Affiliation: | 1. Program on Chemical Biology, Chulabhorn Graduate Institute, Center of Excellence on Environmental Health and Toxicology (EHT), Ministry of Education, 54 Kamphaeng Phet 6, Laksi, Bangkok, 10210 Thailand;2. Department of Molecular Tropical Medicine and Genetics, Faculty of Tropical Medicine, Mahidol University, 420/6 Ratchawithi Road, Thung Phayathai Subdistrict Ratchathewi, Bangkok, 10400 Thailand;3. Laboratory of Biochemistry, Chulabhorn Research Institute, 54 Kamphaeng Phet 6, Laksi, Bangkok, 10210 Thailand;4. Program on Chemical Biology, Chulabhorn Graduate Institute, Center of Excellence on Environmental Health and Toxicology (EHT), Ministry of Education, 54 Kamphaeng Phet 6, Laksi, Bangkok, 10210 Thailand
Laboratory of Medicinal Chemistry, Chulabhorn Research Institute, 54 Kamphaeng Phet 6, Laksi, Bangkok, 10210 Thailand;5. Laboratory of Medicinal Chemistry, Chulabhorn Research Institute, 54 Kamphaeng Phet 6, Laksi, Bangkok, 10210 Thailand |
Abstract: | Eighteen hybrid compounds between 8-bromo-2-fluoro-isocryptolepine ( 4 ) and 1,2,3-triazole were synthesized via azide rearrangement-annulation reaction. Compound 4 underwent regioselective N-propargylation and click reaction to form 8-bromo-2-fluoro-isocryptolepine-triazole hybrids 11 which were evaluated for cytotoxic activity. Compound 11 c containing 1-anisyltriazole was the most effective in inhibiting HepG2, HuCCA-1 and A549 cell lines (IC50 values of 1.65–3.07 μM) while compounds 11 a (1-phenyltriazole), 11 j (1-para-CF3-benzyltriazole) and 11 l (1-meta-Cl-benzyltriazole) were potent inhibitors of HuCCA-1, HepG2 and A549 cell lines, respectively. Moreover, 11 l showed the lowest cytotoxicity to normal human kidney cell line. Compounds 11 c and 11 l provided improvement of cytotoxic activity over 4 . Compounds 4 , 11 c and 11 l were selected to investigate their mechanisms of action. The results showed that 4 could induce G2/M cell cycle arrest and was involved in the upregulation of p53 and p21 proteins. However, the mechanisms of growth inhibition by 11 c and 11 l were associated with G0/G1 cell cycle arrest and mediated by induction of oxidative stress. |