Anticancer Activity and Safety Profile of Novel 1-(4-Fluorophenoxyacetyl)-4-substituted Thio/Semicarbazide Derivatives
Abstract
1. Introduction
2. Results and Discussion
2.1. Chemistry
2.2. X-Ray Structure Determination
2.3. ADMET Analysis
2.4. Biological Activity
2.4.1. Cytotoxicity Assessment
2.4.2. Cell Cycle Analysis and Apoptosis Detection
2.4.3. Analysis of Gene Expression Related to Antioxidant Defense, Cell Cycle Regulation, DNA Damage Sensing and Repair and Apoptosis
2.5. Molecular Docking
3. Experimental
3.1. Chemical Reagents and General Method
3.2. General Procedure for the Synthesis of 1-(4-Fluorophenoxyacetyl)-4-substituted Thiosemicarbazide (AB1–AB6)
3.3. General Procedure for the Synthesis of 1-(4-Fluorophenoxyacetyl)-4-substituted Semicarbazide (AB7–AB12)
3.4. X-Ray Structure Determinations
3.5. ADMET Analysis
3.6. Biological Evaluation
3.6.1. Cell Culture and Treatment
3.6.2. MTT Assay
3.6.3. Cell Cycle Analysis
3.6.4. Apoptosis Detection
3.6.5. Quantitative Real-Time PCR Analysis (qRT-PCR)
3.6.6. Statistical Analysis
3.7. Molecular Docking
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Compound | CYP1A2 | CYP2C19 | CYP2C9 | CYP2D6 | CYP3A4 |
---|---|---|---|---|---|
Inhibitor | Inhibitor | Inhibitor | Inhibitor | Inhibitor | |
AB1 | No | Yes | Yes | No | No |
AB2 | No | Yes | Yes | No | No |
AB3 | Yes | Yes | Yes | No | No |
AB4 | Yes | Yes | Yes | Yes | Yes |
AB5 | Yes | Yes | Yes | No | Yes |
AB6 | Yes | Yes | Yes | No | Yes |
AB7 | No | No | No | No | No |
AB8 | No | Yes | Yes | No | No |
AB9 | No | Yes | No | No | No |
AB10 | No | Yes | No | No | No |
AB11 | No | Yes | Yes | No | No |
AB12 | No | Yes | Yes | No | No |
Compound | Cell Lines | |||||||||
---|---|---|---|---|---|---|---|---|---|---|
Fibroblast | Prostate Cancer | Melanoma | Breast Cancer | Lung Cancer | ||||||
BJ | PC-3 | DU-145 | LNCaP | SK-MEL28 | A375 | G-361 | MCF-7 | MDA-MB-231 | NCI-H1563 | |
IC50 (μM) | ||||||||||
AB1 | 497.71 | >500 | >500 | 252.14 | >500 | >500 | 369.37 | >500 | >500 | >500 |
AB2 | 453.31 | >500 | >500 | 108.14 | 469.96 | 428.8 | 222.74 | >500 | >500 | >500 |
AB3 | 421.67 | 467.13 | 267.67 | 175.42 | 302.11 | 400.17 | 247.55 | 455.76 | 495.32 | 437.25 |
AB4 | 312.55 | 355.29 | 297.31 | 257.12 | 321.71 | 398.54 | 265.32 | 342.92 | 421.27 | 293.01 |
AB5 | 302.68 | 395.24 | 401.2 | 154.31 | 297.33 | 383.66 | 276.39 | 421.31 | 444.78 | 371.59 |
AB6 | <100 | 387.79 | 342.67 | 121.11 | 195.28 | 257.48 | 210.24 | 239.77 | 334.12 | 241.58 |
Cisplatin (reference) | - | 52.24 | 64.13 | 31.52 | 25.79 | 18.22 | 12.45 | 22.64 | 38.66 | 2.78 |
Compounds | ChemScore Value | Ligand–Amino Acids Interactions |
---|---|---|
AB1 | 70.91 | (C=)O6…H-N(Gly488)(B) N1-H…O(=C)(Arg487)(B) |
AB2 | 75.42 | C33-H…N(DA12)(D) |
AB3 | 74.18 | (C=)S3…H-C(DC8)(E) C33-H…N(DA12)(D) |
AB4 | 73.96 | (C=)34…H-C(ARG487)(B) N1-H…H-C(DC8)(E) C33-H…N(DG13)(D) C33-H…N(DA12)(D) |
AB5 | 74.55 | C22-Cl…H-N(DG13)(D) C24-Cl…H-O(ASP463)(B) |
AB6 | 72.16 | (C=)S3…H-C(DC8)(E) C33-H…N(DA12)(D) |
Data Collection/Crystal Data | AB2 | AB5 |
---|---|---|
Diffractometer | KM4 CCD four-circle diffractometer | |
Crystal size (mm) | 0.40 × 0.30 × 0.20 | 0.30 × 0.20 × 0.10 |
Radiation type | Mo Kα (λ = 0.71073 Å) | Mo Kα (λ = 0.71073 Å) |
Collected data scan | ω | ω |
Absorption correction | multi-scan CrysAlisPro [75] | multi-scan CrysAlisPro [75] |
Transmission factors, Tmin, Tmax | 0.609/1.000 | 0.730/1.000 |
Chemical formula | C15H13ClFN3O2S | C15H12Cl2FN3O2S, |
Mr (g mol−1) | 353.79 | 388.24 |
Crystal system, space group | ||
Lattice constant, a, b, c (Å), α, β, γ (°) | 8.6773 (15), 9.3488 (16), 10.6905 (15), 89.835 (13), 70.387 (14), 76.972 (15) | 8.7626 (8), 9.5122 (6), 10.7018 (9), 86.446 (6), 72.915 (7), 77.803 (6) |
V (Å3) | 793.4 (2) | 833.40 (12) |
Z | 2 | 2 |
Calculated density, Dcalc. (g cm−1) | 1.481 | 1.547 |
F(000) | 364 | 396 |
Absorption coefficient, µ (mm−1) | 0.395 | 0.538 |
Temperature (K) | 293 (2) | 293 (2) |
No. of measured reflections | 6495 | 5484 |
θ range (°) | 2.029–28.744 | 2.190–28.517 |
No. of unique reflections | 6495 | 3654 |
R[F2 > 2σ(F2)], wR(F2), S | 0.052, 0.119, 0.861 | 0.050, 0.117, 1.041 |
No. of observed reflections with I > 2σ(I), | 3395 | 2650 |
Δρmax, Δρmin (eÅ−3) | +0.290, –0.062 | +0.316, –0.069 |
Gene Symbol | Gene Name | Forward Sequence (3′→5′) | Reverse Sequence (3′→5′) |
---|---|---|---|
ATM | Ataxia telangiectasia mutated protein kinase | GCCGCGGTTGATACTACTTTG | GCAGCAGGGTGACAATAAACA |
ATR | ATR serine/threonine kinase | AATGGTTGGAGAATGCTGGC | ACATCACCCTTGGACCAGAG |
BAX | Bcl-2-like protein 4 | TCAGGATGCGTCCACCAAGAAG | TGTGTCCACGGCGGCAATCATC |
BCL-2 | BCL-2 apoptosis regulator | ACTGAGTACCTGAACCGGCA | TACAGTTCCACAAAGGCATCCCAG |
SOD2 | Superoxide dismutase 2 | CTTCAGGGTGGTATGGCTGT | TGGCCAGACCTTAATGTTCC |
CAT | Catalase | GCTCCGCAATCCTACACCAT | GGACATCGGGTTTCTGAGGG |
GPX1 | Glutathione peroxidase 1 | CAATCAGTTCGGACATCAGGAGA | TAAAGAGCGGGTGAGCCTTC |
TP53 | Tumor protein p53 | CCTCAGCATCTTATCCGAGTGG | TGGATGGTGGTACAGTCAGAGC |
CDKN1A | Cyclin dependent kinase inhibitor 1A/CDKN1A (p21) | CCTCATCCCGTGTTCTCCTTT | GTACCACCCAGCGGACAAGT |
CYCD | D-type cyclins | CCGTCCATGCGGAAGATC | GAAGACCTCCTCCTCGCACT |
RNA18SN5 | 18S ribosomal N5 | GAAACTGCGAATGGCTCATTAAA | CACAGTTATCCAAGTGGGAGAGG |
BACT | Beta-actin | AGAGCTACGAGCTGCCTGAC | AGCACTGTGTTGGCGTACAG |
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Kozyra, P.; Humeniuk, E.; Karczmarzyk, Z.; Borzęcki, A.; Adamczuk, G.; Korga-Plewko, A.; Wysocki, W.; Pitucha, M. Anticancer Activity and Safety Profile of Novel 1-(4-Fluorophenoxyacetyl)-4-substituted Thio/Semicarbazide Derivatives. Molecules 2025, 30, 1576. https://doi.org/10.3390/molecules30071576
Kozyra P, Humeniuk E, Karczmarzyk Z, Borzęcki A, Adamczuk G, Korga-Plewko A, Wysocki W, Pitucha M. Anticancer Activity and Safety Profile of Novel 1-(4-Fluorophenoxyacetyl)-4-substituted Thio/Semicarbazide Derivatives. Molecules. 2025; 30(7):1576. https://doi.org/10.3390/molecules30071576
Chicago/Turabian StyleKozyra, Paweł, Ewelina Humeniuk, Zbigniew Karczmarzyk, Adrian Borzęcki, Grzegorz Adamczuk, Agnieszka Korga-Plewko, Waldemar Wysocki, and Monika Pitucha. 2025. "Anticancer Activity and Safety Profile of Novel 1-(4-Fluorophenoxyacetyl)-4-substituted Thio/Semicarbazide Derivatives" Molecules 30, no. 7: 1576. https://doi.org/10.3390/molecules30071576
APA StyleKozyra, P., Humeniuk, E., Karczmarzyk, Z., Borzęcki, A., Adamczuk, G., Korga-Plewko, A., Wysocki, W., & Pitucha, M. (2025). Anticancer Activity and Safety Profile of Novel 1-(4-Fluorophenoxyacetyl)-4-substituted Thio/Semicarbazide Derivatives. Molecules, 30(7), 1576. https://doi.org/10.3390/molecules30071576