Structural requirements for activity of phenoxazines for reversal of drug resistance in cancer cells

Eregowda, G. B. and Krishnegowda, G. and Kalpana, H. N. and Channu, B. C. and Dass, C. and Horton, J. K. and Houghton, P. J. and Thimmaiah, K. N. (1999) Structural requirements for activity of phenoxazines for reversal of drug resistance in cancer cells. ASIAN JOURNAL OF CHEMISTRY, 11 (3). pp. 878-905.

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In the course of a chemical program aimed at identifying chemically useful modulators of MDR in cancer therapy, a series of twentyone 2-tri-fluoromethyl-N-10-substituted phenoxazines (1-21) has been synthesised. The novel 2-trifluoromechylphenoxazine (1) was prepared by the pyrolytic condensation of a;bromophenol and 4-chloro-3-nitrobenzotrifluoride as outlined in Scheme-I. This compound undergoes N-alkylation in the presence of phase transfer catalyst (PTC). Stirring of 2-trifluoromethylphenoxazine with 1-bromo,-3-chloropropane or 1-bromo-4-chlorobutane in a two phase system consisting of an organic solvent (benzene) and 6N potassium hydroxide in the presence of tetrabutylammonium bromide leads to the formation of compounds 2 and 9 in good yield. N-(omega-chloroalkyl)- and N-(chloroacetyl) analogues were found to undergo iodide catalysed nucleophilic substitution reaction with various secondary amines including N,N-diethylamine, N,N-diethanol-amine, morpholine, piperidine, pyrrolidine and (beta-hydroxyethyl)-piperazine. Purified products were characterized by UV, IR, H-1 and C-13-NMR and mass-spectral data. The lipophilicity expressed in log(10) P and pKa of compounds were determined. The effect of 1-21 at 100 mu M on the steady-state accumulation of vinblastine (VLB) was studied in KBCh(R)-8-5 cells and the data revealed that the compounds (3-8, 10, 12-15) exhibited a significant VLB uptake enhancing effect (8.3-58.5-fold relative to control) compared to a standard modulator, verapamil (VRP) (7.5-fold). These eleven compounds caused a 1.10-7.82-fold greater uptake of VLB than did a similar concentration of VRP. Comparison of the derivatives for their ability to potentiate the uptake of VLB revealed that they largely follow the order: N-10-propyl > N-10-butyl > N-10-acetyl compounds. To determine whether the increase in VLB uptake upon coincubation with 1-21 modulators was due to a slowing of P-gp mediated efflux, KBCh(R)-8-5 cells were loaded with H-3] VLB in the absence of modulator and efflux examined in the absence or presence of 100 mu M Of 8 or VRP. Less than 10% in the absence or about 40% of cell associated VLB in the presence of 100 mu M 8 remained at the end of a 2 h efflux period, suggesting that modulator 8, like VRP, is able to inhibit p-glycoprotein (P-gp) mediated afflux. Cytotoxicity was determined and the IC10 and IC50 values lie respectively in the range 0.1-30.9 mu M and 2.1-70.9 mu M for KBCh(R)-8-5 cells. Substitution of hydrogen by CF3 in C-2 of phenoxazine ring caused a greater enhancement in the antiproliferative protency by 1.1-3.3-fold for KBCHR-8-5 cells than their counterparts, presumably due to increased hydrophobicity. Compounds at IC10 were evaluated for their efficacy to modulate the cytotoxicity of VLB in KBCh(R)- 8-5 cells and compounds 3, 5, 11 and 13, like VRP, were able to completely reverse the 24-fold resistance of KBCh(R)-8-5 cells to VLB. The structural features for reversal of MDR seem to include a hydrophobic phenoxazine ring with a -CF3 in C-2 position and a tertiary amino group at a distance of three or four carbon chain from the tricyclic ring. Examination of the relationship between partition coefficient and cytotoxicity or anti-MDR activity showed no correlation suggesting that lipophilicity is not the sole determinant of potency for biological activity.

Item Type: Article
Subjects: Physical Sciences > Chemistry
Divisions: PG Campuses > Manasagangotri, Mysore > Chemistry
Depositing User: Users 13 not found.
Date Deposited: 19 Apr 2013 08:43
Last Modified: 20 Aug 2013 07:35

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