Synthesis and Structure-Activity Relationships of Tetrahydroindazolone Derivatives as Anticancer Agents
Rong-Yu Chen,a Chien-Yu Chen,a Tzung-Han Tang,b Jau-Yang Chen,a Chien-Fu Huang,c Chun-Tang Chiou,d Shin-Hun Juang,a Chih-Shiang Changa,*
a
Graduate Institute of Pharmaceutical Chemistry, College of Pharmacy, China Medical University, Taiwan.
b
School of Pharmacy, College of Pharmacy, China Medical University, Taiwan.
c
Department of Biological Science and Technology, I-Shou University, Taiwan.
d
Division of Herbal Drugs and Natural Products, National Research Institute of Chinese Medicine, Taiwan.
Tetrahydroindazolone (THI) was recently recognized as an important pharmacophore because of its excellent biological activity as a potent inhibitor of heat-shock protein 90. SNX-2112, a novel THI core inhibitor of Hsp90, is currently in phase III clinical trials. In here, tetrahydroindazolone derivatives were synthesized and evaluated for biological activity against colon cancer cell (H226), Human T cell lymphoblast-like cell line (Jurkat), and nasopharyngeal cancer (NPC-TW01). The structure-activity relationship of THI derivatives results were shown that the N-1 substituted tetrahydroindazolone possessed more potential activity against cancer cell line than those of corresponding N-2 substituted THI derivatives. The 4-methylphenyl THI (10k), 2-methylphenyl THI (10m), and 3,5-dichlorophenyl THI (10p) were demonstrated potent activity against H226, Jurkat, and NPC-TW01 in vitro, respectively.
The 4-chlorophenyl THI (10e) was also shown good activity antitumor efficacy in vivo.
