Design, synthesis and biological evaluation of thiosemicarbazones, hydrazinobenzothiazoles and arylhydrazones as anticancer agents with a potential to overcome multidrug resistance

There is a constant need for new therapies against multidrug resistant (MDR) cancer. An attractive strategy is to develop chelators that display significant antitumor activity in multidrug resistant cancer cell lines overexpressing the drug efflux pump P-glycoprotein. In this study we used a panel of sensitive and MDR cancer cell lines to evaluate the toxicity of picolinylidene and salicylidene thiosemicarbazone, arylhydrazone, as well as picolinylidene and salicylidene hydrazino-benzothiazole derivatives. Our results confirm the collateral sensitivity of MDR cells to isatin-β-thiosemicarbazones, and identify several chelator scaffolds with a potential to overcome multidrug resistance. Analysis of structure-activity-relationships within the investigated compound library indicates that NNS and NNN donor chelators show superior toxicity as compared to ONS derivatives regardless of the resistance status of the cells. © 2016 Elsevier Masson SAS

Identification and Validation of Compounds Selectively Killing Resistant Cancer: Delineating Cell Line-Specific Effects from P-Glycoprotein-Induced Toxicity.

Despite significant progress, resistance to chemotherapy is still the main reason why cancer remains a deadly disease. An attractive strategy is to target the collateral sensitivity of otherwise multidrug resistant (MDR) cancer. In this study, our aim was to catalog various compounds that were reported to elicit increased toxicity in P-glycoprotein (Pgp)-overexpressing MDR cells. We show that the activity of most of the serendipitously identified compounds reported to target MDR cells is in fact cell-line specific, and is not influenced significantly by the function of Pgp. In contrast, novel 8-hydroxyquinoline derivatives that we identify in the National Cancer Institute (NCI) drug repository possess a robust Pgp-dependent toxic activity across diverse cell lines. Pgp expression associated with the resistance of the doxorubicin-resistant Brca1-/-;p53-/- spontaneous mouse mammary carcinoma cells could be eliminated by a single treatment with NSC57969, suggesting that MDR-selective compounds can effectively revert the MDR phenotype of cells expressing Pgp at clinically relevant levels. The discovery of new MDR-selective compounds shows the potential of this emerging technology and highlights the 8-hydroxyquinoline scaffold as a promising starting point for the development of compounds targeting the Achilles heel of drug-resistant cancer. Mol Cancer Ther; 16(1); 45-56. (c)2016 AACR

Comparative solution equilibrium studies of antitumor ruthenium(η6-p-cymene) and rhodium(η5-C5Me5) complexes of 8-hydroxyquinolines

Complex formation processes of [ Ru(η 6 - p - cymene) (H 2 O) 3 ] + and [ Rh( η 5 - C 5 Me 5 )(H 2 O) 3 ] + organometallic cations with 8 - hydroxyquinoline (HQ) ligands were studied in aqueous solution by the combined use of 1 H NMR spectroscopy, UV - visible spectrophotometry and pH - potentiometry. Solution stability, chloride ion affinity and lipophilicity of the complexes were characterized together with the in vitro cytotoxicity against a pair of cancer cell lines, responsive and resistant to classic chemotherapy. The solid phase structure of the [Rh( η 5 - C 5 Me 5 )( 8 - quinolinolato )(Cl)] complex was characterized by s ingle - crystal X - ray diffraction analysis. In addition to the unsubstituted HQ its 7 - (1 - piperidinylmethyl) (PHQ) and 5 - sulfonate ( HQS) derivatives were involved. PHQ has a significant preference for targeting multidrug resistant cancer cell lines , while HQS served as a water soluble model compound. The equilibrium studies revealed the formation of mono [M(L)(H 2 O)] complexes with prominently high solution stability, which predominate at physiological pH even in the micromolar concentration range , and f ormation of mixed hydroxido [M(L)(OH)] complexes was characterized by relatively high p K a values (8.5 – 10.3). In comparison to the Rh(η 5 - C 5 Me 5 ) species the complex ation process with Ru(η 6 - p - cymene) is much slower, and both the p K a values and the H 2 O/Cl − co - ligand exchange constants are lower by 1 - 1.5 orders of magnitude. The stability order obtained for these organometallic complexes is as follows: HQS > HQ > PHQ. Cytotoxicity of the ligands and their Ru(η 6 - p - cymene) and Rh(η 5 - C 5 Me 5 ) complexes was investigated against MES - SA (human uterine sarcoma) cell line and its multidrug resistant counterpart (MES - SA/Dx5). HQ and its complexes show similar cytotoxicity in both cell lines. In contrast, PHQ and its Rh(η 5 - C 5 Me 5 ) complex are more potent against MES - SA/Dx5 cells, while this selectivity could not be observed for the Ru(η 6 - p - cymene) complex

Unshielding Multidrug Resistant Cancer through Selective Iron Depletion of P-Glycoprotein–Expressing Cells

Clinical evidence shows that following initial response to treatment, drug-resistant cancer cells frequently evolve and, eventually, most tumors become resistant to all available therapies. We compiled a focused library consisting of >500 commercially available or newly synthetized 8-hydroxyquinoline (8OHQ) derivatives whose toxicity is paradoxically increased rather than decreased by the activity of P-glycoprotein (Pgp), a transporter conferring multidrug resistance (MDR). Here, we deciphered the mechanism of action of NSC297366 that shows exceptionally strong Pgp-potentiated toxicity. Treatment of cells with NSC297366 resulted in changes associated with the activity of potent anticancer iron chelators. Strikingly, iron depletion was more pronounced in MDR cells due to the Pgp-mediated efflux of NSC297366-iron complexes. Our results indicate that iron homeostasis can be targeted by MDR-selective compounds for the selective elimination of multidrug resistant cancer cells, setting the stage for a therapeutic approach to fight transporter-mediated drug resistance. SIGNIFICANCE: Modulation of the MDR phenotype has the potential to increase the efficacy of anticancer therapies. These findings show that the MDR transporter is a "double-edged sword" that can be turned against resistant cancer