Diversity-Oriented Synthesis Catalyzed by Diethylaminosulfur-Trifluoride-Preparation of New Antitumor Ecdysteroid Derivatives

• Published in: International journal of molecular sciences Vol. 23; no. 7; p. 3447
• Main Authors: Vágvölgyi, Máté, Kocsis, Endre, Nové, Márta, Szemerédi, Nikoletta, Spengler, Gabriella, Kele, Zoltán, Berkecz, Róbert, Gáti, Tamás, Tóth, Gábor, Hunyadi, Attila
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 22.03.2022; MDPI
• Subjects: Animals; Beckmann-rearrangement; Bioactive compounds; Biocompatibility; Biological activity; Cancer; Catalysis; Chemical reactions; Chemistry; Cyclopropane; Cytotoxicity; DAST; Diethylamines - chemistry; Doxorubicin; Drug resistance; Ecdysteroids; Ecdysteroids - chemistry; Experiments; Fluorides; fluorination; Fluorine; Fluorine - chemistry; Hydroxyl groups; Lymphocytes T; Materials selection; Mice; Multidrug resistance; natural product; Natural products; Pharmaceutical sciences; Reagents; semi-synthesis; Severe acute respiratory syndrome coronavirus 2; T-cell lymphoma; DAST; NMR; cyclopropane; semi-synthesis; natural product; ecdysteroid; fluorination; structure elucidation; Beckmann-rearrangement; anticancer
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms23073447

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 , 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- -acetylecdysteroid ( ) exerted potent antiproliferative activity and no cytotoxicity on drug susceptible and multi-drug resistant mouse T-cell lymphoma cells. Further, compound 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.