Thimmaiah, K. N. and Horton, J. K. and Seshadri, R. and Israel, M. and Houghton, J. A. and Harwood, F. C. and Houghton, P. J. (1992) Synthesis and Chemical Characterization of N-Substituted Phenoxazines Directed toward Reversing Vinca Alkaloid Resistance in Multidrug-Resistant Cancer Cells. Journal of Medicinal Chemistry, 35 (18). pp. 3358-3364.
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Abstract
A series of 21 N-substituted phenoxazines has been synthesized in an effort to find more specific and less toxic modulators of multidrug resistance (MDR) in cancer chemotherapy. Thus, N-(omega-chloroalkyl)- and N-(chloroacyl)phenoxazines were found to undergo iodide-catalyzed nucleophilic substitution on reaction with various secondary amines, including N,N-diethylamine, NN-diethanolamine, morpholine, piperidine, pyrrolidine and (beta-hydroxyethyl) piperazine. Products were characterized by UV, IR, H-1-, and C-13-NMR, mass spectral data, and elemental analyses. All of the compounds were examined for cytotoxicity and for their ability to increase the accumulation of the vinca alkaloids, vincristine (VCR) and vinblastine (VLB) in multidrug-resistant GC3/Cl (human colon adenocarcinoma) and KBChR-8-5 (HeLa variant) cell lines. Compounds were compared to the standard modulator verapamil (VRP). Substitutions on the phenoxazine ring at position 10 were associated with an increase in anti-proliferative and anti-MDR activities. Modification of the length of the alkyl bridge and the type of amino side chain also influenced the potency of these effects. From among the compounds examined, 10 derivatives were found to increase the accumulation of VCR and VLB in GC3/Cl and KBChR-8-5 cells relative to the effect of VRP, suggesting that with the exception of pyrrolidinyl, the tertiary amine attachments to the phenoxazine nucleus linked through a three- or four-carbon alkyl chain resulted m enhanced anti-MDR activity. On the bass of their 50% growth inhibitory (IC50) values, five of the ten compounds, namely, 10-(3'-chloropropyl)phenoxazine, 10-3'-N-bis(hydroxyethyl)-amino]propyl]phenoxazine, 10-(3'-N-morpholinopropyl)phenoxazine, 10-(4'-N-morpholinobutyl)phenoxazine and 10-(N-piperidinoacetyl)phenoxazine were selected as relatively nontoxic chemosensitizers. These modulators, at nontoxic concentrations, potentiated the cytotoxicity of VCR and VLB in GC3/Cl and KBChR-8-5 cells. Further, two compounds 10-(3'-N-morpholinopropyl)phenoxazine, and the butyl derivative, enhanced accumulation of VLB in GC3/Cl, KBChR8-5 and highly resistant KB-V1 cells to a level significantly greater than the maximal level achieved with VRP. Additional experiments to understand the mechanism of action of these agents in modulating MDR are in progress.
| Item Type: | Article |
|---|---|
| Subjects: | C Chemical Science > Chemistry |
| Divisions: | Department of > Chemistry |
| Depositing User: | Users 23 not found. |
| Date Deposited: | 18 May 2021 06:23 |
| Last Modified: | 18 Nov 2022 10:32 |
| URI: | http://eprints.uni-mysore.ac.in/id/eprint/16424 |
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