Synthesis of Novel Biologically Active Proflavine Ureas Designed on the Basis of Predicted Entropy Changes
Abstract
:1. Introduction
2. Results and Discussion
3. Materials and Methods
3.1. General Remarks
3.2. Synthesis
3.2.1. Synthesis of 3,6-Diisothiocyanatoacridine (9)
3.2.2. General Protocol for the Synthesis of Thioureas 10a–10k
3.2.3. General Protocol for the Synthesis of the Ureas 11a–11l
3.3. Biology
3.3.1. Cell Line
3.3.2. Agilent xCELLigence Real-Time Cell Analysis
Statistical Analysis
3.3.3. Screening of Anticancer Activity-NCI-60 Panels
3.4. Molecular Modeling
3.4.1. Normal Mode Analysis
3.4.2. Calculation of ΔS° Value
3.4.3. Calculation of LogP Value
3.4.4. Calculation of Score Value
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Sample Availability
References
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R– a | Urea a | S°300Kb | S°340Kc | ΔS° d | LogP e | IC50 f | KB g |
---|---|---|---|---|---|---|---|
(Cal/K.Mol) | (Cal/K.Mol) | (Cal/K.Mol) | (μM) | (105) | |||
n-Hexyl | 11j | 235.004 | 252.682 | 17.67 | 7.03 | 3.7 | 0.9 |
n-Pentyl | 11k | 215.063 | 231.541 | 16.47 | 6.02 | 13.3 | 1.7 |
n-Butyl | 11l | 197.441 | 212.554 | 15.11 | 5.01 | 11.5 | 2.4 |
n-Propyl | 11m | 188.083 | 201.859 | 13.77 | 3.89 | 29.2 | 3.8 |
Ethyl | 11n | 172.036 | 184.490 | 12.45 | 2.88 | 60.1 | 4.2 |
R– a | Model a | S°300K b | S°340K c | ΔS° d | LogP e | Score f |
---|---|---|---|---|---|---|
(Cal/K.Mol) | (Cal/K.Mol) | (Cal/K.Mol) | ||||
Aziridine | I | 153.9 | 165.7 | 11.4 | 2.35 | 13.75 |
N,N’-Dimethylamine | XXI | 171.9 | 184.5 | 12.5 | 1.84 | 14.34 |
Azetidine | III | 163.9 | 176.4 | 12.6 | 2.89 | 15.49 |
Cyklopropylamine | II | 176.9 | 189.8 | 12.9 | 2.86 | 15.76 |
Pyrolidine | V | 184.1 | 197.8 | 13.7 | 3.43 | 17.13 |
Cyklobutylamine | IV | 186.1 | 200.1 | 14 | 3.45 | 17.45 |
N,N’-Diethylamine | XXII | 196.6 | 211.9 | 15.1 | 4.13 | 19.23 |
Piperidine | VII | 184.6 | 199.4 | 14.8 | 4.44 | 19.24 |
Cyklopentylamine | VI | 195.6 | 210.7 | 15.1 | 4.93 | 20.03 |
Aniline | X | 177.7 | 192.2 | 14.5 | 5.53 | 20.03 |
Benzylamine | XII | 178.1 | 193.3 | 15.3 | 4.93 | 20.23 |
Azepane | IX | 194.6 | 210.6 | 16 | 5.45 | 21.45 |
Cyklohexylamine | VIII | 210.2 | 226.4 | 16.3 | 5.94 | 22.24 |
4-Methylbenzylamine | XIV | 240.4 | 223.0 | 17.4 | 5.38 | 22.78 |
4-Methylaniline | XI | 205.5 | 221.8 | 16.36 | 6.42 | 22.78 |
Phenylethylamine | XIII | 211.6 | 228.8 | 17.2 | 5.74 | 22.94 |
(R/S)-Methylethylamine | XVII/XVIII | 227.6 | 245.2 | 17.6 | 6.05 | 23.65 |
N,N’-Dipropylamine | XXIII | 239.3 | 257.2 | 17.9 | 6.14 | 24.04 |
Phenylpropylamine | XV | 230.2 | 248.6 | 18.48 | 6.78 | 25.26 |
Phenylbutylamine | XVI | 235.5 | 255.2 | 19.73 | 7.32 | 27.05 |
Adamantylamine | XX | 210.2 | 229.3 | 19.2 | 7.98 | 27.18 |
n-Dekylamine | XIX | 283.5 | 306.3 | 22.8 | 11.07 | 33.87 |
HL-60 | NCI-H522 | HCT-116 | U251 | LOXIMVI | OVCAR-8 | RXF393 | DU-145 | HS578T | |
---|---|---|---|---|---|---|---|---|---|
GI50 (μM) | |||||||||
Hexyl-11j | 0.26 | 0.32 | 0.36 | 0.65 | 0.22 | 0.45 | 1.41 | 2.00 | 0.63 |
Azepyl-11b | 0.23 | 1.58 | 0.44 | 0.54 | 1.41 | 1.70 | 0.22 | 1.74 | 0.78 |
Phenyl-11c | 1.20 | 1.58 | 0.23 | 0.98 | 0.47 | 1.15 | 1.48 | 2.40 | 1.51 |
Phenylethyl-11f | 0.26 | 0.32 | 0.35 | 0.74 | 0.20 | 0.81 | 1.32 | 1.23 | 0.28 |
Fluorouracil | 4.57 | 11.48 | 0.49 | 2.24 | 0.49 | 2.40 | 2.88 | 0.63 | 14.13 |
Cisplatin | 6.61 | 9.12 | 17.78 | 11.22 | 6.61 | 28.18 | 20.42 | 6.76 | 23.44 |
Amsacrine | 0.02 | 0.89 | 0.50 | 0.21 | 0.15 | 0.83 | 2.24 | nd * | nd * |
Doxorubicin | 0.08 | 0.03 | 0.03 | 0.03 | 0.03 | 0.07 | 0.08 | 0.07 | 0.13 |
Cancer Cell Line | Hexyl-11j | Azepyl-11b | Phenyl-11c | Phenylethyl-11f |
---|---|---|---|---|
Log10 GI50 (M) | ||||
CCRF-CEM | −6.56 | −6.44 | −6.56 | −6.52 |
HL-60(TB) | −6.59 | −6.64 | −5.92 | −6.58 |
K-562 | −6.49 | −6.46 | −6.44 | −6.41 |
MOLT-4 | −6.67 | −6.28 | −6.25 | −6.59 |
RPMI-8226 | −5.79 | −6.5 | −5.27 | −5.65 |
SR | −6.58 | −6.53 | −6.54 | −6.41 |
COLO205 | −5.85 | −5.87 | −6.24 | −6.5 |
HCC-2998 | −5.84 | −5.73 | −6.25 | −6.35 |
HCT-116 | −6.44 | −6.36 | −6.63 | −6.46 |
HCT-15 | −4.00 | −5.94 | −4.43 | −4.00 |
HT29 | −5.65 | −6.37 | −5.72 | −5.86 |
KM12 | −5.71 | −5.72 | −5.83 | −5.79 |
SW-620 | −6.25 | −5.97 | −6.48 | −6.46 |
Average | −6.03 | −6.22 | −6.04 | −6.12 |
Urea | IC50 (μM) | ||
---|---|---|---|
24 h | 48 h | 96 h | |
Hexyl-11j | 0.15 | 0.13 | 0.13 |
Phenylethyl-11f | 131.00 | 180.00 | 137.00 |
Azepyl-11b | 131.00 | 180.00 | 137.00 |
Phenyl-11c | 3.20 | 34.80 | 38.50 |
Amsacrine | 0.01 | 27.70 | 5.80 |
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Janovec, L.; Kovacova, E.; Semelakova, M.; Kvakova, M.; Kupka, D.; Jager, D.; Kozurkova, M. Synthesis of Novel Biologically Active Proflavine Ureas Designed on the Basis of Predicted Entropy Changes. Molecules 2021, 26, 4860. https://doi.org/10.3390/molecules26164860
Janovec L, Kovacova E, Semelakova M, Kvakova M, Kupka D, Jager D, Kozurkova M. Synthesis of Novel Biologically Active Proflavine Ureas Designed on the Basis of Predicted Entropy Changes. Molecules. 2021; 26(16):4860. https://doi.org/10.3390/molecules26164860
Chicago/Turabian StyleJanovec, Ladislav, Eva Kovacova, Martina Semelakova, Monika Kvakova, Daniel Kupka, David Jager, and Maria Kozurkova. 2021. "Synthesis of Novel Biologically Active Proflavine Ureas Designed on the Basis of Predicted Entropy Changes" Molecules 26, no. 16: 4860. https://doi.org/10.3390/molecules26164860
APA StyleJanovec, L., Kovacova, E., Semelakova, M., Kvakova, M., Kupka, D., Jager, D., & Kozurkova, M. (2021). Synthesis of Novel Biologically Active Proflavine Ureas Designed on the Basis of Predicted Entropy Changes. Molecules, 26(16), 4860. https://doi.org/10.3390/molecules26164860