title: Discovery and SAR of indole-2-carboxylic acid benzylidene-hydrazides as a new series of potent apoptosis inducers using a cell-based HTS assay.
abstract: A series of indole-2-carboxylic acid benzylidene-hydrazides has been identified as a new class of potent apoptosis inducers through a novel cell-based caspase HTS assay. The screening hit, 5-chloro-3-methyl-indole-2-carboxylic acid (4-nitrobenzylidene)-hydrazide (3a), was found to arrest T47D cells in G(2)/M and to induce apoptosis as measured by the flow cytometric analysis assay. A SAR study was carried out by modification of the substitutions on the indole and benzene rings. Substitution at the 3-position of the indole ring was found to be important for apoptotic activity. A 20-fold increase of apoptotic activity was achieved from screening hit 3a to 5-methyl-3-phenyl-indole-2-carboxylic acid (4-methylbenzylidene)-hydrazide (9a) and 5-chloro-3-phenyl-indole-2-carboxylic acid (4-nitrobenzylidene)-hydrazide (9b), with EC(50) value of 0.1microM in the caspase activation assay in T47D breast cancer cells. Compound 9b also was found to be highly active in a standard growth inhibition assay with a GI(50) value of 0.9microM in T47D cells. Compound 3a and its analogs were found to inhibit tubulin polymerization, which is the most probable primary mechanism of action of these compounds.
authors.affiliation: Maxim Pharmaceuticals, Inc., 6650 Nancy Ridge Drive, San Diego, CA 92121, USA.
authors.forename: Han-Zhong
authors.initials: HZ
authors.lastname: Zhang
authors.forename: John
authors.initials: J
authors.lastname: Drewe
authors.forename: Ben
authors.initials: B
authors.lastname: Tseng
authors.forename: Shailaja
authors.initials: S
authors.lastname: Kasibhatla
authors.forename: Sui Xiong
authors.initials: SX
authors.lastname: Cai
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D002264:Carboxylic Acids; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D005434:Flow Cytometry; D006801:Humans; D006834:Hydrazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D007211:Indoles / Q000737:chemistry*; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D002264:Carboxylic Acids; D006834:Hydrazines; D007211:Indoles; C058980:indole-2-carboxylic acid; C006730:benzylhydrazine; D020169:Caspases