Synthesis and Chemical Characterization of N-Substituted Phenoxazines Directed toward Reversing Vinca Alkaloid Resistance in Multidrug-Resistant Cancer Cells

Kuntebommanahalli N. Thimmaiah, Julie K. Horton, Ramakrishnan Seshadri, Mervyn Israel, Janet A. Houghton, Franklin C. Harwood, Peter J Houghton

Research output: Contribution to journalArticle

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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-(ω-chloroalkyl)- and N-(chloroacyl) phenoxazines were found to undergo iodide-catalyzed nucleophilic substitution on reaction with various secondary amines, including N,N-diethylamine, N,N-diethanolamine, morpholine, piperidine, pyrrolidine and (β-hydroxyethybpiperazine. Products were characterized by UV, IR, 1H-, and 13C-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 antiproliferative 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/C1 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 in enhanced anti-MDR activity. On the basis 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)phenoxazme, 10-(4′-N-morpholmobutyl)phenoxazme 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.

Original languageEnglish (US)
Pages (from-to)3358-3364
Number of pages7
JournalJournal of Medicinal Chemistry
Volume35
Issue number18
DOIs
StatePublished - Sep 1 1992
Externally publishedYes

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Vinca Alkaloids
Multiple Drug Resistance
Neoplasms
Vincristine
Verapamil
diethanolamine
Amines
Carbon
KB Cells
Vinblastine
phenoxazine
Poisons
Iodides
HeLa Cells
Inhibitory Concentration 50
Colon
Adenocarcinoma
Drug Therapy
Cell Line

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Synthesis and Chemical Characterization of N-Substituted Phenoxazines Directed toward Reversing Vinca Alkaloid Resistance in Multidrug-Resistant Cancer Cells. / Thimmaiah, Kuntebommanahalli N.; Horton, Julie K.; Seshadri, Ramakrishnan; Israel, Mervyn; Houghton, Janet A.; Harwood, Franklin C.; Houghton, Peter J.

In: Journal of Medicinal Chemistry, Vol. 35, No. 18, 01.09.1992, p. 3358-3364.

Research output: Contribution to journalArticle

Thimmaiah, Kuntebommanahalli N. ; Horton, Julie K. ; Seshadri, Ramakrishnan ; Israel, Mervyn ; Houghton, Janet A. ; Harwood, Franklin C. ; Houghton, Peter J. / Synthesis and Chemical Characterization of N-Substituted Phenoxazines Directed toward Reversing Vinca Alkaloid Resistance in Multidrug-Resistant Cancer Cells. In: Journal of Medicinal Chemistry. 1992 ; Vol. 35, No. 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-(ω-chloroalkyl)- and N-(chloroacyl) phenoxazines were found to undergo iodide-catalyzed nucleophilic substitution on reaction with various secondary amines, including N,N-diethylamine, N,N-diethanolamine, morpholine, piperidine, pyrrolidine and (β-hydroxyethybpiperazine. Products were characterized by UV, IR, 1H-, and 13C-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 antiproliferative 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/C1 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 in enhanced anti-MDR activity. On the basis 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)phenoxazme, 10-(4′-N-morpholmobutyl)phenoxazme 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.",
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AU - Thimmaiah, Kuntebommanahalli N.

AU - Horton, Julie K.

AU - Seshadri, Ramakrishnan

AU - Israel, Mervyn

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N2 - 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-(ω-chloroalkyl)- and N-(chloroacyl) phenoxazines were found to undergo iodide-catalyzed nucleophilic substitution on reaction with various secondary amines, including N,N-diethylamine, N,N-diethanolamine, morpholine, piperidine, pyrrolidine and (β-hydroxyethybpiperazine. Products were characterized by UV, IR, 1H-, and 13C-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 antiproliferative 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/C1 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 in enhanced anti-MDR activity. On the basis 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)phenoxazme, 10-(4′-N-morpholmobutyl)phenoxazme 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.

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