TY - JOUR
T1 - Synthesis and chemical characterization of 2-methoxy-N10-substituted acridones needed to reverse vinblastine resistance in multidrug resistant (MDR) cancer cells
AU - Krishnegowda, Gowdahalli
AU - Thimmaiah, Padma
AU - Hegde, Ravi
AU - Dass, Chhabil
AU - Houghton, Peter J.
AU - Thimmaiah, Kuntebommanahalli N.
PY - 2002/5/8
Y1 - 2002/5/8
N2 - In an attempt to find clinically useful modulators of multidrug resistance (MDR), a series of 19 N10-substituted-2-methoxyacridone analogues has been synthesized. 2-Methoxyacridone and its derivatives (1-19) were synthesized. Compound 1 was prepared by the Ullmann condensation of o-chlorobenzoic acid and p-anisidine followed by cyclization using polyphosphoric acid. This compound undergoes N-alkylation in the presence of phase transfer catalyst (PTC). Stirring of 2-methoxy acridone with 1-bromo-3-chloropropane or 1-bromo-4-chlorobutane in a two-phase system consisting of organic phase (tetrahydrofuran) and 6 N potassium hydroxide in the presence of tetrabutylammonium bromide leads to the formation of compounds 2 and 11 in good yield. N-(ω-Chloroalkyl) analogues were found to undergo iodide catalyzed nucleophilic substitution reaction with various secondary amines. Products were characterized by UV, IR, 1H and 13C NMR, mass-spectral data and elemental analysis. The lipophilicity expressed in log10 P and pKa of compounds have been determined. All compounds were examined for their ability to increase the uptake of vinblastine (VLB) in MDR KBChR-8-5 cells and the results showed that the compounds 7, 10, 12, and 15-19 at 100 μM caused a 1.05- to 1.7-fold greater accumulation of vinblastine than did a similar concentration of the standard modulator, verapamil (VRP). However, the effects on VLB uptake were specific because these derivatives had little effect in the parental drug sensitive line KB-3-1. Steady state accumulation of VLB, a substrate for P-glycoprotein (P-gp) mediated efflux, was studied in the MDR cell line KBChR-8-5 in the presence and absence of novel MDR modulators. Results of the efflux experiment showed that VRP and each of the modulators (1-19) significantly inhibited the efflux of VLB, suggesting that they may be competitors for P-gp. From among the compounds examined, 14 except 1, 2, 4, 8, and 11, exhibited greater efflux inhibiting activity than VRP. All the 19 compounds effectively compete with [3H] azidopine for binding to P-gp, pointed out this transport membrane protein as their likely site of action. Cytotoxicity has been determined and the IC50 values lie in the range 8.00-18.50 μM for propyl and 4-15 μM for butyl derivatives against KBChR-8-5 cells suggesting that the antiproliferative activity increases as chain length increases from 3 to 4 carbons at N10-position. Compounds at IC10 were evaluated for their efficacy to modulate the cytotoxicity of VLB in KBChR-8-5 cells and found that the modulators enhanced the cytotoxicity of VLB by 5- to 35-fold. Modulators 12, 14-16, and 19 like VRP, were able to completely reverse the 24-fold resistance of KBChR-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-methoxyacridones.
AB - In an attempt to find clinically useful modulators of multidrug resistance (MDR), a series of 19 N10-substituted-2-methoxyacridone analogues has been synthesized. 2-Methoxyacridone and its derivatives (1-19) were synthesized. Compound 1 was prepared by the Ullmann condensation of o-chlorobenzoic acid and p-anisidine followed by cyclization using polyphosphoric acid. This compound undergoes N-alkylation in the presence of phase transfer catalyst (PTC). Stirring of 2-methoxy acridone with 1-bromo-3-chloropropane or 1-bromo-4-chlorobutane in a two-phase system consisting of organic phase (tetrahydrofuran) and 6 N potassium hydroxide in the presence of tetrabutylammonium bromide leads to the formation of compounds 2 and 11 in good yield. N-(ω-Chloroalkyl) analogues were found to undergo iodide catalyzed nucleophilic substitution reaction with various secondary amines. Products were characterized by UV, IR, 1H and 13C NMR, mass-spectral data and elemental analysis. The lipophilicity expressed in log10 P and pKa of compounds have been determined. All compounds were examined for their ability to increase the uptake of vinblastine (VLB) in MDR KBChR-8-5 cells and the results showed that the compounds 7, 10, 12, and 15-19 at 100 μM caused a 1.05- to 1.7-fold greater accumulation of vinblastine than did a similar concentration of the standard modulator, verapamil (VRP). However, the effects on VLB uptake were specific because these derivatives had little effect in the parental drug sensitive line KB-3-1. Steady state accumulation of VLB, a substrate for P-glycoprotein (P-gp) mediated efflux, was studied in the MDR cell line KBChR-8-5 in the presence and absence of novel MDR modulators. Results of the efflux experiment showed that VRP and each of the modulators (1-19) significantly inhibited the efflux of VLB, suggesting that they may be competitors for P-gp. From among the compounds examined, 14 except 1, 2, 4, 8, and 11, exhibited greater efflux inhibiting activity than VRP. All the 19 compounds effectively compete with [3H] azidopine for binding to P-gp, pointed out this transport membrane protein as their likely site of action. Cytotoxicity has been determined and the IC50 values lie in the range 8.00-18.50 μM for propyl and 4-15 μM for butyl derivatives against KBChR-8-5 cells suggesting that the antiproliferative activity increases as chain length increases from 3 to 4 carbons at N10-position. Compounds at IC10 were evaluated for their efficacy to modulate the cytotoxicity of VLB in KBChR-8-5 cells and found that the modulators enhanced the cytotoxicity of VLB by 5- to 35-fold. Modulators 12, 14-16, and 19 like VRP, were able to completely reverse the 24-fold resistance of KBChR-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-methoxyacridones.
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U2 - 10.1016/S0968-0896(02)00068-8
DO - 10.1016/S0968-0896(02)00068-8
M3 - Article
C2 - 11983534
AN - SCOPUS:0036238375
VL - 10
SP - 2367
EP - 2380
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
SN - 0968-0896
IS - 7
ER -