Molecular insight into quinazoline derivatives with cytotoxic activity

Abstract

Quinazoline nucleus is found in many bioactive molecules exhibiting anticancer activity. Herein we report crystallographic investigation, as well as in vitro determination of the biological activity of symmetrical molecules containing two quinazoline systems tethered by various polyamine linkers e.g. 4-bis(3-aminopropyl)piperazine (I), 4,9-dioxa-1,12-dodecanediamine (II), 3,3′-diamino-N-methyldipropylamine (III). Three new crystal structures are determined that differ in the linker. Molecules of compounds I and II adopt stretched conformations and molecules of III adopt bent conformation in the crystal state. The arrangement of molecules in the crystal structures is determined by weak hydrogen bonds and stacking interactions. Geometry optimization for the molecules was carried out with ab initio calculations. Cytotoxic activity of quinazoline derivatives differs markedly depending upon the cancer cell line. Endometrial cancer cells are more sensitive to examined compounds than prostate or breast cancer cells. Investigated quinazoline derivatives are able to induce HEC1A cell death in concentration and time-dependent manner while they exhibit relatively low cytotoxicity to peripheral blood mononuclear cells (PBMCs). The most promising compound is quinazoline derivative with 4,9-dioxa-1,12-dodecanediamine as the linker (II) which induced HEC1A cells apotosis in a significant manner.