Cytotoxicity studies of some novel fluoro acridone derivatives against sensitive and resistant cancer cell lines and their mechanistic studies

• Published in: European journal of pharmaceutical sciences 2011-07, Vol.43 (4), p.217-224
• Main Authors: Rajendra Prasad, V.V.S., Peters, G.J., Lemos, Clara, Kathmann, Ietje, Mayur, Y.C.
• Format: Article
• Language: English
• Subjects: 3',5'-Cyclic-AMP Phosphodiesterases - antagonists & inhibitors; 3',5'-Cyclic-AMP Phosphodiesterases - metabolism; Acridone; Acridones - chemistry; Acridones - pharmacology; Aminoacridines - pharmacology; Animals; ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism; Biological and medical sciences; Calcium - metabolism; Calmodulin; Calmodulin - metabolism; Cell Line, Tumor; DNA - chemistry; DNA - metabolism; Doxorubicin; Doxorubicin - pharmacology; Doxorubicin - therapeutic use; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Female; General pharmacology; HEK293 Cells; HL-60 Cells; Humans; Male; Medical sciences; Multidrug resistance (MDR); P-glycoprotein; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; Structure-Activity Relationship
• ISSN: 0928-0987; 1879-0720
• DOI: 10.1016/j.ejps.2011.04.010

A series of novel N 10-substituted acridone derivatives bearing alkyl side-chain with tertiary amine groups at the terminal position were evaluated for their in vitro cytotoxic effects against drug sensitive and resistant cancer cell lines. All the molecules were designed on the basis of hydrogen bond acceptors, carbonyl, fluoro groups with precise spatial separation and structural features of lipophilicity, positive charge at neutral pH and presence of aromatic rings. The in vitro cytotoxic effects in comparison with reference drugs doxorubicin (DX) and C 1311 against cancer cell lines SW 1573, SW 1573 2R 160 (Pg-P expressing) which are non-small cell lung cancer cells, human embryo kidney cells HEK 293, HEK 293 MRP4, HEK 293 MRP5i, human promyelocytic leukemia sensitive cell line HL-60, including its multidrug cross-resistant of two main (P-gp and MRP) phenotype sublines vincristine resistant HL-60/VINC and doxorubicin resistant HL-60/DX cancer cell lines are presented. Compounds 14, 15 and 16 exhibited highest cytotoxicity among the derivatives. On the other hand, the in vitro cytotoxic activity of compound 14 (with butyl side-chain and tertiary amino group β-hydroxy ethyl piperizine) against resistant cancer cell lines indicate that it might be a promising new hit for further development as an anti-MDR agent. The non-covalent interaction of these molecules with DNA duplexes have been investigated by ESI-MS technique. The results indicate, these acridone derivatives interact with duplex DNA by intercalation, possesses higher affinity to GC than AT base pairs of the DNA and they could not interact non-covalently with the minor grooves of the DNA. The ability of acridones to inhibit calmodulin dependent cAMP phosphodiesterase has been determined. The results suggest that acridones inhibit the Ca 2+/calmodulin stimulated cAMP-phosphodiesterase activity and have no direct effects on the enzyme itself and a strong correlation between calmodulin inhibition and cytotoxicity against HL-60/VINC and HL-60/DX MDR cancer cell lines.