1. Antitumor Agents 295. E-Ring Hydroxylated Antofine and Cryptopleurine Analogues as Antiproliferative Agents: Design, Synthesis, and Mechanistic Studies
- Author
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Chin Yu Lai, Shuenn Chen Yang, Qian Shi, Xiaoming Yang, Che-Ming Teng, Shiow Lin Pan, Kuo Hsiung Lee, Kenneth F. Bastow, Chih Ya Wang, Tian Shung Wu, Pan-Chyr Yang, Emika Ohkoshi, and Chi-Yuan Chen
- Subjects
Indoles ,Lung Neoplasms ,Quinolizidines ,Stereochemistry ,Down-Regulation ,Antineoplastic Agents ,Stereoisomerism ,Adenocarcinoma ,medicine.disease_cause ,Article ,Structure-Activity Relationship ,Alkaloids ,Carcinoma, Non-Small-Cell Lung ,Cell Line, Tumor ,Drug Discovery ,medicine ,Humans ,Structure–activity relationship ,HSP90 Heat-Shock Proteins ,Hedgehog ,beta Catenin ,Cell Proliferation ,biology ,Cell growth ,Chemistry ,medicine.disease ,Hsp90 ,Cell culture ,Drug Design ,Cancer research ,biology.protein ,Molecular Medicine ,Drug Screening Assays, Antitumor ,Carcinogenesis ,Phenanthrolines - Abstract
Various E-ring hydroxylated antofine and cryptopleurine analogues were designed, synthesized, and tested against five human cancer cell lines. Interesting structure-activity relationship (SAR) correlations were found among these new compounds. The most potent compound 13b was further tested against a series of nonsmall cell lung cancer (NSCLC) cell lines in which it showed impressive antiproliferative activity. Mechanistic studies revealed that 13b is able to down-regulate HSP90 and β-catenin in A549 lung adenocarcinoma cells in a dose-dependent manner, suggesting a potential use for treating hedgehog pathway-driven tumorigenesis.
- Published
- 2012