Chloro acridone derivatives as cytotoxic agents active on multidrug-resistant cell lines and their duplex DNA complex studies by electrospray ionization mass spectrometry

• Published in: Chemico-biological interactions 2008-11, Vol.176 (2), p.212-219
• Main Authors: Rajendra Prasad, V.V.S., Venkat Rao, J., Giri, R.S., Sathish, N.K., Shanta Kumar, S.M., Mayur, Y.C.
• Format: Article
• Language: English
• Subjects: Acridone; Acridones - chemistry; Acridones - toxicity; Cell Proliferation - drug effects; DNA - chemistry; DNA - drug effects; Dose-Response Relationship, Drug; Doxorubicin; Drug Resistance, Multiple; Drug Screening Assays, Antitumor; HL-60 Cells; Humans; Molecular Structure; Molecular Weight; Multidrug resistance (MDR); P-glycoprotein (P-gp); Spectrometry, Mass, Electrospray Ionization; Stereoisomerism; Structure-Activity Relationship; Vincristine
• ISSN: 0009-2797; 1872-7786
• DOI: 10.1016/j.cbi.2008.06.007

We report herein in vitro anti-proliferative activity and duplex DNA complex studies of a series of N 10-substituted acridone derivatives. All the molecules have been designed on the basis of the presence of specific recognition patterns consisting of hydrogen bond acceptors (or electron donors), carbonyl, chloro groups with precise spatial separation and structural features (lipophilicity, positive charge at neutral pH and presence of aromatic rings). The in vitro cytotoxic effects have been demonstrated against human promyelocytic leukemia sensitive cell line (HL-60), including its multidrug cross-resistance of two main (P-gp and MRP) phenotype sublines vincristine-resistant (HL-60/VINC) and doxorubicin-resistant (HL-60/DX) cancer cell lines. Compound 4 showed very good activity against sensitive and resistant cell lines. The noncovalent complexes of these molecules with DNA duplex has been investigated in gas phase by using a fast, robust and sensitive electrospray ionization mass spectrometry (ESI-MS) technique. Equilibrium association constants ( K 1) and percentage of intact complexes were determined. The combined results show that these acridone derivatives interact with DNA duplex by intercalation between the base pairs, possess higher affinity to GC than AT base pairs of the DNA and they could not interact noncovalently with the minor grooves of the DNA in solution-free gas phase. Examination of the relationship between lipophilicity and cytotoxic properties of acridone derivatives showed a poor correlation. The in vitro cytotoxic studies in resistant cancer cell lines of compound 4 showed that it might be a promising new hit for further development of anti-MDR agent.