Anti-calmodulin acridone derivatives modulate vinblastine resistance in multidrug resistant (MDR) cancer cells

Ravi Hegde; Padma Thimmaiah; Mayur C. Yerigeri; Gowdahalli Krishnegowda; Kuntebommanahalli N. Thimmaiah; Peter J. Houghton

doi:10.1016/j.ejmech.2003.12.001

Anti-calmodulin acridone derivatives modulate vinblastine resistance in multidrug resistant (MDR) cancer cells

Ravi Hegde, Padma Thimmaiah, Mayur C. Yerigeri, Gowdahalli Krishnegowda, Kuntebommanahalli N. Thimmaiah, Peter J. Houghton

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Abstract

Multidrug resistance (MDR) is one of the main obstacles limiting the efficacy of chemotherapy treatment of tumors. Parent acridones 1A and 1B were prepared by the Ullmann reaction followed by cyclization and N-alkylation. N-(ω-Chloroalkyl) analogues were subjected to iodide catalyzed nucleophilic substitution reaction with secondary amines to get the compounds 3A-13A and 3B-13B, which enhanced the uptake of vinblastine in KBCh ^R-8-5 cells to a greater extent (2.6-13.1-fold relative to control) than verapamil. The study on the structure-activity relationship revealed that substitution of -H at position C-4 in acridone nucleus by -OCH₃ increased the cytotoxic and anti-MDR activities. The ability of acridones to inhibit calmodulin dependent cyclic AMP phosphodiesterase has been determined and the results have shown a strong positive correlation between anti-calmodulin activity and cytotoxicity in KBCh^R-8-5 cells or anti-MDR activity.

Original language	English (US)
Pages (from-to)	161-177
Number of pages	17
Journal	European Journal of Medicinal Chemistry
Volume	39
Issue number	2
DOIs	https://doi.org/10.1016/j.ejmech.2003.12.001
State	Published - Feb 2004

All Science Journal Classification (ASJC) codes

Pharmacology
Drug Discovery
Organic Chemistry

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10.1016/j.ejmech.2003.12.001

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title = "Anti-calmodulin acridone derivatives modulate vinblastine resistance in multidrug resistant (MDR) cancer cells",

abstract = "Multidrug resistance (MDR) is one of the main obstacles limiting the efficacy of chemotherapy treatment of tumors. Parent acridones 1A and 1B were prepared by the Ullmann reaction followed by cyclization and N-alkylation. N-(ω-Chloroalkyl) analogues were subjected to iodide catalyzed nucleophilic substitution reaction with secondary amines to get the compounds 3A-13A and 3B-13B, which enhanced the uptake of vinblastine in KBCh R-8-5 cells to a greater extent (2.6-13.1-fold relative to control) than verapamil. The study on the structure-activity relationship revealed that substitution of -H at position C-4 in acridone nucleus by -OCH3 increased the cytotoxic and anti-MDR activities. The ability of acridones to inhibit calmodulin dependent cyclic AMP phosphodiesterase has been determined and the results have shown a strong positive correlation between anti-calmodulin activity and cytotoxicity in KBChR-8-5 cells or anti-MDR activity.",

author = "Ravi Hegde and Padma Thimmaiah and Yerigeri, {Mayur C.} and Gowdahalli Krishnegowda and Thimmaiah, {Kuntebommanahalli N.} and Houghton, {Peter J.}",

note = "Funding Information: Miss. Padma Thimmaiah extends her sincere thanks to the Indian Council of Medical Research (ICMR), Government of India, for awarding the Senior Research Fellowship. The authors thank Professor Chhabil Dass, Department of Chemistry, The University of Memphis, Tennessee, USA, for providing mass spectral data. The authors would like to thank Dr. John Easton and Mr. Christopher Lee Morton for their helpful advice and discussion regarding the statistical analysis.",

year = "2004",

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doi = "10.1016/j.ejmech.2003.12.001",

language = "English (US)",

volume = "39",

pages = "161--177",

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T1 - Anti-calmodulin acridone derivatives modulate vinblastine resistance in multidrug resistant (MDR) cancer cells

AU - Hegde, Ravi

AU - Thimmaiah, Padma

AU - Yerigeri, Mayur C.

AU - Krishnegowda, Gowdahalli

AU - Thimmaiah, Kuntebommanahalli N.

AU - Houghton, Peter J.

N1 - Funding Information: Miss. Padma Thimmaiah extends her sincere thanks to the Indian Council of Medical Research (ICMR), Government of India, for awarding the Senior Research Fellowship. The authors thank Professor Chhabil Dass, Department of Chemistry, The University of Memphis, Tennessee, USA, for providing mass spectral data. The authors would like to thank Dr. John Easton and Mr. Christopher Lee Morton for their helpful advice and discussion regarding the statistical analysis.

PY - 2004/2

Y1 - 2004/2

N2 - Multidrug resistance (MDR) is one of the main obstacles limiting the efficacy of chemotherapy treatment of tumors. Parent acridones 1A and 1B were prepared by the Ullmann reaction followed by cyclization and N-alkylation. N-(ω-Chloroalkyl) analogues were subjected to iodide catalyzed nucleophilic substitution reaction with secondary amines to get the compounds 3A-13A and 3B-13B, which enhanced the uptake of vinblastine in KBCh R-8-5 cells to a greater extent (2.6-13.1-fold relative to control) than verapamil. The study on the structure-activity relationship revealed that substitution of -H at position C-4 in acridone nucleus by -OCH3 increased the cytotoxic and anti-MDR activities. The ability of acridones to inhibit calmodulin dependent cyclic AMP phosphodiesterase has been determined and the results have shown a strong positive correlation between anti-calmodulin activity and cytotoxicity in KBChR-8-5 cells or anti-MDR activity.

AB - Multidrug resistance (MDR) is one of the main obstacles limiting the efficacy of chemotherapy treatment of tumors. Parent acridones 1A and 1B were prepared by the Ullmann reaction followed by cyclization and N-alkylation. N-(ω-Chloroalkyl) analogues were subjected to iodide catalyzed nucleophilic substitution reaction with secondary amines to get the compounds 3A-13A and 3B-13B, which enhanced the uptake of vinblastine in KBCh R-8-5 cells to a greater extent (2.6-13.1-fold relative to control) than verapamil. The study on the structure-activity relationship revealed that substitution of -H at position C-4 in acridone nucleus by -OCH3 increased the cytotoxic and anti-MDR activities. The ability of acridones to inhibit calmodulin dependent cyclic AMP phosphodiesterase has been determined and the results have shown a strong positive correlation between anti-calmodulin activity and cytotoxicity in KBChR-8-5 cells or anti-MDR activity.

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Anti-calmodulin acridone derivatives modulate vinblastine resistance in multidrug resistant (MDR) cancer cells

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