New geldanamycin derivatives with anti Hsp properties by mutasynthesis

authored by

Jekaterina Hermane, Simone Eichner, Lena Mancuso, Benjamin Schröder, Florenz Sasse, Carsten Zeilinger, Andreas Kirschning

Abstract

Mutasynthetic supplementation of the AHBA blocked mutant strain of S. hygroscopicus, the geldanamycin producer, with 21 aromatic and heteroaromatic amino acids provided new nonquinoid geldanamycin derivatives. Large scale (5 L) fermentation provided four new derivatives in sufficient quantity for full structural characterisation. Among these, the first thiophene derivative of reblastatin showed strong antiproliferative activity towards several human cancer cell lines. Additionally, inhibitory effects on human heat shock protein Hsp90α and bacterial heat shock protein from H. pylori HpHtpG were observed, revealing strong displacement properties for labelled ATP and demonstrating that the ATP-binding site of Hsps is the target site for the new geldanamycin derivatives.

Organisation(s)

Institute of Organic Chemistry
Department of Cell Physiology and Biophysics
Centre of Biomolecular Drug Research (BMWZ)
Institute of Cell Biology and Biophysics

External Organisation(s)

Helmholtz Centre for Infection Research (HZI)

Type

Article

Journal

Organic and Biomolecular Chemistry

Volume

17

Pages

5269-5278

No. of pages

10

ISSN

1477-0520

Publication date

07.06.2019

Publication status

Published

Peer reviewed

Yes

ASJC Scopus subject areas

Biochemistry, Physical and Theoretical Chemistry, Organic Chemistry

Sustainable Development Goals

SDG 3 - Good Health and Well-being

Electronic version(s)

https://doi.org/10.1039/c9ob00892f (Access: Open)
https://doi.org/10.15488/10458 (Access: Open)