On the Discorhabdins Leading to the Aleutianamine Ring System: A One‐Step in Situ Transformation Characterized Through Computational and Experimental Studies and Its Implications on Biosynthesis, Synthesis, and Pharmacology
Abstract
ABSTRACT We disclose an efficient transformation of the relatively common pyrroloiminoquinone discorhabdin alkaloids from Alaskan Latrunculia spp. to the complex ring system of aleutianamine by an acid catalyzed process that mimics the proposed endogenous genesis from 3‐dihydrodienyl discorhabdin precursors. The azepine ring system is formed by a concerted 1,2‐alkyl shift of a proposed thiocarbenium‐iminium dication and this mechanism is supported by extensive density functional theory (DFT) analysis. Additional in vitro biological data further supports the aleutianamines as novel and highly potent inhibitors of multidrug resistant cancer lines exemplified further with cytotoxicity toward chemotherapy resistant chromophobe renal cell carcinoma (IC 50 = 130 nM). This report provides a key transformation that allows the incorporation of either synthetic or biosynthetic starting materials leading to the generation of the aleutianamine complex ring system in just a single step from the discorhabdin ring system.
Article Details
Authors (14)
Cody F. Dickinson
Department of Drug Discovery & Biomedical Sciences Medical University of South Carolina Charleston South Carolina USA
Abhay Potluri
Department of Chemistry
Alison M. Bland
Department of Biochemistry and Molecular Biology Medical University of South Carolina Charleston South Carolina USA
Samuel M. Flipse
Department of Chemistry University of Hawaii at Manoa Honolulu Hawaii USA
George S. Hanna
Department of Public Health Sciences Medical University of South Carolina Charleston South Carolina USA
Ryan T. Wagner
Department of Molecular Pharmacology and Experimental Therapeutics Mayo Clinic Rochester Minnesota USA
Keith D. Robertson
Thai H. Ho
Division of Hematology and Medical Oncology Hollings Cancer Center Medical University of South Carolina Charleston South Carolina USA
Daniel J. Sprague
Department of Biochemistry and Molecular Biology Medical University of South Carolina Charleston South Carolina USA
Gerald R. Hoff
Resource Assessment and Conservation Division Alaska Fisheries Science Center National Marine Fisheries Service National Oceanic and Atmospheric Administration Seattle Washington USA
Robert P. Stone
Auke Bay Laboratories Alaska Fisheries Science Center National Marine Fisheries Service National Oceanic and Atmospheric Administration Seattle Washington USA
Marcus A. Tius
Department of Chemistry University of Hawaii at Manoa Honolulu Hawaii USA
Dean J. Tantillo
Department of Chemistry, University of California Davis, One Shields Ave. Davis, Sacramento, California 95616, United States
Mark T. Hamann
Department of Drug Discovery & Biomedical Sciences Medical University of South Carolina Charleston South Carolina USA