Synthesis and chemical characterization of 2-methoxy-N10-substituted acridones needed to reverse vinblastine resistance in multidrug resistant (MDR) cancer cells

Krishne Gowda, Padma Thimmaiah, Ravi Hegde, Chhabil Dass, Peter J. Houghton, Kuntebommanahalli N. Thimmaiah

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)2367-2380
Number of pages14
JournalBioorganic and Medicinal Chemistry
Volume10
Issue number7
DOIs
StatePublished - May 8 2002

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Acridones
Vinblastine
Multiple Drug Resistance
Verapamil
Modulators
P-Glycoprotein
Cells
Cytotoxicity
Neoplasms
Chlorobenzoates
Derivatives
Membrane Transport Proteins
Alkylation
Iodides
Cyclization
Hydrophobic and Hydrophilic Interactions
Inhibitory Concentration 50
Amines
Carbon
Hydrophobicity

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

Cite this

Gowda, Krishne ; Thimmaiah, Padma ; Hegde, Ravi ; Dass, Chhabil ; Houghton, Peter J. ; Thimmaiah, Kuntebommanahalli N. / Synthesis and chemical characterization of 2-methoxy-N10-substituted acridones needed to reverse vinblastine resistance in multidrug resistant (MDR) cancer cells. In: Bioorganic and Medicinal Chemistry. 2002 ; Vol. 10, No. 7. pp. 2367-2380.
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Synthesis and chemical characterization of 2-methoxy-N10-substituted acridones needed to reverse vinblastine resistance in multidrug resistant (MDR) cancer cells. / Gowda, Krishne; Thimmaiah, Padma; Hegde, Ravi; Dass, Chhabil; Houghton, Peter J.; Thimmaiah, Kuntebommanahalli N.

In: Bioorganic and Medicinal Chemistry, Vol. 10, No. 7, 08.05.2002, p. 2367-2380.

Research output: Contribution to journalArticle

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 - Gowda, Krishne

AU - Thimmaiah, Padma

AU - Hegde, Ravi

AU - Dass, Chhabil

AU - Houghton, Peter J.

AU - Thimmaiah, Kuntebommanahalli N.

PY - 2002/5/8

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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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