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Peace Mabeta, Kristina Pavić and Branka Zorc

Abstract

In our previous paper, we showed that three primaquine-cinnamic acid conjugates composed of primaquine (PQ) residue and cinnamic acid derivatives (CADs) bound directly by an amide linkage (1) or through an acylsemicarbazide spacer (2 and 3) had significant growth inhibitory effects on some cancer cell lines. Compound 1 induced significant growth inhibition in the colorectal adenocarcinoma (SW620), human breast adenocarcinoma (MCF-7) and cervical carcinoma (HeLa) cell lines, while compounds 2 and 3 selectively inhibited the growth of MCF-7 cells. To better understand the underlying mechanisms of action of these PQ-CADs, morphological studies of the effects of test compounds on MCF-7 cells were undertaken using haematoxylin and eosin stain. Further analysis to determine the effects of test compounds on caspase activity and on the levels of apoptosis proteins were undertaken using the enzyme-linked immunosorbent assay (ELISA). Haematoxylin and eosin staining revealed that compounds 1 and 3 induced morphological changes in MCF-7 cells characteristic of apoptosis, while 2-treated cells were in interphase. Cell cycle analysis showed that cells treated with 1 and 3 were in sub-G1, while cells treated with 2 were mainly in interphase (G1 phase). Further, the study showed that the treatment of MCF-7 cells with 1 and 3 resulted in poly ADP ribose polymerase (PARP) cleavage as well as caspase-9 activation, indicating that they induced apoptotic cell death. We further investigated their effects on two important processes during metastasis, namely, migration and invasion. Compounds 1 and 3 inhibited the migration and invasion of MCF-7 cells, while compound 2 had a marginal effect.

Open access

Kristina Pavić Zrinka Rajić, Zvonimir Mlinarić, Lidija Uzelac, Marijeta Kralj and Branka Zorc

Abstract

In the current paper, we describe the design, synthesis and antiproliferative screening of novel chloroquine derivatives with a quinoline core linked to a hydroxy or halogen amine through a flexible aminobutyl chain and urea spacer. Synthetic pathway leading to chloroquine urea derivatives 4-10 includes two crucial steps: i) synthesis of chloroquine benzotriazolide 3 and ii) formation of urea derivatives through the reaction of compound 3 with the corresponding amine. Testing of antiproliferative activity against four human cancer cell lines revealed that chloroquine urea derivatives 9 and 10 with aromatic moieties show activity at micromolar concentrations. Therefore, these molecules represent interesting lead compounds that might provide an insight into the design of new anticancer agents.