Combined muta- and semisynthesis

A powerful synthetic hybrid approach to access target specific antitumor agents based on ansamitocin P3

verfasst von

Florian Taft, Kirsten Harmrolfs, Irinia Nickeleit, Anja Heutling, Miriam Kiene, Nisar Malek, Florenz Sasse, Andreas Kirschning

Abstract

Access of four new tumor specific folic acid/ansamitocin conjugates is reported that relies on a synthetic strategy based on the combination of mutasynthesis and semisynthesis. Two bromo-ansamitocin derivatives were prepared by mutasynthesis or by a modified fermentation protocol, respectively, that served as starting point for the semisynthetic introduction of an allyl amine linker under Stille conditions. A sequence of standard coupling steps introduced the pteroic acid/glutamic acid/cysteine unit to the modified ansamitocins. All new derivatives, including those that are expected to be generated after internalization of the folic acid/ansamitocin conjugates into the cancer cell and reductive cleavage of the disulfide linkage showed good to strong antiproliferative activity (IC ₅₀ <10 nM) for different cancer cell lines. Finally, the four conjugates were exposed to two cancer cell lines [cervix carcinoma, KB-3-1 (FR+) and lung carcinoma, A-459 (FR-)], the latter devoid of the membrane-bound folic acid receptor (FR-). All four conjugates showed strong antiproliferative activity for the FR+ cancer cell line but were inactive against the FR- cell line. The synthetic strategy pursued is based on the combination of mutasynthesis and semisynthesis and proved to be powerful for accessing new ansamitocin derivatives that are difficult to prepare by total synthesis. Synthetic power: Four novel folate-ansamitocin conjugates were prepared by a combined muta-/semisynthetic approach. They exert strong selectivity between cell lines that have expressed and that are devoid of folate receptors (FR). The study demonstrates both the power of target-specific chemotherapy with ansamitocins and reveals the diverse options mutasynthesis combined with semisynthesis provides.

Organisationseinheit(en)

Institut für Organische Chemie
Zentrum für Biomolekulare Wirkstoffe (BMWZ)

Externe Organisation(en)

Medizinische Hochschule Hannover (MHH)
Eberhard Karls Universität Tübingen
Helmholtz-Zentrum für Infektionsforschung GmbH (HZI)

Typ

Artikel

Journal

Chemistry - A European Journal

Band

18

Seiten

880-886

Anzahl der Seiten

7

ISSN

0947-6539

Publikationsdatum

14.12.2011

Publikationsstatus

Veröffentlicht

Peer-reviewed

Ja

ASJC Scopus Sachgebiete

Katalyse, Organische Chemie

Ziele für nachhaltige Entwicklung

SDG 3 – Gute Gesundheit und Wohlergehen

Elektronische Version(en)

https://doi.org/10.1002/chem.201101640 (Zugang: Unbekannt)