Self‐Assembly of Charged and Flexible Pyrimidine‐Based [2 + 2] Platinum (II) Macrocycles and Their Anticancer Activities

ABSTRACT We report the design and synthesis of a new pyrimidine‐based organoplatinum (II) complex ( 3 ), constructed over three consecutive steps starting from 4,6‐dichloropyrimidine. This flexible precursor acted as a key acceptor tecton to compose the self‐assembly of three distinct ionic [2 + 2] macrocycles ( M 1 – M 3 ) in high yields through coordination with neutral N‐donor ligands. Comprehensive spectroscopic and analytical techniques such as FT‐IR, NMR, and HRMS were employed to validate the purity, symmetry, and structural integrity of the macrocycles. Notably, the appearance of sharp singlets in 31 P NMR spectra and the presence of a single diffusion trace in 1 H‐DOSY NMR unequivocally confirmed the formation of discrete, well‐defined assemblies. High‐resolution mass spectra further supported this, revealing the signature [M‐3NO 3 ] 3+ peaks for all macrocycles. MTT assay was performed to evaluate the cytotoxic potential of these compounds against human breast cancer cell line MCF‐7 and human normal breast epithelial cell line MCF‐10A. The findings revealed that the macrocycles exhibited greater cytotoxicity than the precursor molecule and cisplatin in MCF‐7 cells. Furthermore, all the compounds showed much lesser cytotoxicity toward normal MCF‐10A cells. These results indicate that self‐assembled, charged organoplatinum macrocycles manifest enhanced anticancer potential and may serve as promising scaffolds for the development of next‐generation chemotherapeutic agents.