa | KB | MCF-7 | A-549 | |
1 (OA) | --- | H2 | OH | 1.51 | 1.20 | 1.28 | 2.03 |
2 | H | H2 | OMe | 1.60 | 1.70 | 1.38 | 1.62 |
5a | CH3- | 2.62 | 2.55 | 2.76 | 2.74 | ||
5b | Cl-CH2- | 1.87 | 2.01 | 2.05 | 1.87 | ||
5c | CH3-CH2- | 1.05 | 1.03 | 1.05 | 1.10 | ||
5d | C6H5- | 1.33 | 1.36 | 1.36 | 1.53 | ||
5e | 3′-NO2-C6H4- | 1.88 | 1.59 | 1.74 | 1.80 | ||
5f | 4′-NO2-C6H4- | 2.13 | 2.18 | 2.15 | 1.89 | ||
5g | 3′,5′-di-NO2-C6H3- | 1.48 | 1.35 | 1.20 | 1.29 | ||
3 | H | O2 | OMe | 0.49 | 1.01 | 1.26 | 0.97 |
6a | CH3- | 1.79 | 1.76 | 1.75 | 1.74 | ||
6b | Cl-CH2- | 1.44 | 1.44 | 1.37 | 1.42 | ||
6c | CH3-CH2- | 2.04 | 1.97 | 2.13 | 2.03 | ||
6d | C6H5- | 1.48 | 1.54 | 1.53 | 1.51 | ||
6e | 3′-NO2-C6H4- | 1.36 | 1.39 | 1.29 | 1.31 | ||
6f | 4′-NO2-C6H4- | 1.31 | 1.41 | 1.43 | 1.32 | ||
6g | 3′,5′-di-NO2-C6H3- | 1.19 | 0.81 | 1.10 | 1.34 | ||
4 | H | 1.60 | 1.60 | 1.88 | 1.91 | ||
7a | CH3- | 1.41 | 1.42 | 1.43 | 1.37 | ||
7b | Cl-CH2- | 2.03 | 1.97 | 2.50 | 2.02 | ||
7c | CH3-CH2- | H2 | OMor | 1.27 | 1.20 | 1.17 | 1.21 |
7d | C6H5- | 1.46 | 1.44 | 1.58 | 1.41 | ||
7e | 3′-NO2-C6H4- | 2.32 | 2.02 | 2.75 | 2.03 | ||
7f | 4′-NO2-C6H4- | 1.42 | 1.38 | 1.49 | 1.35 | ||
7g | 3′,5′-di-NO2-C6H3- | 1.47 | 1.52 | 1.26 | 1.40 |
Comp. No. | Cell Line, IC50 [μM] | Compound Structure, Position, and Type of Substituent | Lit. | ||||
---|---|---|---|---|---|---|---|
HeLa | MCF-7 | KB | at the C-17 | at the C-12 | at the C-3 | ||
1 (OA) | 11.82 | 13.95 | 14.93 | -COOH | double bond (C12–C-13) | -OH | [22] |
3 | 5.03 | >10 | 6.19 | -COOCH3 | =O | =O | [22] |
4 | 1.80 | 1.60 | 1.74 | -COOCH3 | =O | =NOH | [22] |
6 | 7.38 | >10 | 8.51 | -COOCH3 | =O | CH3COO- | [22] |
7 | 1.34 | >10 | 2.06 | -COOCH3 | =NOH | CH3COO- | [22] |
8b | 9.19 | 7.26 | 9.42 | -COOCH3 | =NOC(O)CH2Cl | CH3COO- | [22] |
8c | 4.41 | 3.76 | 4.90 | -COOCH3 | =NOC(O)CH2Br | CH3COO- | [22] |
8d | 1.87 | 2.13 | 0.72 | -COOCH3 | =NOC(O)CH2CH3 | CH3COO- | [22] |
8e | 9.84 | 9.28 | >10 | -COOCH3 | =NOC(O)C6H4-(o-NO2) | CH3COO- | [22] |
13 | 3.93 | 2.69 | 3.93 | -COOCH3 | double bond (C12–C-13) | A-lactam system | [23] |
17 | 2.81 | 1.61 | 3.42 | -COOCH3 | double bond (C12–C-13) and =O at the C-11 | A-lactam system | [23] |
19 | 8.72 | 7.42 | 8.72 | -C(O)Morph | double bond (C12–C-13) | =NOH | [23] |
21 | 1.48 | 2.41 | 1.48 | -C(O)Morph | double bond (C12–C-13) | A-lactam system | [23] |
6 | 4.19 | 5.18 | 4.61 | -COOCH3 | double bond (C12–C-13) | =NOC(O)-C6H3-(3,5-di-NO2) | [27] |
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Bednarczyk-Cwynar, B.; Ruszkowski, P. Acylation of Oleanolic Acid Oximes Effectively Improves Cytotoxic Activity in In Vitro Studies. Pharmaceutics 2024, 16, 86. https://doi.org/10.3390/pharmaceutics16010086
Bednarczyk-Cwynar B, Ruszkowski P. Acylation of Oleanolic Acid Oximes Effectively Improves Cytotoxic Activity in In Vitro Studies. Pharmaceutics. 2024; 16(1):86. https://doi.org/10.3390/pharmaceutics16010086
Chicago/Turabian StyleBednarczyk-Cwynar, Barbara, and Piotr Ruszkowski. 2024. "Acylation of Oleanolic Acid Oximes Effectively Improves Cytotoxic Activity in In Vitro Studies" Pharmaceutics 16, no. 1: 86. https://doi.org/10.3390/pharmaceutics16010086
APA StyleBednarczyk-Cwynar, B., & Ruszkowski, P. (2024). Acylation of Oleanolic Acid Oximes Effectively Improves Cytotoxic Activity in In Vitro Studies. Pharmaceutics, 16(1), 86. https://doi.org/10.3390/pharmaceutics16010086