Synthesis, structure and properties of Pt(II) α-pyrrolyl dipyrrin complexes that exhibit anticancer activities.

The α-formyl pyrrolyl dipyrrin ligands were reacted with PtCl2 in toluene/Et3N under inert reflux conditions to afford unprecedented Pt(II) pyrrolyl dipyrrin complexes bearing a bulky N,N-diethyl ethenamine moiety at the α-position of the appended pyrrole ring. This transformation occurred via a Schiff base-type reaction between the α-formyl group and triethylamine. Notably, the α-pyrrolyl dipyrrin lacking the formyl substituent failed to form the Pt(II) complex, highlighting the critical role of the formyl group in complex formation and stabilization. Single-crystal X-ray diffraction analysis revealed that the Pt(II) center adopts a distorted square-planar geometry, coordinated by three pyrrolic nitrogen atoms from the pyrrolyl dipyrrin ligand and one chloride ion. The appended pyrrolyl ring remained nearly coplanar with the dipyrrin core due to Pt(II) coordination, indicating enhanced π-conjugation and electron delocalization across the ligand framework. The Pt(II) complexes exhibited two sharp intense absorption bands along with a less intense band in the 480-670 nm region. Electrochemical studies demonstrated one reversible reduction at -1.08 V and a quasi-reversible oxidation at 0.84 V. Density Functional Theory (DFT) and Time-Dependent DFT (TD-DFT) calculations showed good agreement with the experimental observations. The biological activities of the Pt(II) complexes were evaluated using MCF-7 breast cancer cells and HEK293T normal cells through MTT assays. Among the synthesized compounds, compound 4a exhibited lower toxicity toward HEK293T cells, indicating selective anticancer activity. To understand the molecular basis of activity, molecular docking studies were carried out using caspase-1 as the target protein. Docking analysis identified a favourable binding pocket at the interface of the p20 and p10 subunits. Compound 4b displayed good binding affinity with a docking score of -6.93 kcal mol-1, although it also showed toxicity toward normal cells, whereas compound 4a demonstrated comparatively selective biological activity. Mechanistic studies revealed increased expression of cleaved PARP-1 and cleaved caspase-1 together with downregulation of p27, indicating activation of apoptotic signalling accompanied by caspase-1 associated cellular responses. However, neither cleavage of gasdermin D (GSDMD) nor IL-1β release was detected, indicating that canonical GSDMD-dependent pyroptosis was not induced. Flow cytometric analysis further showed an increase in PI-positive cells following treatment with compound 4a, consistent with increased cell death. Overall, the combined experimental and computational investigations suggested that Pt(II) α-pyrrolyl dipyrrin complexes possess promising photophysical and selective anticancer properties by primarily inducing caspase-1 associated apoptosis, highlighting their potential as platinum-based anticancer agents.