Unsymmetrical Ethylenediamine Heterocyclic Schiff-Base Ligands for Potential Anticancer Metal Complexes

Salphen-type ligands are known to form stable chelate complexes with different metals. Those metal complexes with Pt(II), Pd(II), Ni(II), Cu(II), Zn(II) etc. are capable of selective G-quadruplex DNA binding and therefore are promising anticancer agents. Such compounds may provide a basis for developing metal-containing systems capable of targeting telomeric and oncogene-associated G-quadruplex DNA structures while retaining structural variability for comparative coordination studies. The recent works also showed that imidazole-4-carbaldehyde can replace salicylic aldehyde in Schiff base ligands. We focused out synthetic efforts on preparation of potential ligands with either salicylic aldehyde or imidazole-4-carbaldehyde Schiff base on one side of ethylenediamine. While the other amino-group of the ethylenediamine was modified with heterocyclic fragment. As heterocycles we have chosen 4-aminoquinazoline, which is the core structure of Gefitinib a well-known highly effective anticancer drug and many others. We also paid our attention on the thieno[2,3-d]pyrimidine core, which could be considered as bioisosteric to quinazoline and it is also a privileged scaffold for anticancer drug discovery. The synthetic scheme was started from readily available 4-chloroquinazoline and 4-chloro-5-methylthieno[2,3-d]pyrimidine by treatment with mono-Boc protected ethylenediamine. Subsequent deprotection of Boc-group in the obtained product followed by condensation with the corresponding aldehyde produced the desired ligands. The obtained combination of substituents on both sides of ethylenediamine can provide additional flexibility and could improve QSAR parameters of the formed complexes for such ligands, which is interesting for further extended studies.