Synthesis, Selective Cytotoxic Activity against Human Breast Cancer MCF7 Cell Line and Molecular Docking of Some Chalcone-Dihydropyrimidone Hybrids
Abstract
:1. Introduction
2. Results and Discussion
2.1. Syntehsis of Chalcone-DHPM Hybrids
2.2. Cytotoxicity of Chalcone-DHPM Hybrids
2.3. Comparative Cytotoxicity Profile of Hybrids and Their Parental Molecules
3. Materials and Methods
3.1. Chemistry
3.1.1. General Procedure for Synthesis of Propargyloxy Benzaldehydes (2a–e) [43]
2-(Prop-2-ynil-1-oxy)benzaldehyde (2a)
3-(Prop-2-ynil-1-oxy)benzaldehyde (2b)
4-(Prop-2-ynil-1-oxy)benzaldehyde (2c)
3-Methoxy-4-(prop-2-ynil-1-oxy)benzaldehyde (2d)
4-Methoxy-3-(prop-2-ynil-1-oxy)benzaldehyde (2e)
3.1.2. General Procedure for Synthesis of Chalcones (4a–e) [44]
1-Phenyl-3-(2-prop-2-ynil-1-oxyphenyl)-(2E)-propen-1-one (4a)
1-Phenyl-3-(3-prop-2-ynil-1-oxyphenyl)-(2E)-propen-1-one (4b)
1-Phenyl-3-(4-prop-2-ynil-1-oxyphenyl)-(2E)-propen-1-one (4c)
1-Phenyl-3-(3-methoxy-4-prop-2-ynil-1-oxyphenyl)-(2E)-propen-1-one (4d)
1-Phenyl-3-(4-methoxy-3-prop-2-ynil-1-oxyphenyl)-(2E)-propen-1-one (4e)
3.1.3. General Procedure for the Synthesis of Chloro-DHPMs (7a,b) [45]
Ethyl 6-(2-chloromethyl)-4-phenyl-3,4-dihydropyrimidin-(1H)-2-one-5-carboxylate (7a)
Ethyl 6-chloromethyl-4-(3,4,5-trimethoxyphenyl)-3,4-dihydropyrimidin-(1H)-2-one-5-carboxylate (7b)
3.1.4. General Procedure for the Synthesis of Azido-DHPMs (8a,b) [46]
Ethyl 6-(azidomethyl)-4-phenyl-3,4-dihydropyrimidin-(1H)-2-one-5-carboxylate (8a)
Ethyl 6-(azidomethyl)-4-(3,4,5-trimethoxyphenyl)-3,4-dihydropyrimidin-(1H)-2-one-5-carboxylate (8b)
3.1.5. General Procedure for the Synthesis of Chalcone-DHPM Hybrids (9a–j) [47]
Ethyl 6-((4-((2-(3-oxo-3-phenylprop-1-(E)-en-1-yl)phenoxy)methyl)-(1H)-1,2,3-triazol-1-yl)methyl)-4-phenyl-3,4-dihydropyrimidin-(1H)-2-one-5-carboxylate (9a)
Ethyl 6-((4-((3-(3-oxo-3-phenylprop-1-(E)-en-1-yl)phenoxy)methyl)-(1H)-1,2,3- triazol-1-yl)methyl)-4-phenyl-3,4-dihydropyrimidin-(1H)-2-one-5-carboxylate (9b)
Ethyl 6-((4-((4-(3-oxo-3-phenylprop-1-(E)-en-1-yl)phenoxy)methyl)-(1H)-1,2,3-triazol-1-yl)methyl)-4-phenyl-3,4-dihydropyrimidin-(1H)-2-one-5-carboxylate (9c)
Ethyl 6-((2-methoxy-4-((4-(3-oxo-3-phenylprop-1-(E)-en-1-yl)phenoxy)methyl)-(1H)-1,2,3-triazol-1-yl)methyl)-4-phenyl-3,4-dihydropyrimidin-(1H)-2-one-5-carboxylate (9d)
Ethyl 6-((3-methoxy-4-((3-(3-oxo-3-phenylprop-1-(E)-en-1-yl)phenoxy)methyl)-(1H)-1,2,3-triazol-1-yl)methyl)-4-phenyl-3,4-dihydropyrimidin-(1H)-2-one-5-carboxylate (9e)
6-((4-((2-(3-oxo-3-phenylprop-1-(E)-en-1-yl)phenoxy)methyl)-(1H)-1,2,3-triazol-1-yl)methyl)-4-(3,4,5-trimethoxyphenyl)-3,4-dihydropyrimidin-(1H)-2-one-5 carboxylate (9f)
Ethyl 6-((4-((3-(3-oxo-3-phenylprop-1-(E)-en-1-yl)phenoxy)methyl)-(1H)-1,2,3-triazol-1-yl)methyl)-4-(3,4,5-trimethoxyphenyl)-3,4-dihydropyrimidin-(1H)-2-one-5-carboxylate (9g)
Ethyl 6-((4-((4-(3-oxo-3-phenylprop-1-(E)-en-1-yl)phenoxy)methyl)-(1H)-1,2,3-triazol-1-yl)methyl)-4-(3,4,5-trimethoxyphenyl)-3,4-dihydropyrimidin-(1H)-2-one-5-carboxylate (9h)
Ethyl 6-((3-methoxy-4-((4-(3-oxo-3-phenylprop-1-(E)-en-1-yl)phenoxy)methyl)-(1H)-1,2,3-triazol-1-yl)methyl)-4-(3,4,5-trimethoxyphenyl-3,4-dihydropyrimidin-(1H)-2-one-5-carboxylate (9i)
Ethyl 6-((3-methoxy-4-((3-(3-oxo-3-phenylprop-1-(E)-en-1-yl)phenoxy) methyl)-(1H)-1,2,3-triazol-1-yl)methyl)-4-(3,4,5-trimethoxyphenyl)-3,4-dihydropyrimidin-(1H)-2-one-5-carboxylate (9j)
3.2. Cell Culture and MTT Assay
3.3. Molecular Docking
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Data Availability Statement
Conflicts of Interest
References
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Entry | Hybrid Compounds | H-Triazole (ppm) | Yield (%) a | |
---|---|---|---|---|
1 | 9a | 9.00 | 75 | |
2 | 9b | 8.35 | 70 | |
3 | 9c | 8.43 | 78 | |
4 | 9d | 8.48 | 90 | |
5 | 9e | 8.39 | 75 | |
6 | 9f | 9.39 | 72 | |
7 | 9g | 8.42 | 70 | |
8 | 9h | 8.56 | 62 | |
9 | 9i | 8.49 | 90 | |
10 | 9j | 8.43 | 85 |
Hybrid | U-251 | MCF-7 | NCI/ADR-RES | OVCAR-3 | HT-29 | HaCaT |
---|---|---|---|---|---|---|
9a | 27.0 ± 11.0 | 6.2 ± 3.4 | 6.4 ± 3.4 | 9.9 ± 3.5 | 18.6 ± 8.7 | 6.7 ± 3.0 |
9b | 26.1 ± 8.2 | 5.3 ± 2.7 | 14.5 ± 5.5 | 9.4 ± 3.4 | 43.8 ± 12.8 | 22.0 ± 3.9 |
9c | 65.1 ± 11.0 | 11.5 ± 5.1 | 54.8 ± 9.6 | 70.6 ± 12.1 | 134.1 ± 33.7 | 22.0 ± 3.9 |
9d | 74.6 ± 17.5 | 4.7 ± 2.5 | 89.8 ± 12.1 | 109.7 ± 31.8 | 109.7 ± 46.5 | 17.5 ± 2.3 |
9e | 24.6 ± 6.6 | 12.3 ± 3.4 | 26.8 ± 7.2 | 15.3 ± 3.4 | 41.1 ± 7.9 | 12.0 ± 2.2 |
9f | 10.9 ± 4.1 | 7.5 ± 2.7 | 40.4 ± 11.2 | 12.5 ± 4.7 | 25.1 ± 12.5 | 6.4 ± 3.0 |
9g | 13.3 ± 3.8 | 4.9 ± 1.4 | 39.6 ± 7.9 | 17.9 ± 5.8 | 93.9 ± 29.8 | 15.1 ± 4.1 |
9h | 70.4 ± 9.5 | 5.8 ± 2.6 | >153.0 | 36.4 ± 7.2 | >153.0 | 100.7 ± 13.0 |
9i | 104.1 ± 33.2 | 5.3 ± 2.5 | >146.3 | 23.5 ± 6.0 | 103.4 ± 18.1 | 34.8 ± 4.8 |
9j | 128.7 ± 35.5 | 14.6 ± 4.5 | >146.3 | 88.9 ± 11.0 | >146.3 | 69.3 ± 7.9 |
DOXO | >18.4 | 0.4 ± 0.0 | 22.6 ± 3.9 | 11.6 ± 5.1 | >18.4 | 1.6 ± 0.0 |
Cell Lines | Chalcone | DHPM | Hybrid | Selectivity Index (SI) |
---|---|---|---|---|
4d | 8a | 9d (4d + 8a) | 9d | |
U-251 | 251.51 | >332 | 74.62 | 0.23 |
MCF-7 | >342 | >332 | 4.72 | 3.71 |
NCI/ADR-RES | >342 | >332 | 89.79 | 0.19 |
HaCaT | 97.05 | >332 | 17.52 | - |
4b | 8b | 9g (4b + 8b) | 9g | |
U-251 | 24.47 | >255 | 13.30 | 1.14 |
MCF-7 | 80.33 | >255 | 4.89 | 3.10 |
NCI/ADR-RES | >381 | >255 | 39.62 | 0.38 |
HaCaT | 23.33 | >255 | 15.14 | - |
4c | 8b | 9h (4c + 8b) | 9h | |
U-251 | 126.50 | >255 | 70.37 | 1.43 |
MCF-7 | >381 | >255 | 5.81 | 17.33 |
NCI/ADR-RES | >381 | >255 | >153 | - |
HaCaT | 37.59 | >255 | 100.7 | - |
Hybrid | Binding Energy (kcal/mol) | Binding Interaction | Bond Lenght (Å) |
---|---|---|---|
9d | −10.32 | Leu346 | 6.96 |
Thr347a | 3.93 | ||
Asp351a | 3.29 | ||
Glu353a | 8.27 | ||
9g | −12.02 | Leu346 | 6.33 |
Thr347a | 4.05 | ||
Asp351a | 3.68 | ||
Asn532 | 2.36 | ||
Leu536 | 2.50 | ||
9h | −7.52 | Leu346 | 4.86 |
Thr347a | 5.35 | ||
Asp351a | 4.27 |
Hybrid | Binding Energy (kcal/mol) | Binding Interaction | Bond Lenght (Å) |
---|---|---|---|
9d | −9.38 | Cys530 | 2.38 |
Ser537 | 9.88 | ||
Asp351 | 4.46 | ||
9g | −7.85 | Cys530 | 2.59 |
Ser537 | 7.26 | ||
Leu536 | 2.36 | ||
9h | −8.51 | Cys530 | 4.24 |
Ser537 | 7.01 | ||
Leu536 | 7.62 |
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Mass, E.B.; de Lima, C.A.; D’Oca, M.G.M.; Sciani, J.M.; Longato, G.B.; Russowsky, D. Synthesis, Selective Cytotoxic Activity against Human Breast Cancer MCF7 Cell Line and Molecular Docking of Some Chalcone-Dihydropyrimidone Hybrids. Drugs Drug Candidates 2022, 1, 3-21. https://doi.org/10.3390/ddc1010002
Mass EB, de Lima CA, D’Oca MGM, Sciani JM, Longato GB, Russowsky D. Synthesis, Selective Cytotoxic Activity against Human Breast Cancer MCF7 Cell Line and Molecular Docking of Some Chalcone-Dihydropyrimidone Hybrids. Drugs and Drug Candidates. 2022; 1(1):3-21. https://doi.org/10.3390/ddc1010002
Chicago/Turabian StyleMass, Eduardo B., Carolina A. de Lima, Marcelo G. M. D’Oca, Juliana M. Sciani, Giovanna B. Longato, and Dennis Russowsky. 2022. "Synthesis, Selective Cytotoxic Activity against Human Breast Cancer MCF7 Cell Line and Molecular Docking of Some Chalcone-Dihydropyrimidone Hybrids" Drugs and Drug Candidates 1, no. 1: 3-21. https://doi.org/10.3390/ddc1010002