TY - JOUR
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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U2 - 10.1016/j.ejmech.2003.12.001
DO - 10.1016/j.ejmech.2003.12.001
M3 - Article
C2 - 14987825
AN - SCOPUS:1342345198
SN - 0223-5234
VL - 39
SP - 161
EP - 177
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
IS - 2
ER -
