Podophyllotoxin analogue with bicyclo[3.2.1]octane moiety annelated with indole: synthesis, molecular modeling, and biological testing

   
Zefirov N.A.1 , Lavrushkina E.A.2, Kuznetsov S.A.3, Zefirova O.N.1

1. Department of Chemistry, Lomonosov Moscow State University, Moscow, Russia; Institute of Physiologically active compounds, Russian Academy of Sciences, Chernogolovka, Russia
2. Department of Chemistry, Lomonosov Moscow State University, Moscow, Russia
3. Institute of Biological Sciences, University of Rostock, Rostock, Germany
Section: Bioinformatics and Chemoinformatics
DOI: 10.18097/PBMC20196502086      PubMed Id: 30950812
Year: 2019  Volume: 65  Issue: 2  Pages: 86-90
C4-Ester derivatives of the anticancer agent podophyllotoxin with bridged moieties can either inhibit polymerization of alpha,beta-tubulin with the formation of microtubules (analogously to the parent molecule) or cause an unusual effect of “curling and shortening” of the microtubules (MT). In order to predict the effect of bridged podophyllotoxin derivatives on the MT network using computer molecular modeling it is desirable to enhance the structural diversity of their bridged substituents. In the present work we synthesized novel podophyllotoxin ester with bicyclo[3.2.1]octane moiety annelated with indole core. The target compound was obtained by Steglich esterification of podophyllotoxin by rac-exo-(indolo[2,3-b])bicyclo[3.2.1]oct-2-ene-6-carboxylic acid as diastereomeric (6RS,8SR,9RS) mixture, which could not be separated by thin layer or preparative column chromatography on silica gel. Results of biotesting of 4-O-{(6R,8S,9R)-5,6,7,8,9,10-hexahydro-6,9-methanocyclohepto[b]indol-8-ylcarbonyl}-Lpodophyllotoxin on the carcinoma A549 cells proved its ability to cause full depolymerization of microtubules without curling effect at a concentration 10 μM. Cytotoxicity value of the compound estimated in MTT test was in a high nanomolar concentration interval (EC50=710±30 nM). Computer molecular docking of both isomers of novel compound and earlier synthesized podophyllotoxin esters with bridged moieties into the 3D model of the colchicine domain in alpha,beta-tubulin revealed the difference in positions of the bridge moieties of new compound and MT-curling ligands and allowed to hypothesize that the atypical action on MT might be caused by positioning of their bridge groups near the GTP binding site in alpha-tubulin.
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Keywords: podophyllotoxin, molecular modeling, bridged groups, carcinoma A549
Citation:

Zefirov, N. A., Lavrushkina, E. A., Kuznetsov, S. A., Zefirova, O. N. (2019). Podophyllotoxin analogue with bicyclo[3.2.1]octane moiety annelated with indole: synthesis, molecular modeling, and biological testing. Biomeditsinskaya khimiya, 65(2), 86-90.
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