Molecular mechanisms of indirubin and its derivatives: novel anticancer molecules with their origin in traditional Chinese phytomedicine.
Indirubin, a 3, 2' bisindole isomer of indigo, has originally been identified as the active principle of a traditional Chinese preparation and has been proven to exhibit antileukemic effectiveness in chronic myelocytic leukemia. Indirubin was detected to represent a novel lead structure with potent inhibitory potential towards cyclin-dependent kinases (CDKs) resulting from high affinity binding into the enzymes ATP binding site. This seminal finding triggered our research to improve the pharmacological activities of the parent molecule within comprehensive structure-activity studies. Molecular modifications made novel anticancer compounds accessible with strongly improved CDK inhibitory potential and with broad spectrum antitumour activity. This novel family of compounds holds strong promise for clinical anticancer activity and might be useful also in several important noncancer indications, including Alzheimer's disease or diabetes.
Eisenbrand
Gerhard
G
Division of Food Chemistry and Environmental Toxicology, Department of Chemistry, University of Kaiserslautern, P.O. Box 3049, 67663, Kaiserslautern, Germany. eisenbra@rhrk.uni-kl.de
Hippe
Frankie
F
Jakobs
Sandra
S
Muehlbeyer
Stephan
S
D000255:Adenosine Triphosphate / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy; D000903:Antibiotics, Antineoplastic / Q000737:chemistry / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D003920:Diabetes Mellitus / Q000188:drug therapy; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy*; D008516:Medicine, Chinese Traditional; D013329:Structure-Activity Relationship
D000903:Antibiotics, Antineoplastic; D004791:Enzyme Inhibitors; D007211:Indoles; D000255:Adenosine Triphosphate; D018844:Cyclin-Dependent Kinases; C027185:indirubin