Tricyclic analogues of epidithiodioxopiperazine alkaloids with promising in vitro and in vivo antitumor activity† †Electronic supplementary information (ESI) available: Table summarizing yields and diastereoselectivity in the synthesis of ETP alkaloid analogues 3, experimental procedures, and characterization data for all new compounds. CCDC 1061869–1061873. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c5sc01536g Click here for additional data file. Click here for additional data file

Autor: Baumann, Marcus, Dieskau, André P., Loertscher, Brad M., Walton, Mary C., Nam, Sangkil, Xie, Jun, Horne, David, Overman, Larry E.
Jazyk: angličtina
Rok vydání: 2015
Předmět:
Zdroj: Chemical Science
ISSN: 2041-6539
2041-6520
Popis: A short synthesis of 1,4-dioxohexahydro-6H-3,8a-epidithiopyrrolo[1,2-a]pyrazines will enable future mechanistic and translational studies of these structurally novel and promising clinical antitumor candidates.
Epipolythiodioxopiperazine (ETP) alkaloids are structurally elaborate alkaloids that show potent antitumor activity. However, their high toxicity and demonstrated interactions with various biological receptors compromises their therapeutic potential. In an effort to mitigate these disadvantages, a short stereocontrolled construction of tricyclic analogues of epidithiodioxopiperazine alkaloids was developed. Evaluation of a small library of such structures against two invasive cancer cell lines defined initial structure–activity relationships (SAR), which identified 1,4-dioxohexahydro-6H-3,8a-epidithiopyrrolo[1,2-a]pyrazine 3c and related structures as particularly promising antitumor agents. ETP alkaloid analogue 3c exhibits low nanomolar activity against both solid and blood tumors in vitro. In addition, 3c significantly suppresses tumor growth in mouse xenograft models of melanoma and lung cancer, without obvious signs of toxicity, following either intraperitoneal (IP) or oral administration. The short synthesis of molecules in this series will enable future mechanistic and translational studies of these structurally novel and highly promising clinical antitumor candidates.
Databáze: OpenAIRE
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