Array-based structure and gene expression relationship study of antitumor sulfonamides including N-[2-[(4-hydroxyphenyl)amino]-3-pyridinyl]-4-methoxybenzenesulfonamide and N-(3-chloro-7-indolyl)-1,4-benzenedisulfonamide.
Compounds from sulfonamide-focused libraries have been evaluated in cell-based antitumor screens using the COMPARE analysis with a panel of 39 human cancer cell lines and flow cytometric cell cycle analysis. Thus far, 2 (N-[2-[(4-hydroxyphenyl)amino]-3-pyridinyl]-4-methoxybenzenesulfonamide (E7010)) and 3 (N-(3-chloro-7-indolyl)-1,4-benzenedisulfonamide (E7070)) have been selected from the collections as potent cell cycle inhibitors, which have progressed to clinical trials. Compound 2 is an orally active antimitotic agent disrupting tubulin polymerization, whereas compound 3 belongs to a novel class of antiproliferative agents causing a decrease in the S phase fraction along with G1 and/or G2 accumulation in various cancer cell lines. Because both compounds exhibited preliminary clinical activities in the phase I setting, we decided to examine further this series of oncolytic small molecules, particularly by using high-density oligonucleotide microarray analysis. The array data have enabled us to characterize these two classes of antitumor sulfonamides on the basis of gene expression changes, illuminating the essential pharmacophore structure and drug-sensitive cellular pathways for each class. Moreover, the dual character of 5 (N-(3-chloro-7-indolyl)-4-methoxybenzenesulfonamide (ER-67880)), resembling both 2 and 3, was revealed by array-based transcription profiling, though the 3-type profile of this molecule had not been apparent in the cell-based phenotypic screens. These results provide an example of the utility of structure and gene expression relationship studies in medicinal genomics.
Owa
Takashi
T
Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba, Ibaraki 300-2635, Japan. t-owa@hhc.eisai.co.jp
Yokoi
Akira
A
Yamazaki
Kanami
K
Yoshimatsu
Kentaro
K
Yamori
Takao
T
Nagasu
Takeshi
T
D000465:Algorithms; D000627:Aminophenols / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001704:Biopolymers; D002453:Cell Cycle / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D005434:Flow Cytometry; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects; D014404:Tubulin / Q000737:chemistry; D014407:Tumor Cells, Cultured; D000096926:Benzenesulfonamides
D000627:Aminophenols; D000970:Antineoplastic Agents; D001704:Biopolymers; D013449:Sulfonamides; D014404:Tubulin; C439829:N-(3-chloro-7-indolyl)-1,4-benzenedisulphonamide; C079199:E 7010; D000096926:Benzenesulfonamides