TY - JOUR
T1 - Synthesis and in vitro cancer cell growth inhibition evaluation of 11-amino-modified 5-Me-indolo[2,3-b]quinolines and their COMPARE analyses
AU - Okada, Masashi
AU - Mei, Zhen Wu
AU - Imran Hossain, Md
AU - Wang, Li
AU - Tominaga, Taihei
AU - Takebayashi, Takeshi
AU - Murakami, Masaharu
AU - Yasuda, Mizuki
AU - Shigehiro, Tsukasa
AU - Kasai, Tomonari
AU - Mizutani, Akifumi
AU - Murakami, Hiroshi
AU - El Sayed, Ibrahim El Tantawy
AU - Dan, Shingo
AU - Yamori, Takao
AU - Seno, Masaharu
AU - Inokuchi, Tsutomu
N1 - Funding Information:
We are grateful to Okayama University for its support and to the Advanced Science Research Center for the NMR experiments. We are thankful to Prof. X.-Q. Yu, Sichuan University, for the HRMS analyses. This study was partially supported by the Adaptable and Seamless Technology Transfer Program of JST, No. AS242Z02199Q. Screening Committee of Anticancer Drugs supported by Grant-in-Aid for Scientific Research on Innovative Areas, Scientific Support Programs for Cancer Research, from The Ministry of Education, Culture, Sports, Science and Technology, Japan, is gratefully acknowledged.
Publisher Copyright:
© 2016 Springer Science+Business Media New York.
PY - 2016/5/1
Y1 - 2016/5/1
N2 - A plant-derived neocryptolepine core, the 5-Me-indolo[2,3-b]quinoline skeleton, was emblazoned with substituents at C11 and C2 and then tested against various cancer cell lines to find potent anticancer agents. In the in vitro antiproliferative activity assay against the breast cancer MDA-MB-453 cell line, the attachment of alkylamino substituents at C11 of the 5-Me-indolo[2,3-b]quinoline induced improved activities. Specifically, 11-(3-aminopropylamino) and 11-(4-aminobutylamino) derivatives indicated the highest activity and selectivity against MDA-MB-453 (IC50 = 0.3-0.5 μM) and also exhibited a higher cytotoxicity against the colon adenocarcinoma (WiDr) and ovarian cancer (SKOv3) cell lines. A synergistic effect by attachment of substituents at C2 was favorably observed with an electron-donating group, such as CH3O, and unfavorably observed with an electron-withdrawing one, such as F and CF3. Further modification of the terminal free amino group of the lariat attachment at C11 into the corresponding acylamides and 2,3-dihydrobenzo[e][1,3]thiazin-4-ones was not effective for the antiproliferative activity. The computer-assisted database analysis, COMPARE, suggested that 14e and 13b have a mode of action similar to actinomycin D and 13c has a mode of actions similar to vindesine sulfate or aclarubicin hydrochloride. However, the new compounds may have other unique mode of actions since the correlation coefficients (r) were in relatively low levels.
AB - A plant-derived neocryptolepine core, the 5-Me-indolo[2,3-b]quinoline skeleton, was emblazoned with substituents at C11 and C2 and then tested against various cancer cell lines to find potent anticancer agents. In the in vitro antiproliferative activity assay against the breast cancer MDA-MB-453 cell line, the attachment of alkylamino substituents at C11 of the 5-Me-indolo[2,3-b]quinoline induced improved activities. Specifically, 11-(3-aminopropylamino) and 11-(4-aminobutylamino) derivatives indicated the highest activity and selectivity against MDA-MB-453 (IC50 = 0.3-0.5 μM) and also exhibited a higher cytotoxicity against the colon adenocarcinoma (WiDr) and ovarian cancer (SKOv3) cell lines. A synergistic effect by attachment of substituents at C2 was favorably observed with an electron-donating group, such as CH3O, and unfavorably observed with an electron-withdrawing one, such as F and CF3. Further modification of the terminal free amino group of the lariat attachment at C11 into the corresponding acylamides and 2,3-dihydrobenzo[e][1,3]thiazin-4-ones was not effective for the antiproliferative activity. The computer-assisted database analysis, COMPARE, suggested that 14e and 13b have a mode of action similar to actinomycin D and 13c has a mode of actions similar to vindesine sulfate or aclarubicin hydrochloride. However, the new compounds may have other unique mode of actions since the correlation coefficients (r) were in relatively low levels.
KW - 5Me-indolo[2,3-b]quinoline
KW - Antiproliferative agent
KW - C11-alkylamino-substituted
KW - COMPARE study
KW - JFCR39 panel
KW - MDA-MB-453
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UR - http://www.scopus.com/inward/citedby.url?scp=84962978230&partnerID=8YFLogxK
U2 - 10.1007/s00044-016-1508-z
DO - 10.1007/s00044-016-1508-z
M3 - Article
AN - SCOPUS:84962978230
VL - 25
SP - 879
EP - 892
JO - Medicinal Chemistry Research
JF - Medicinal Chemistry Research
SN - 1054-2523
IS - 5
ER -