Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Diversity-Oriented Synthesis Catalyzed by DAST – Preparation of New Antitumor Ecdysteroid Derivatives

Máté Vágvölgyi
ORCID logo ,
Endre Kocsis
,
Márta Nové
,
Gabriella Spengler
ORCID logo ,
Zoltán Kele
,
Róbert Berkecz
ORCID logo ,
Tamás Gáti
,
Gábor Tóth
* ,
Attila Hunyadi
* ORCID logo
Version 1 : Received: 27 January 2022 / Approved: 31 January 2022 / Online: 31 January 2022 (21:35:38 CET)

A peer-reviewed article of this Preprint also exists.

Vágvölgyi, M.; Kocsis, E.; Nové, M.; Szemerédi, N.; Spengler, G.; Kele, Z.; Berkecz, R.; Gáti, T.; Tóth, G.; Hunyadi, A. Diversity-Oriented Synthesis Catalyzed by Diethylaminosulfur-Trifluoride—Preparation of New Antitumor Ecdysteroid Derivatives. Int. J. Mol. Sci. 2022, 23, 3447. Vágvölgyi, M.; Kocsis, E.; Nové, M.; Szemerédi, N.; Spengler, G.; Kele, Z.; Berkecz, R.; Gáti, T.; Tóth, G.; Hunyadi, A. Diversity-Oriented Synthesis Catalyzed by Diethylaminosulfur-Trifluoride—Preparation of New Antitumor Ecdysteroid Derivatives. Int. J. Mol. Sci. 2022, 23, 3447.

Abstract

Fluorine represents a privileged building block in pharmaceutical chemistry. Diethylaminosulfur-trifluoride (DAST) is a reagent commonly used for replacement of alcoholic hydroxyl groups with fluorine and is also known to catalyze water elimination and cyclic Beckmann-rearrangement type reactions. In this work we aimed to use DAST for diversity-oriented semisynthetic transformation of natural products bearing multiple hydroxyl groups to prepare new bioactive compounds. Four ecdysteroids, including a new constituent of Cyanotis arachnoidea, were selected as starting materials for DAST-catalyzed transformations. The newly prepared compounds represented combinations of various structural changes DAST was known to catalyze, and a unique cyclopropane ring closure that was found for the first time. Several compounds demonstrated in vitro antitumor properties. A new 17-N-acetylecdysteroid (13) exerted potent antiproliferative activity and no cytotoxicity on drug susceptible and multi-drug resistant mouse T-cell lymphoma cells. Further, compound 13 acted in significant synergism with doxorubicin without detectable direct ABCB1 inhibition. Our results demonstrate that DAST is a versatile tool for diversity-oriented synthesis to expand chemical space towards new bioactive compounds.

Keywords

DAST; semi-synthesis; fluorination; Beckmann-rearrangement; cyclopropane; natural product; ecdysteroid; NMR; structure elucidation; anticancer

Subject

Chemistry and Materials Science, Medicinal Chemistry

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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