Tripeptide linked dispiro cyclotriphosphazene conjugates: Synthesis, molecular docking analysis of compounds binding within cancer cell line receptors and in vitro cytotoxic and genotoxic activities.

The novel dioxybiphenyl bridged-cyclotriphosphazenes (DPP) bearing tripeptide were synthesized and investigated for their molecular docking analysis, visualizing their binding profiles within various cancer cell line receptors and in vitro cytotoxic and genotoxic properties. The dipeptide compound (Tyr-Phe) was treated with various amino acids to obtain the tripeptide compounds (Tyr-Phe-Gly, Tyr-Phe-Ala, Tyr-Phe-Val, Tyr-Phe-Phe, and Tyr-Phe-Leu). These synthesized tripeptides were subsequently treated with DPP to obtain novel phosphazene compounds bearing tripeptide structures. As a result, the synthesis of target molecules with phosphazene compound in the center and biphenyl and tripeptide groups in the side arms was obtained for the first time in this study. Examining the cytotoxic studies in vitro of our newly synthesized compounds demonstrated the anticancer properties against four selected human cancer cell lines, including breast (MCF-7), ovarian (A2780), prostate (PC-3), and colon (Caco-2) cancer cells. The Comet Assay analysis determined that the cell death mechanism of most of the compounds with cytotoxic activity stemmed from the DNA damage mechanism. Among the compounds, the DPP-Tyr-Phe-Phe compound seems to have the best anticancer activity against the subjected cell lines (Except for A2780) with IC50 values equal to 20.18, 72.14, 12.21, and 5.17 µM against breast, ovarian, prostate, and colon cancer cell lines, respectively. For this reason, the molecular docking analysis was conducted for the DTPP compound to visualize its binding geometry and profile within the target enzyme's binding site associated with the specific cancer cell line. The analysis revealed that the DTPP derivative exhibited an optimal binding conformation and characteristics within the target enzyme's binding site, aligning well with the experimental data. Based on the data, these compounds are believed to be strong candidate molecules for both pharmaceutical and clinical applications.

The first peptide derivatives of dioxybiphenyl-bridged spiro cyclotriphosphazenes: In vitro cytotoxicity activities and DNA damage studies.

In this study, we aimed to synthesize new peptide-substituted cyclotriphosphazenes from a series of tyrosine-based peptides and dioxyphenyl-substituted spirocyclotriphosphazenes, and to evaluate their in vitro cytotoxicity and genotoxicity activities. Genotoxicity studies were conducted to understand whether the cytotoxic compounds cause cell death through DNA damage. The structures of the novel series of phosphazenes were characterized by FT-IR, elemental analysis, MS, 1D (31P, 1H, and 13C-APT NMR), and 2D (HETCOR) NMR spectroscopic techniques. In vitro cytotoxic activities were carried out against human breast (MCF-7), ovarian (A2780), prostate (PC-3), colon (Caco-2) cancer cell lines and human normal epithelial cell line (MCF-10A) at different concentrations by using an MTT assay. The compounds showed considerable reductions in cell viability against all human cancer cell lines. Especially, the compounds exhibited notable effects in A2780 cell lines (p < 0.05). The IC50 values of the compounds in the A2780 cell line were calculated to be 1.914 µM for TG, 20.21 µM for TV, 20.45 µM for TA, 4.643 µM for TP, 5.615 µM for BTG, 1.047 µM for BTV, 27.02 µM for BTA, 0.7734 µM for BTP, 21.5 µM for DTG, 1.65 µM for DTV, 2.89 µM for DTA and 4.599 µM for DTP. DNA damage studies of the compounds were conducted by the comet assay method using tail length, tail density, olive tail moment, head length, and head density parameters, and the results showed that the cell death occurred through DNA damage mechanism. In a nutshell, these compounds show promising cytotoxic effects and can be considered powerful candidate molecules for pharmaceutical applications.

Hexa-substituted cyclotriphosphazene derivatives containing hetero-ring chalcones: Synthesis, in vitro cytotoxic activity and their DNA damage determination.

In this study, hetero ring hexasubstituted cyclotriphosphazes were obtained in two steps and these compounds were investigated in terms of in vitro cytotoxicity and genotoxicity. The structural characterizations of the starting compounds 1-4 were defined by FT-IR, elemental analysis, and NMR (1H and 13C) spectroscopy techniques. In addition to these techniques, the 31P NMR spectroscopy technique was also used in the characterization of cyclotriphosphazenes (FSC 1-4). The changes in cell viability at 1, 5, 25, 50, and 100 µM concentrations against human ovarian (A2780) and human prostate (PC-3 and LNCaP) cell lines for 24 h were determined by the MTT assay method. According to MTT assay results, the inhibitory concentration 50 (IC50/LogIC50) value was calculated in Graphpad Prism 6 program. The comet assay was performed to determine whether the effects of compounds on cell viability were through DNA damage. In the comet assay experiments, the highest concentration of compounds (100 µM) was applied to the cells for 24 h and tail length (TL), tail intensity (TI), olive tail moment (OTM) parameters were examined. The results showed that the compound 1-4 and FSC 1-4 compounds reduced the cell viability against all cancer cell lines (p < 0.05). At the same time, different concentrations of these compounds caused DNA damage in all three cell types (p < 0.05). The possible interactions and chemical mechanisms of the synthesized compounds were explained by computational methods with molecular docking. In addition, pharmacological properties of drug candidate molecules have been defined. Experimental and calculated data comply with each other. The study results showed that these compounds have cytotoxic effects against cancer cells and suggested that these effects have occurred through genotoxicity.