Pyrazole–Cyclotriphosphazene Hybrids: Synthesis, Structural Insights, and Cytotoxic Effects against Pancreatic Cancer Cells

Pancreatic cancer carries an extremely poor long-term survival, with under 5% of patients living more than five years after diagnosis. Thus, the demand for innovative therapeutic medications to treat pancreatic cancer is essential. In this study, inorganic–organic hybrid molecules were synthesized by performing nucleophilic substitution reactions of 4-chloro-2-(1H-pyrazol-3-yl)phenol (2a) containing the pyrazole scaffold, which has a biologically active skeleton, with hexachlorocyclotriphosphazene, HCCTP (1). The reactions were carried out with two different bases (NaH and Et3N) to isolate various cyclotriphosphazene derivatives that could form due to the tautomerization of the pyrazole skeleton and to compare the reaction yields. Products were formed in which HCCTP (1) was substituted at the monospiro (3a), dispiro (trans 4a-I and cis 4a-II), and trispiro (cis–trans–trans 5a-I and all-cis 5a-II) positions of the chloro phenol pyrazole group. The structures of these newly synthesized hybrid molecules have been elucidated using various spectroscopic techniques (31P, 1H, 13C NMR, and mass spectroscopy), elemental analysis, and single-crystal X-ray diffraction techniques. For the purpose of evaluating biological properties (in vitro studies on potential pancreatic cancer cells), monospiro, trans- dispiro, and cis–trans–trans trispiro 2-(1H-pyrazol-3-yl)phenol substituted cyclotriphosphazene compounds (3b, 4b-I, and 5b-I) were synthesized according to the literature. The biological properties of all compounds (3a, 4a-I, 5a-I, 3b, 4b-I, and 5b-I) were investigated for the first time in pancreatic cancer cell lines (PANC-1 and MIA PaCa-2). Compound 3a displays potent anticancer activity against PANC-1 (IC50 = 24.57 μg/mL) and MIA PaCa-2 (IC50 = 23.30 μg/mL) cells.