title: Synthesis and biological evaluation of selective aromatase expression regulators in breast cancer cells.
abstract: Aromatase converts androgens to estrogens and is a particularly attractive target in the treatment of estrogen receptor positive breast cancer. The enzyme is encoded by the CYP19 gene, which is expressed in a tissue-specific manner. Prostaglandin E2 (PGE2), the major product of cyclooxygenase-2 (COX-2), stimulates aromatase gene expression via protein kinase A and C signaling pathways. Our previous study demonstrated that COX-2 selective inhibitor nimesulide decreased aromatase activity from the transcriptional level in breast cancer cells. In this manuscript, the synthesis and biological evaluation of a series of nimesulide analogues as potential selective aromatase expression regulators are described. Several novel sulfonanilide compounds demonstrate IC50 values from 0.33 to 2.68 microM in suppressing aromatase enzyme activity in SK-BR-3 breast cancer cells and are 10- to 80-fold more active than nimesulide. Also, the sulfonanilide compounds selectively decrease aromatase gene expression in breast cancer cells, without exhibiting cytotoxic or apoptotic effects at low micromole concentrations.
authors.affiliation: Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, and Ohio State Biochemistry Program, The Ohio State University, 500 W. 12th Avenue, Columbus, Ohio 43210, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Su
authors.forename: Serena
authors.initials: S
authors.lastname: Landini
authors.forename: Danyetta D
authors.initials: DD
authors.lastname: Davis
authors.forename: Robert W
authors.initials: RW
authors.lastname: Brueggemeier
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis; D001141:Aromatase / Q000096:biosynthesis* / Q000235:genetics; D047072:Aromatase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001943:Breast Neoplasms; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D047072:Aromatase Inhibitors; D013449:Sulfonamides; D001141:Aromatase; C012655:nimesulide