title: Leinamycin E1 acting as an anticancer prodrug activated by reactive oxygen species.
abstract: Leinamycin (LNM) is a potent antitumor antibiotic produced by Streptomyces atroolivaceus S-140, featuring an unusual 1,3-dioxo-1,2-dithiolane moiety that is spiro-fused to a thiazole-containing 18-membered lactam ring. Upon reductive activation in the presence of cellular thiols, LNM exerts its antitumor activity by an episulfonium ion-mediated DNA alkylation. Previously, we have cloned the lnm gene cluster from S. atroolivaceus S-140 and characterized the biosynthetic machinery responsible for the 18-membered lactam backbone and the alkyl branch at C3 of LNM. We now report the isolation and characterization of leinamycin E1 (LNM E1) from S. atroolivacues SB3033, a ΔlnmE mutant strain of S. atroolivaceus S-140. Complementary to the reductive activation of LNM by cellular thiols, LNM E1 can be oxidatively activated by cellular reactive oxygen species (ROS) to generate a similar episulfonium ion intermediate, thereby alkylating DNA and leading to eventual cell death. The feasibility of exploiting LNM E1 as an anticancer prodrug activated by ROS was demonstrated in two prostate cancer cell lines, LNCaP and DU-145. Because many cancer cells are under higher cellular oxidative stress with increased levels of ROS than normal cells, these findings support the idea of exploiting ROS as a means to target cancer cells and highlight LNM E1 as a novel lead for the development of anticancer prodrugs activated by ROS. The structure of LNM E1 also reveals critical new insights into LNM biosynthesis, setting the stage to investigate sulfur incorporation, as well as the tailoring steps that convert the nascent hybrid peptide-polyketide biosynthetic intermediate into LNM.
authors.affiliation: Department of Chemistry, The Scripps Research Institute, Jupiter, FL 33458;
authors.forename: Sheng-Xiong
authors.initials: SX
authors.lastname: Huang
authors.affiliation: Division of Pharmaceutical Sciences, University of Wisconsin-Madison, Madison, WI 53705;
authors.forename: Bong-Sik
authors.initials: BS
authors.lastname: Yun
authors.affiliation: Department of Chemistry, The Scripps Research Institute, Jupiter, FL 33458;
authors.forename: Ming
authors.initials: M
authors.lastname: Ma
authors.affiliation: University of Wisconsin Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI 53705;
authors.forename: Hirak S
authors.initials: HS
authors.lastname: Basu
authors.affiliation: University of Wisconsin Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI 53705;
authors.forename: Dawn R
authors.initials: DR
authors.lastname: Church
authors.affiliation: Division of Pharmaceutical Sciences, University of Wisconsin-Madison, Madison, WI 53705;
authors.forename: Gudrun
authors.initials: G
authors.lastname: Ingenhorst
authors.affiliation: Division of Pharmaceutical Sciences, University of Wisconsin-Madison, Madison, WI 53705;
authors.forename: Yong
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Department of Chemistry, The Scripps Research Institute, Jupiter, FL 33458;
authors.forename: Dong
authors.initials: D
authors.lastname: Yang
authors.affiliation: Department of Chemistry, The Scripps Research Institute, Jupiter, FL 33458;
authors.forename: Jeremy R
authors.initials: JR
authors.lastname: Lohman
authors.affiliation: Division of Pharmaceutical Sciences, University of Wisconsin-Madison, Madison, WI 53705;
authors.forename: Gong-Li
authors.initials: GL
authors.lastname: Tang
authors.affiliation: Division of Pharmaceutical Sciences, University of Wisconsin-Madison, Madison, WI 53705;
authors.forename: Jianhua
authors.initials: J
authors.lastname: Ju
authors.affiliation: Division of Pharmaceutical Sciences, University of Wisconsin-Madison, Madison, WI 53705;
authors.forename: Tao
authors.initials: T
authors.lastname: Liu
authors.affiliation: University of Wisconsin Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI 53705; Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705;
authors.forename: George
authors.initials: G
authors.lastname: Wilding
authors.affiliation: Department of Chemistry, The Scripps Research Institute, Jupiter, FL 33458; Division of Pharmaceutical Sciences, University of Wisconsin-Madison, Madison, WI 53705; Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, FL 33458; Natural Products Library Initiative, The Scripps Research Institute, Jupiter, FL 33458 shenb@scripps.edu.
authors.forename: Ben
authors.initials: B
authors.lastname: Shen
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007769:Lactams / Q000737:chemistry / Q000378:metabolism*; D018942:Macrolides / Q000737:chemistry / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D015394:Molecular Structure; D011355:Prodrugs / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013302:Streptomyces / Q000235:genetics / Q000378:metabolism; D013844:Thiazoles / Q000737:chemistry / Q000378:metabolism*; D013871:Thiones / Q000737:chemistry / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D007769:Lactams; D018942:Macrolides; D011355:Prodrugs; D017382:Reactive Oxygen Species; D013844:Thiazoles; D013871:Thiones; C059000:leinamycin
keywords: cancer targeting; drug discovery; natural product; pathway engineering; sulfur metabolism