1. Synthesis of Isocryptolepine-Triazole Adducts and Evaluation of Their Cytotoxic Activity
- Author
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Charnsak Thongsornkleeb, Pavitra Laohapaisan, Nantamon Supantanapong, Lukana Ngiwsara, Nisachon Khunnawutmanotham, Warabhorn Rodphon, Jumreang Tummatorn, Kriengsak Lirdprapamongkol, Jisnuson Svasti, Onrapak Reamtong, and Somsak Ruchirawat
- Subjects
Triazole ,Antineoplastic Agents ,Biochemistry ,Cell Line ,Indole Alkaloids ,chemistry.chemical_compound ,Structure-Activity Relationship ,Drug Discovery ,Cytotoxic T cell ,Humans ,General Pharmacology, Toxicology and Pharmaceutics ,Cytotoxicity ,Cell Proliferation ,Pharmacology ,A549 cell ,Dose-Response Relationship, Drug ,Molecular Structure ,Organic Chemistry ,Cell Cycle Checkpoints ,Triazoles ,chemistry ,Cell culture ,Quinolines ,Molecular Medicine ,Azide ,Growth inhibition ,Drug Screening Assays, Antitumor ,G1 phase - 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.
- Published
- 2021