These tools will no longer be maintained as of December 31, 2024. Archived website can be found here. PubMed4Hh GitHub repository can be found here. Contact NLM Customer Service if you have questions.


Pubmed for Handhelds

PUBMED FOR HANDHELDS

Search MEDLINE/PubMed

  • Title: 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: Zhao W, He L, Xiang TL, Tang YJ.
    Journal: Eur J Med Chem; 2019 May 15; 170():73-86. PubMed ID: 30878833.
    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.
    [Abstract] [Full Text] [Related] [New Search]