Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The . gov means it’s official. Federal government websites often end in . gov or . mil. Before sharing sensitive information, make sure you’re on a federal government site VSports app下载. .

Https

The site is secure. The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely. V体育官网.

. 2019 Nov 26;24(23):4319.
doi: 10.3390/molecules24234319.

The Masked Polar Group Incorporation (MPGI) Strategy in Drug Design: Effects of Nitrogen Substitutions on Combretastatin and Isocombretastatin Tubulin Inhibitors (VSports最新版本)

Myriam González  1   2   3 , Younes Ellahioui  1   4 , Raquel Álvarez  1   2   3 , Laura Gallego-Yerga  1   2   3 , Esther Caballero  1   2   3 , Alba Vicente-Blázquez  1   2   3   5 , Laura Ramudo  6 , Miguel Marín  1   2   3 , Cristina Sanz  1   2   3 , Manuel Medarde  1   2   3 , Rafael Pelaéz  1   2   3
Affiliations

The Masked Polar Group Incorporation (MPGI) Strategy in Drug Design: Effects of Nitrogen Substitutions on Combretastatin and Isocombretastatin Tubulin Inhibitors

Myriam González et al. Molecules. .

"VSports手机版" Abstract

Colchicine site ligands suffer from low aqueous solubility due to the highly hydrophobic nature of the binding site. A new strategy for increasing molecular polarity without exposing polar groups-termed masked polar group incorporation (MPGI)-was devised and applied to nitrogenated combretastatin analogues. Bulky ortho substituents to the pyridine nitrogen hinder it from the hydrophobic pocket while increasing molecular polarity. The resulting analogues show improved aqueous solubilities and highly potent antiproliferative activity against several cancer cell lines of different origin. The more potent compounds showed moderate tubulin polymerization inhibitory activity, arrested the cell cycle of treated cells at the G2/M phase, and subsequently caused apoptotic cell death represented by the cells gathered at the subG0/G1 population after 48 h of treatment. Annexin V/Propidium Iodide (PI) double-positive cells observed after 72 h confirmed the induction of apoptosis VSports手机版. Docking studies suggest binding at the colchicine site of tubulin in a similar way as combretastatin A4, with the polar groups masked by the vicinal substituents. These results validate the proposed strategy for the design of colchicine site ligands and open a new road to increasing the aqueous solubility of ligands binding in apolar environments. .

Keywords: colchicine-site; combretastatins; cytotoxicity; docking; isocombretastatins; masked polar group introduction; nitrogenated; phenstatins; solubility; tubulin V体育安卓版. .

PubMed Disclaimer

"V体育ios版" Conflict of interest statement

The authors declare no conflicts of interest V体育ios版. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Figures

Figure 1
Figure 1
Structures of representative colchicine-site ligands and a summary of the masked polar group incorporation strategy followed in this work.
Scheme 1
Scheme 1
Synthesis of compounds 1a–9i. (a) 1. nBuLi, THF, −78 °C; 2. 3,4,5-trimethoxybenzoic acid, NaH, 0 °C—rt; (b) 1. nBuLi, THF, −78 °C; 2. ArCHO, THF; 3. PDC, HSO4 Bu4N; (c) NH2OH·HCl, pyridine, MeOH, reflux; (d) Ph3PMeI, nBuLi, THF, −40 °C; (e) H2, Pd/C, EtOH, rt; (f) MeI, acetone, reflux; (g) nBuLi, THF, −78 °C.
Figure 2
Figure 2
Annexin V-FITC and propidium iodide (PI) profiles, and pie charts of the different cell populations of the cell cycle of HeLa cells after 24, 48, and 72 h after treatment with the drugs at the indicated doses.
Figure 3
Figure 3
Docking poses for compounds 1f, 1h, 3b and 8b superimposed with the X-ray pose of CA-4 (light green).
See this image and copyright information in PMC

V体育官网入口 - References

    1. Dumontet C., Jordan M.A. Microtubule-binding agents: A dynamic field of cancer therapeutics. Nat. Rev. Drug Discov. 2010;9:790–803. doi: 10.1038/nrd3253. - DOI - PMC - PubMed
    1. Bates D., Eastman A. Microtubule destabilising agents: Far more than just antimitotic anticancer drugs. Br. J. Clin. Pharmacol. 2017;83:255–268. doi: 10.1111/bcp.13126. - DOI - PMC - PubMed
    1. Perez-Perez M.J., Priego E.M., Bueno O., Martins M.S., Canela M.D., Liekens S. Blocking blood flow to solid tumors by destabilizing tubulin: An approach to targeting tumor growth. J. Med. Chem. 2016;59:8685–8711. doi: 10.1021/acs.jmedchem.6b00463. - DOI (VSports注册入口) - PubMed
    1. Tron G.C., Pirali T., Sorba G., Pagliai F., Busacca S., Genazzani A.A. Medicinal chemistry of combretastatin A4: Present and future directions. J. Med. Chem. 2006;49:3033–3044. doi: 10.1021/jm0512903. - VSports手机版 - DOI - PubMed
    1. Seddigi Z.S., Malik M.S., Saraswati A.P., Ahmed S.A., Babalghith A.O., Lamfon H.A., Kamal A. Recent advances in combretastatin based derivatives and prodrugs as antimitotic agents. MedChemComm. 2017;8:1592–1603. doi: 10.1039/C7MD00227K. - DOI - PMC - PubMed

MeSH terms (V体育安卓版)

LinkOut - more resources