Synthesis of α-Aminophosphonic Acid Derivatives Through the Addition of O- and S-Nucleophiles to 2H-Azirines and Their Antiproliferative Effect on A549 Human Lung Adenocarcinoma Cells
Abstract
:1. Introduction
2. Results
2.1. Chemistry
2.2. Biological Results
3. Materials and Methods
3.1. Chemistry
3.1.1. General Information
3.1.2. Experimental Procedure and Characterization Data for Compounds 4, 5 and 6
General Procedure and Spectral Data for the Addition of Aliphatic Alcohols to Functionalized 2H-Azirines 1
General Procedure and Spectral Data for the N-Tosyl Functionalization of α-Aminophosphine Oxide and Phosphonate Acetals 4
One Pot Procedure for the Synthesis of N-tosyl-α-Aminophosphonate Acetal 5d
General Procedure and Spectral Data of β-Keto-α-Aminophosphine Oxide 6
3.1.3. Experimental Procedure and Characterization Data for Compounds 7, 8 and 9
General procedure and spectral data for the addition of 2,2,2-trifluoroethanol (2c) to functionalized 2H-azirines 1
General Procedure and Spectral Data of Allylic α-Aminophosphine Oxide 8
General Procedure and Spectral Data of Allylic N-Tosyl α-Aminophosphine Oxide 9
3.1.4. Experimental Procedure and Characterization Data for Compounds 10, 11 and 12
General Procedure and Spectral Data for the Addition of Phenols (2d–e) to Functionalized 2H-Azirines 1
General Procedure for the Preparation of Allylic α-Aminophosphine Oxides 11
One Pot Procedure for the Synthesis of N-Tosyl Allyl Amines 12 Derived From Phosphonate
3.1.5. Experimental Procedure and Characterization Data for Compounds 14, 15 and 16
General Procedure and Spectral Data for the Addition of Thiophenols and Thiols to 2H-Azirines 1
General Procedure and Spectral Data for the N-Tosyl Functionalization of Allylic α-Amino-phosphine Oxides and Phosphonates 15
One pot procedure for the synthesis of N-tosyl allylic α-aminophosphonates 16d–e
3.2. Biology
3.2.1. Materials
3.2.2. Cytotoxicity Assays
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Entry | Compound | R | R1 | R2 | Yield (%) 1 |
---|---|---|---|---|---|
1 | 4a | Ph | Me | Me | 74 |
2 | 4b | Ph | Et | Me | 92 |
3 | 4c | Ph | Ph | Me | 81 |
4 | 4d | Ph | Me | Et | 56 |
5 | 4e | OiPr | Me | Me | 69 |
6 | 4f | OEt | Me | Me | 61 |
7 | 5a | Ph | Me | Me | 80 |
8 | 5b | OiPr | Me | Me | 62 |
9 | 5c | OEt | Me | Me | 64 |
10 | 5d | OEt | Me | Et | 70 2 |
11 | 6 | OiPr | Me | 68 |
Entry | Compound 1 | R | Ar | Yield (%) 2 |
---|---|---|---|---|
1 | 10a | Ph | Ph | 70 |
2 | 10b | Ph | 2-Naph | 3 |
3 | 11a | Ph | Ph | 93 |
4 | 11b | Ph | 2-Naph | 74 |
5 | 12a | OEt | Ph | 88 4 |
6 | 12b | OEt | 2-Naph | 67 4 |
Entry | Compound | R | R1 | R2 | Yield (%) 1 |
---|---|---|---|---|---|
1 | 14a | Ph | Me | Ph | 92 2 |
2 | 14b | Ph | Me | p-MeC6H4 | 3,4 |
3 | 14c | Ph | Ph | Ph | 60 2 |
4 | 15a | Ph | Ph | 91 2 | |
5 | 15b | Ph | p-MeC6H4 | 89 4 | |
6 | 15c | Ph | p-FC6H4 | 76 4 | |
7 | 15d | Ph | p-MeOC6H4 | 70 4 | |
8 | 15e | OEt | Ph | 41 4 | |
9 | 15f | Ph | Et | 64 2 | |
10 | 16a | Ph | Ph | 87 | |
11 | 16b | Ph | p-MeC6H4 | 84 | |
12 | 16c | OEt | Ph | 85 | |
13 | 16d | OEt | p-FC6H4 | 85 5 | |
14 | 16e | OEt | p-MeC6H4 | 73 5 |
Entry | Comp. | R | R1 | R2 | Cytotoxicity IC50 (µM) 1 | |
---|---|---|---|---|---|---|
Lung A549 | MRC-5 | |||||
1 | 0.48 ± 0.017 [50] | >50 [51] | ||||
2 2 | 4a | Ph | Me | Me | 4.4 ± 0.72 | >50 |
3 | 4b | Ph | Et | Me | 21.3 ± 0.22 | >50 |
4 | 4c | Ph | Ph | Me | 16.1 ± 2.03 | >50 |
5 | 4d | Ph | Me | Et | 9.6 ± 1.13 | >50 |
6 | 4e | OiPr | Me | Me | 4.6 ± 0.31 | >50 |
7 | 4f | OEt | Me | Me | 1.3 ± 0.10 | >50 |
8 | 5a | Ph | Me | Me | 8.2 ± 0.23 | >50 |
9 | 5b | OiPr | Me | Me | 1.7 ± 0.30 | >50 |
10 | 5c | OEt | Me | Me | 4.5 ± 0.45 | >50 |
11 | 5d | OEt | Me | Et | 3.7 ± 0.49 | >50 |
12 | 6 | OiPr | Me | >50 | 3 | |
13 | 7 | Ph | CH2CF3 | 3.6 ± 0.70 | >50 | |
14 | 10a | Ph | Ph | 13.3 ± 1.69 | >50 | |
15 | 8 | Ph | CH2CF3 | >50 | >50 | |
16 2 | 11a | Ph | Ph | 1.9 ± 0.13 | >50 | |
17 | 11b | Ph | 2-Naph | 2.7 ± 0.44 | 33.6 ± 3.73 | |
18 | 9 | Ph | CH2CF3 | 3.5 ± 0.77 | >50 | |
19 | 12a | OEt | Ph | 4.8 ± 0.90 | >50 | |
20 | 12b | OEt | 2-Naph | 2.1 ± 0.22 | 17.5 ± 1.47 |
Entry | Comp. | R | R1 | R2 | Cytotoxicity IC50 (µM) 1 | |
---|---|---|---|---|---|---|
Lung A549 | MRC-5 | |||||
1 | DOX | 0.48 ± 0.017 [27] | >50 [28] | |||
2 2 | 14c | Ph | Ph | Ph | 1.1 ± 0.32 | 4.9 ± 0.49 |
3 3 | 15a | Ph | Ph | 2.6 ± 0.68 | 15.9 ± 2.79 | |
4 | 15b | Ph | p-MeC6H4 | 5.1 ± 0.77 | 14.9 ± 1.61 | |
5 3 | 15c | Ph | p-FC6H4 | 0.1 ± 0.08 | >50 | |
6 | 15d | Ph | p-MeOC6H4 | 2.6 ± 0.42 | >50 | |
7 | 15e | OEt | Ph | 7.2 ± 0.49 | >50 | |
8 | 16a | Ph | Ph | 1.2 ± 0.09 | >50 | |
9 | 16b | Ph | p-MeC6H4 | 2.1 ± 0.15 | >50 | |
10 3 | 16c | OEt | Ph | 0.2 ± 0.07 | 24.1 ± 3.55 | |
11 | 16d | OEt | p-FC6H4 | 3.0 ± 0.98 | >50 | |
12 | 16e | OEt | p-MeC6H4 | 3.9 ± 0.63 | >50 |
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Carramiñana, V.; Ochoa de Retana, A.M.; Palacios, F.; de los Santos, J.M. Synthesis of α-Aminophosphonic Acid Derivatives Through the Addition of O- and S-Nucleophiles to 2H-Azirines and Their Antiproliferative Effect on A549 Human Lung Adenocarcinoma Cells. Molecules 2020, 25, 3332. https://doi.org/10.3390/molecules25153332
Carramiñana V, Ochoa de Retana AM, Palacios F, de los Santos JM. Synthesis of α-Aminophosphonic Acid Derivatives Through the Addition of O- and S-Nucleophiles to 2H-Azirines and Their Antiproliferative Effect on A549 Human Lung Adenocarcinoma Cells. Molecules. 2020; 25(15):3332. https://doi.org/10.3390/molecules25153332
Chicago/Turabian StyleCarramiñana, Victor, Ana M. Ochoa de Retana, Francisco Palacios, and Jesús M. de los Santos. 2020. "Synthesis of α-Aminophosphonic Acid Derivatives Through the Addition of O- and S-Nucleophiles to 2H-Azirines and Their Antiproliferative Effect on A549 Human Lung Adenocarcinoma Cells" Molecules 25, no. 15: 3332. https://doi.org/10.3390/molecules25153332