Synthesis, biological evaluation and molecular modeling of new analogs of the anti-cancer agent 2-methoxyestradiol: potent inhibitors of angiogenesis

Eirik Johansson Solum; Jing-Jy Cheng; Ingebrigt Sylte; Anders Vik; Trond Vidar Hansen

doi:10.1039/C5RA03570H

Synthesis, biological evaluation and molecular modeling of new analogs of the anti-cancer agent 2-methoxyestradiol: potent inhibitors of angiogenesis†

Eirik Johansson Solum,^a Jing-Jy Cheng,*^bc Ingebrigt Sylte,^d Anders Vik^a and Trond Vidar Hansen*^a

* Corresponding authors

^a Department of Pharmaceutical Chemistry, School of Pharmacy, University of Oslo, PO Box 1068 Blindern, N-0316 Oslo, Norway
E-mail: e.j.solum@farmasi.uio.no, anders.vik@farmasi.uio.no, t.v.hansen@farmasi.uio.no
Fax: +47 22855947
Tel: +47 22857450

^b National Research Institute of Chinese Medicine, 155-1 Li-Nung Street, Section 2, Shih-Pai, Taipei, Taiwan
E-mail: verona@nricm.edu.tw
Fax: +886-2-2825-0743
Tel: +886-2-2820-1999-3671

^c Institute of Biophotonics, National Yang-Ming University, Taipei 112, Taiwan

^d Department of Medical Biology, Faculty of Health Sciences, UiT – The Arctic University of Norway, 9037 Tromsø, Norway
E-mail: ingebrigt.sylte@uit.no

Abstract

The synthesis, cytotoxicity, inhibition of tubulin polymerization and anti-angiogenic effects of 10 analogs of 2-methoxyestradiol are reported. These efforts revealed that the analog with a 4-pyridine ring in the 17-position, in combination with 2-ethyl- and 3-sulfamate substituents on the steroid A-ring, is the most interesting anti-cancer agent. This compound showed potent inhibitory effects against angiogenesis (IC₅₀ = 0.1 ± 0.02 μM) and selective cytotoxic effects towards the CEM, H460 and HT-29 cancer cell lines, with no cytotoxicity observed against the healthy VERO cell line. The most interesting analog also displayed inhibition of tubulin polymerization (IC₅₀ = 4.3 μM) almost as potent as 2-methoxyestradiol (IC₅₀ = 3.5 μM). Molecular modeling experiments showed that this analog interacts within the colchicine-binding site of β-tubulin via multiple bonding with several amino acids. These observations provide support that the cytotoxic and anti-angiogenic effects observed for this novel analog are, at least in part, mediated by binding to tubulin.

Supplementary files

Article information

DOI: https://doi.org/10.1039/C5RA03570H
Article type: Paper
Submitted: 27 Feb 2015
Accepted: 27 Mar 2015
First published: 27 Mar 2015
This article is Open Access

Download Citation

RSC Adv., 2015,5, 32497-32504

Author version available

Download author version (PDF)

Permissions

Request permissions

Synthesis, biological evaluation and molecular modeling of new analogs of the anti-cancer agent 2-methoxyestradiol: potent inhibitors of angiogenesis

E. J. Solum, J. Cheng, I. Sylte, A. Vik and T. V. Hansen, RSC Adv., 2015, 5, 32497 DOI: 10.1039/C5RA03570H

This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. You can use material from this article in other publications without requesting further permissions from the RSC, provided that the correct acknowledgement is given.

RSC Advances

Synthesis, biological evaluation and molecular modeling of new analogs of the anti-cancer agent 2-methoxyestradiol: potent inhibitors of angiogenesis†

Abstract

Supplementary files

Article information

Download Citation

Author version available

Permissions

Synthesis, biological evaluation and molecular modeling of new analogs of the anti-cancer agent 2-methoxyestradiol: potent inhibitors of angiogenesis

Social activity

Search articles by author

Spotlight

Advertisements