Finding a Novel Chalcone–Cinnamic Acid Chimeric Compound with Antiproliferative Activity against MCF-7 Cell Line Using a Free-Wilson Type Approach
Abstract
:1. Introduction
2. Results
2.1. QSAR Study
2.2. QSAR Interpretation
2.3. Design and Synthesis of 2′-Hydroxy-4′-cinnamate Chalcone
2.4. Biological Activity
2.5. In Silico ADME/tox Studies of A–K
3. Material and Methods
3.1. Calculation of the Molecular Descriptors
3.2. DataSet
3.3. Construction of QSAR Model
3.4. Statistical Validation
3.5. External Validation
3.6. Chemistry
3.6.1. Synthesis of 2′,4′-Dihydroxychalcone (A)
3.6.2. Synthesis of 2′-Hydroxy-4′-cinnamate Chalcone (B)
3.7. Antiproliferative Activity
3.8. In Silico ADME/tox
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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Compound | IC50 (Mean ± S.D., µM) | IC50 Pred | |||||
---|---|---|---|---|---|---|---|
IHH | HepG2 | Hep3B | Caski | A-549 | MCF-7 | MCF-7 | |
A | 100 ± 2.2 | 58.33 ± 2.5 | 54.16 ± 2 | 58.33 ± 3 | 112.5 ± 2.5 | 62.5 ± 4 | 55.95 |
A1 | 140.47 ± 4.5 | 109.52 ± 3.0 | 90.47 ± 4.0 | 114.28 ± 3.0 | 185.71 ± 7.0 | 88 ± 5.0 | 1.23 |
B | 56.76 ± 2 | 11.89 ± 0.4 | 10.27 ± 0.2 | 29.72 ± 1.4 | 56.75 ± 2.3 | 14.86 ± 0.5 | 17.86 |
Paclitaxel * | 0.08 ± 0.005 | 0.0065 ± 0.0007 | 0.008 ± 0.001 | 0.007 ± 0.0009 | 0.0352 ± 0.007 | 0.0395 ± 0.0046 | - |
Molecule | MLOGP a | TPSA b | BBB c | Pgp Substrate d | GI Absorption e | Lipinski Violations | Ghose Violations | Veber Violations | Mutagenicity | Carcinogenicity | Hepatotoxicity |
---|---|---|---|---|---|---|---|---|---|---|---|
A | 2.17 | 57.53 | Yes | No | High | 0 | 0 | 0 | Inactive | Inactive | Inactive |
B | 3.22 | 63.6 | Yes | No | High | 0 | 0 | 0 | Inactive | Inactive | Inactive |
C | 2.79 | 76.49 | No | No | High | 0 | 2 | 0 | Inactive | Inactive | Inactive |
D | 3.15 | 76.49 | No | No | High | 0 | 2 | 0 | Inactive | Inactive | Active |
E | 3.24 | 76.49 | No | No | High | 0 | 3 | 0 | Inactive | Inactive | Inactive |
F | 3.34 | 76.49 | No | No | Low | 1 | 3 | 0 | Inactive | Inactive | Active |
G | 2.98 | 76.49 | No | No | High | 0 | 2 | 0 | Inactive | Inactive | Inactive |
H | 3.52 | 76.49 | No | Yes | Low | 1 | 3 | 0 | Inactive | Inactive | Inactive |
I | 2.43 | 85.72 | No | No | High | 0 | 3 | 0 | Inactive | Inactive | Inactive |
J | 3.16 | 85.72 | No | Yes | Low | 1 | 3 | 1 | Inactive | Inactive | Inactive |
K | 3.79 | 85.72 | No | Yes | Low | 1 | 3 | 1 | Inactive | Inactive | Active |
Molecular Descriptors | Descriptor Family | Program |
---|---|---|
ZM1, ZM1V, ZM2, ZM2V, Qindex, SNar, HNar, GNar, Xt, Dz, Ram, Pol, LPRS, VDA, MSD, SMTI, SMTIV, GMTI, GMTIV, Xu, SPI, W, WA, Har, Har2, QW, TI1, TI2, STN, HyDp, RHyDp, w, ww, Rww, D/D, Wap, WhetZ, Whetm, Whetv, Whete, Whetp, J, JhetZ, Jhetm, Jhetv, Jhete, Jhetp, MAXDN, MAXDP, DELS, TIE, S0K, S1K, S2K, S3K, PHI, BLI, PW2, PW3, PW4, PW5, PJI2, CSI, ECC, AECC, DECC, MDDD, UNIP, CENT, VAR, BAC, Lop, ICR, D/Dr03, D/Dr04, D/Dr05, D/Dr06, D/Dr07, D/Dr08, D/Dr09, D/Dr10, D/Dr11, D/Dr12, T(N..N), T(N..O), T(N..S), T(N..F), T(N..Cl), T(N..Br), T(N..I), T(O..O), T(O..S), T(O..F), T(O..Cl), T(O..Br), T(S..S), T(S..F), T(S..Cl), T(S..Br),T(F..F), T(F..Cl), T(F..Br), T(Cl..Cl), T(Cl..Br), T(Br..Br) | Topological | DRAGON |
W3D, J3D, H3D, AGDD, DDI, ADDD, G1, G2, RGyr, SPAN, SPAM, MEcc, SPH, ASP, FDI, PJI3, L/Bw, SEig, HOMA, RCI, AROM, HOMT, DISPm, QXXm, QYYm, QZZm, DISPv, QXXv, QYYv, QZZv, DISPe, QXXe, QYYe, QZZe, DISPp, QXXp, QYYp, QZZp, G(N..N), G(N..O), G(N..S), G(N..P), G(N..F), G(N..Cl), G(N..Br), G(N..I), G(O..O), G(O..S), G(O..P), G(O..F), G(O..Cl), G(O..Br), G(O..I), G(S..S), G(S..P), G(S..F), G(S..Cl), G(S..Br), G(S..I), G(P..P), G(P..F), G(P..Cl), G(P..Br), G(P..I), G(F..F), G(F..Cl), G(F..Br), G(F..I), G(Cl..Cl), G(Cl..Br), G(Cl..I), G(Br..Br), G(Br..I), G(I..I) | Geometrical | DRAGON |
nCp, nCs, nCt, nCq, nCrs, nCrt, nCrq, nCar, nCbH, nCb-, nCconj, nR=Cp, nR=Cs, nR=Ct, nR#CH/X, nR#C-, nRCOOH, nArCOOH, nRCOOR, nArCOOR, nRCONH2, nRCONHR, nArCONHR, nRCONR2, nArCONR2, nROCON, nArOCON, nArCOSR, nRCO, nArCO, nCONN, nN=C-N<, nC(=N)N2, nRC=N, nArC=N, nArCNO, nRNH2, nArNH2, nRNHR, nArNHR, nRNR2, nArNR2, nN-N, nRCN, nArCN nN+, nNq, nRNHO, nArNHO, nArNO2, nN(CO)2, nC=N-N<, nROH, nArOH, nOHp, nOHs, nOHt, nROR, nArOR, nRSR, nSO, nS(=O)2, nSO2OH, nSO3OH, nSO2N, nCH2RX, nR=CRX, nCHRX2, nCRX3, nArX, nCXr, nCXr=, nCconjX, nOxiranes, nAzetidines, nBeta-Lactams, nPyrrolidines, nOxolanes, nPyrroles, nPyrazoles, nImidazoles, nFuranes, nThiophenes, nIsoxazoles, nThiazoles, nTriazoles, nPyridines, nPyridazines, nPyrimidines, nPyrazines, nHDon, nHAcc, nHBonds | Functional Groups | DRAGON |
C-001, C-002, C-003, C-004, C-005, C-006, C-007, C-008, C-009, C-010, C-011, C-012, C-013, C-014, C-015, C-016, C-017, C-018, C-019, C-020, C-021, C-022, C-024, C-025, C-026, C-027, C-028, C-029, C-030, C-031, C-032, C-033, C-034, C-035, C-036, C-037, C-038, C-039, C-040, C-041, C-042, C-043, C-044, H-046, H-047, H-048, H-049, H-050, H-051, H-052, H-053, H-054, O-056, O-057, O-058, O-059, O-060, O-061, N-066, N-067, N-068, N-069, N-070, N-071, N-072, N-073, N-074, N-075, N-076, N-077, N-078, N-079, F-081, F-082, F-083, F-084, F-085, Cl-086, Cl-089, Cl-090, Br-091, Br-092, Br-094, S-106, S-107, S-108, S-109, S-110 | Atom-centred fragments | DRAGON |
Ui, Hy, Hy2, AMR, TPSA(NO), TPSA(Tot), MLOGP, MLOGP2, ALOGP, ALOGP2 | Molecular properties | DRAGON |
R2_F, R4_F, R2_Cl, R3_Cl, R4_Cl, R2_Br, R4_Br, R2_Me, R3_Me, R4_Me, R5_Me, R2_OH, R4_OH, R6_OH, R2_OMe, R3_OMe, R4_OMe, R5_OMe, R6_OMe, R2_CF3, R3_CF3, R4_CF3, R5_CF3, R4_Et, R3_OCF3, R3_Bn, R5_Bn, R3_NO2, R2_OAc, R5_OAc, R3_CO2Ph, R4_FA026, R4_FA027, R4_FA028, R4_OC6H13, R4_FA029, R5_(4′MPPD), R4_(4′PPZ), R4_(1PPD), R4_(4′EPPD), R4_(4′MPPZ), R4_(4BiPPD), R4_FA031, R4_FA032, R4_FA033, R4_FA030, R2_TMPhO, R′2_F, R′3_F, R′4_F, R′5_F, R′6_F, R′2_Cl, R′3_Cl, R′4_Cl, R′5_Cl, R′2_Br, R′3_Br, R′4_Br, R′5_Br, R′2_Me, R′3_Me, R′4_Me, R′5_Me, R′2_CF3, R′4_CF3, R′2_OH, R′4_OH, R′2_OMe, R′3_OMe, R′4_OMe, R′5_OMe, R′3_NO2, R′4_NO2, R′5_NO2, R′3_CN, R′4_CN, R′3_OC6H13, R′4_SMe, R′4_(4MPPZ), R′4_FB034, R′4_FB035, R′4_nPr, R′3_NH2, R′4_NMe2 | Indicative variables | N/A |
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Ventura-Salazar, I.A.Y.; Palacios-Can, F.J.; González-Maya, L.; Sánchez-Carranza, J.N.; Antunez-Mojica, M.; Razo-Hernández, R.S.; Alvarez, L. Finding a Novel Chalcone–Cinnamic Acid Chimeric Compound with Antiproliferative Activity against MCF-7 Cell Line Using a Free-Wilson Type Approach. Molecules 2023, 28, 5486. https://doi.org/10.3390/molecules28145486
Ventura-Salazar IAY, Palacios-Can FJ, González-Maya L, Sánchez-Carranza JN, Antunez-Mojica M, Razo-Hernández RS, Alvarez L. Finding a Novel Chalcone–Cinnamic Acid Chimeric Compound with Antiproliferative Activity against MCF-7 Cell Line Using a Free-Wilson Type Approach. Molecules. 2023; 28(14):5486. https://doi.org/10.3390/molecules28145486
Chicago/Turabian StyleVentura-Salazar, Isis A. Y., Francisco J. Palacios-Can, Leticia González-Maya, Jessica Nayelli Sánchez-Carranza, Mayra Antunez-Mojica, Rodrigo Said Razo-Hernández, and Laura Alvarez. 2023. "Finding a Novel Chalcone–Cinnamic Acid Chimeric Compound with Antiproliferative Activity against MCF-7 Cell Line Using a Free-Wilson Type Approach" Molecules 28, no. 14: 5486. https://doi.org/10.3390/molecules28145486