Acridones circumvent P-glycoprotein-associated multidrug resistance (MDR) in cancer cells.
Multidrug resistance (MDR) mediated by overexpression of MDR1 P-glycoprotein (P-gp) is one of the best characterized transporter-mediated barriers to successful chemotherapy in cancer patients. Chemosensitizers are the agents that increase the sensitivity of multidrug-resistant cells to the toxic influence of previously less effective drugs. In an attempt to find such vital chemosensitizers, a series of N(10)-substituted-2-chloroacridone analogous (1-17) have been synthesized. Compound 1 was prepared by the Ullmann condensation of o-chlorobenzoic acid and p-chloroaniline followed by cyclization. The N-(omega-chloroalkyl) analogues were found to undergo iodide catalyzed nucleophilic substitution reaction with secondary amines and the resultant products were characterized by spectral methods. The lipophilicity expressed in log(10)P and pK(a) of compounds has been determined. All compounds were examined for their ability to increase the uptake of vinblastine (VLB) in MDR KBCh(R)-8-5 cells and the results showed that the compounds 6, 8, 11-14, 16, and 17 at their respective IC(50) concentrations caused a 1.0- to 1.7-fold greater accumulation of VLB than did a similar concentration of the standard modulator, verapamil (VRP). Results of the efflux experiment showed that VRP and each of the modulators significantly inhibited the efflux of VLB, suggesting that they may be competitors for P-gp. All modulators effectively competing with [(3)H]azidopine for binding to P-gp pointed out this transport membrane protein as their likely site of action. Compounds at IC(10) were evaluated for their efficacy to modulate the cytotoxicity of VLB and the results showed that modulators 11, 13, 14, 16, and 17 were able to completely reverse the 25-fold resistance of KBCh(R)-8-5 cells to VLB. Examination of the relationship between lipophilicity and antagonism of MDR showed a reasonable correlation suggesting that hydrophobicity is one of the determinants of potency for anti-MDR activity of 2-chloroacridones. The results allowed us to draw preliminary conclusions about structural features of 2-chloroacridones important for MDR modulation.
Gopinath
Vadiraj S
VS
Advinus Therapeutic Pvt. Ltd, 21 & 22, Phase-II, Peenya Industrial Area, Bangalore 560 058, India. vadiraj.gopinath@advinus.com
Thimmaiah
Padma
P
Thimmaiah
Kuntebommanahalli N
KN
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000187:drug effects* / Q000378:metabolism; D054831:Acridones / Q000138:chemical synthesis* / Q000494:pharmacology*; D001667:Binding, Competitive; D002460:Cell Line; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D004357:Drug Synergism; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D020128:Inhibitory Concentration 50; D013329:Structure-Activity Relationship; D014700:Verapamil / Q000493:pharmacokinetics; D014747:Vinblastine / Q000493:pharmacokinetics
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D054831:Acridones; D014747:Vinblastine; D014700:Verapamil