Design, Synthesis, and Biological Evaluation of Artemisinin-Indoloquinoline Hybrids as Potent Antiproliferative Agents
Li Wang,
Marta Świtalska,
Ning Wang,
Zhen-Jun Du,
Yuta Fukumoto,
Nguyen Kim Diep,
Ryo Kiguchi,
Junzo Nokami,
Joanna Wietrzyk,
Tsutomu Inokuchi
Affiliations
Li Wang
Division of Chemistry and Biotechnology, Graduate School of Natural Science and Technology, Okayama University, 3-1-1 Tsushima-naka, Kita-ku, Okayama 700-8530, Japan
Marta Świtalska
Institute of Immunology and Experimental Therapy, Polish Academy of Science, 12, R. Weigl Street, Wroclaw 53-114, Poland
Ning Wang
Division of Chemistry and Biotechnology, Graduate School of Natural Science and Technology, Okayama University, 3-1-1 Tsushima-naka, Kita-ku, Okayama 700-8530, Japan
Zhen-Jun Du
Department of Applied Chemistry, Faculty of Engineering, Okayama University of Science, Ridai-cho, Kita-ku, Okayama, Japan
Yuta Fukumoto
Division of Chemistry and Biotechnology, Graduate School of Natural Science and Technology, Okayama University, 3-1-1 Tsushima-naka, Kita-ku, Okayama 700-8530, Japan
Nguyen Kim Diep
Division of Chemistry and Biotechnology, Graduate School of Natural Science and Technology, Okayama University, 3-1-1 Tsushima-naka, Kita-ku, Okayama 700-8530, Japan
Ryo Kiguchi
Division of Chemistry and Biotechnology, Graduate School of Natural Science and Technology, Okayama University, 3-1-1 Tsushima-naka, Kita-ku, Okayama 700-8530, Japan
Junzo Nokami
Department of Applied Chemistry, Faculty of Engineering, Okayama University of Science, Ridai-cho, Kita-ku, Okayama, Japan
Joanna Wietrzyk
Institute of Immunology and Experimental Therapy, Polish Academy of Science, 12, R. Weigl Street, Wroclaw 53-114, Poland
Tsutomu Inokuchi
Division of Chemistry and Biotechnology, Graduate School of Natural Science and Technology, Okayama University, 3-1-1 Tsushima-naka, Kita-ku, Okayama 700-8530, Japan
A series of artemisinin-indoloquinoline hybrids were designed and synthesized in an attempt to develop potent and selective anti-tumor agents. Compounds 7a–7f, 8 and 9 were prepared and characterized. Their antiproliferative activities against MV4-11, HCT-116, A549, and BALB/3T3 cell lines in vitro were tested. Nearly all of the tested compounds (7–9, except for compounds 7d and 7e against HCT-116) showed an increased antitumor activity against HCT-116 and A549 cell lines when compared to the dihydroartemisinin control. Especially for the artemisinin-indoloquinoline hybrid 8, with an 11-aminopropylamino-10H-indolo[3,2-b]quinoline substituent, the antiproliferative activity against the A549 cell line had improved more than ten times. The IC50 value of hybrid 8 against A549 cell lines was decreased to 1.328 ± 0.586 μM, while dihydroartemisin showed IC50 value of >20 µM in the same cell line. Thus, these results have proven that the strategy of introducing a planar basic fused aromatic moiety, such as the indoloquinoline skeleton, could improve the antiproliferative activity and selectivity towards cancer cell lines.
