title: Tricyclic Analogues of Epidithiodioxopiperazine Alkaloids with PromisingIn VitroandIn VivoAntitumor Activity.
abstract: 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]pyrazine3cand related structures as particularly promising antitumor agents. ETP alkaloid analogue3cexhibits low nanomolar activity against both solid and blood tumorsin vitro. In addition,3csignificantly 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.
authors: Department of Chemistry, 1102 Natural Sciences II, University of California, Irvine, California 92697-2025.
authors: Marcus
authors: M
authors: Baumann
authors: Department of Chemistry, 1102 Natural Sciences II, University of California, Irvine, California 92697-2025.
authors: André P
authors: AP
authors: Dieskau
authors: Department of Chemistry, 1102 Natural Sciences II, University of California, Irvine, California 92697-2025.
authors: Brad M
authors: BM
authors: Loertscher
authors: Department of Chemistry, 1102 Natural Sciences II, University of California, Irvine, California 92697-2025.
authors: Mary C
authors: MC
authors: Walton
authors: Department of Molecular Medicine, Beckman Research Institute of City Hope Comprehensive Cancer Center, Beckman Research Institute, Department of Molecular Medicine, 1500 E. Duarte Road, Duarte, California 91010.
authors: Sangkil
authors: S
authors: Nam
authors: Department of Molecular Medicine, Beckman Research Institute of City Hope Comprehensive Cancer Center, Beckman Research Institute, Department of Molecular Medicine, 1500 E. Duarte Road, Duarte, California 91010.
authors: Jun
authors: J
authors: Xie
authors: Department of Molecular Medicine, Beckman Research Institute of City Hope Comprehensive Cancer Center, Beckman Research Institute, Department of Molecular Medicine, 1500 E. Duarte Road, Duarte, California 91010.
authors: David
authors: D
authors: Horne
authors: Department of Chemistry, 1102 Natural Sciences II, University of California, Irvine, California 92697-2025.
authors: Larry E
authors: LE
authors: Overman