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Anticancer activity and toxicity of new quaternary ammonium geldanamycin derivative salts and their mixtures with potentiators
Authors:
- Natalia Skrzypczak,
- Krystian Krzysztof Pyta,
- Piotr Ruszkowski,
- Przemysław Mikołajczak,
- Małgorzata Kucińska,
- Marek Murias,
- Maria Gdaniec,
- Franz Bartl,
- Piotr Przybylski
- Record ID
- UAMb9628fd2b24a4ab0b1d77a80b769b040
- Author
- Journal series
- Journal of Enzyme Inhibition and Medicinal Chemistry, ISSN 1475-6366, e-ISSN 1475-6374
- Issue year
- 2021
- Vol
- 36
- No
- 1
- Pages
- 1898-1904
- Keywords in original language
- Ansamycins benzoquinones chaperone Hsp90 anticancer SAR
- ASJC Classification
- ; ;
- Abstract in original language
- Geldanamycin (GDM) has been modified by different type neutral/acidic/basic substituents (1–7) and by quinuclidine motif (8), transformed into ammonium salts (9–13) at C(17). These compounds have been characterised by spectroscopic and x-ray methods. Derivative 8 shows better potency than GDM in MCF-7, MDA-MB-231, A549 and HeLa (IC50s = 0.09–1.06 µM). Transformation of 8 into salts 9–13 reduces toxicity (by 11-fold) at attractive potency, e.g. MCF-7 cell line (IC50∼2 µM). Our studies show that higher water solubility contributes to lower toxicity of salts than GDM in healthy CCD39Lu and HDF cells. The use of 13 mixtures with potentiators PEI and DOX enhanced anticancer effects from IC50∼2 µM to IC50∼0.5 µM in SKBR-3, SKOV-3, and PC-3 cancer cells, relative to 13. Docking studies showed that complexes between quinuclidine-bearing 8–13 and Hsp90 are stabilised by extra hydrophobic interactions between the C(17)-arms and K58 or Y61 of Hsp90
- DOI
- DOI:10.1080/14756366.2021.1960829 Opening in a new tab
- URL
- https://www.tandfonline.com/doi/full/10.1080/14756366.2021.1960829 Opening in a new tab
- Language
- eng (en) English
- License
- Score (nominal)
- 140
- Score source
- journalList
- Score
- = 140.0, 22-03-2022, ArticleFromJournal
- Publication indicators
- = 2; = 0; : 2018 = 1.067; : 2019 (2 years) = 4.673 - 2019 (5 years) =3.719
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- Uniform Resource Identifier
- https://researchportal.amu.edu.pl/info/article/UAMb9628fd2b24a4ab0b1d77a80b769b040/
- URN
urn:amu-prod:UAMb9628fd2b24a4ab0b1d77a80b769b040
* presented citation count is obtained through Internet information analysis and it is close to the number calculated by the Publish or PerishOpening in a new tab system.