Abstract
In an attempt to develop effective and potentially safe anticancer agents, thirty-six 4-aminoquinoline derived sulfonyl analogs were designed and synthesized using a hybrid pharmacophore approach. The cytotoxicity of these compounds was determined using three breast tumor cell lines (MDA-MB231, MDA-MB468 and MCF7) and two matching non-cancer breast epithelial cell lines (184B5 and MCF10A). Although most of the compounds were quite effective on the breast cancer cells, the compound 7-chloro-4-(4-(2,4-dinitrophenylsulfonyl)piperazin-1-yl)quinoline (13; VR23) emerged as potentially the most desirable one in this series of compounds. Data from the NCI-60 cancer panel screening show that compound 13 is effective on a wide range of different cancers. Importantly, compound 13 is needed up to 17.6-fold less doses to achieve the same IC50 against cancer than non-cancer cells (MDA-MB468 vs MCF10A), suggesting that it can potentially be less toxic to normal cells. Cancer cells formed multiple centrosomes in the presence of compound 13, resulting in the cell cycle arrest at prometa-meta phase. This abnormality leads to eventual cell demise with sub-G1 DNA content typically shown with apoptotic cells. In addition, compound 13 also causes an increase in lysosomal volume in cancer but not in non-cancer cells, which may contribute at least in part to its preferential cancer cell-killing. The cancer cell-killing effect of compound 13 is highly potentiated when combined with either bortezomib or monastrol.
Highlights
Taking advantage of the tremendous increase in knowledge of the molecular mechanisms and pathophysiology of cancer during the last few decades, much effort has recently been paid to increase cancer cell selectivity in chemotherapy1–3
Further structure-activity relationship (SAR) analysis indicated that more potent antigrowth/cell-killing effects on cancer cells could be achieved when the 7th position with a -Cl/CF3 group of the 4-(quinolin-4-yl)piperazin-1-yl ring system merged with potential pharmacophore groups8
We found that the growth inhibition effects of 4-piperazinylquinoline-isatin hybrid compounds (Fig. 1a) were substantially more active on cancer than non-cancer cells, suggesting that tumor specificity can be increased by a hybrid approach9
Summary
Taking advantage of the tremendous increase in knowledge of the molecular mechanisms and pathophysiology of cancer during the last few decades, much effort has recently been paid to increase cancer cell selectivity in chemotherapy. We successfully applied previously two paralleled approaches in developing effective and selective anticancer agent: repositioning and hybrid pharmacophore approaches5–11 In these studies, we demonstrated that the anti-malarial drug chloroquine (CQ) could be effective on cancer cell-killing, highly synergistically if combined with radiation or Akt inhibitors. We found that the growth inhibition effects of 4-piperazinylquinoline-isatin hybrid compounds (Fig. 1a) were substantially more active on cancer than non-cancer cells, suggesting that tumor specificity can be increased by a hybrid approach. Studies carried out by in vitro and/or in vivo approaches showed that sulfonyl derivatives shown in Fig. 1b (1–III) contain substantial antitumor activity19–22 These previous findings gave impetus to our cancer drug research by further augmenting the realization that rational choice of inputs based on the known 4-aminoquinoline scaffold and the sulfonamide pharmacophore could lead to molecules with desirable anticancer property. Compound 13, the most desirable one in this series was further examined to gain understanding of its molecular mechanisms and effects on other cancer cells using the NCI-60 cancer panel
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