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Eur J Med Chem. 2019 May 15;170:73-86. doi: 10.1016/j.ejmech.2019.03.006. Epub 2019 Mar 8.

Discover 4β-NH-(6-aminoindole)-4-desoxy-podophyllotoxin with nanomolar-potency antitumor activity by improving the tubulin binding affinity on the basis of a potential binding site nearby colchicine domain.

Author information

1
State Key Laboratory of Microbial Technology, Shandong University, Qingdao, 266237, China.
2
Hubei Key Laboratory of Industrial Microbiology, Hubei Provincial Cooperative Innovation Center of Industrial Fermentation, Key Laboratory of Fermentation Engineering (Ministry of Education), Hubei University of Technology, Wuhan, 430068, China.
3
No.11 Middle School of Wuhan, Wuhan, 430068 China.
4
State Key Laboratory of Microbial Technology, Shandong University, Qingdao, 266237, China; Hubei Key Laboratory of Industrial Microbiology, Hubei Provincial Cooperative Innovation Center of Industrial Fermentation, Key Laboratory of Fermentation Engineering (Ministry of Education), Hubei University of Technology, Wuhan, 430068, China. Electronic address: yajietang@sdu.edu.cn.

Abstract

The colchicine binding site of tubulin is an attractive molecular target domain for cancer therapies. However, there was no FDA approved drug for targeting colchicine domain. Our previous crystallography discovered that a potential binding site of αT5 loop-αH7 nearby colchicine domain was beneficial for introducing affinity fragment. In this work, benzo heterocycles (i.e., indole, indazole and quinoline) with the high affinity ability of αT5 loop-αH7 were chosen as affinity fragment to modify the molecule structure of podophyllotoxin for improving the tubulin binding affinity. 4β-NH-(benzo heterocycles)-4-desoxy-podophyllotoxin were synchronously located at α/β interface of tubulin through providing affinity fragment to αT5 loop-αH7 (i.e., α178Ser, α182Val, α241Phe) and colchicine domain (i.e., β241Cys, β124ASP). 4β-NH-(6″-aminoindole)-4-desoxy-podophyllotoxin not only exhibited nanomolar antitumor potency in vitro but also destroyed solid tumor growth without lethal toxicity in vivo. The correctness of rational drug design was strictly demonstrated by bioactivity test.

KEYWORDS:

Binding affinity; Colchicine domain; Nanomolar-potency antitumor activity; Podophyllotoxin; Tubulin

PMID:
30878833
DOI:
10.1016/j.ejmech.2019.03.006
[Indexed for MEDLINE]

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