title: Synthesis and evaluation of 8,4'-dideshydroxy-leinamycin revealing new insights into the structure-activity relationship of the anticancer natural product leinamycin.
abstract: Leinamycin (LNM, 1) is a novel antitumor antibiotic produced by Streptomyces atroolivaceus S-140 and features an unusual 1,3-dioxo-1,2-dithiolane moiety that is spiro-fused to a thiazole-containing 18-membered lactam ring. The 1,3-dioxo-1,2-dithiolane moiety of LNM is essential for its antitumor activity via an episulfonium ion-mediated DNA alkylation upon reductive activation in the presence of cellular thiols. We recently isolated leinamycin E1 (LNM E1, 2) from an engineered strain S. atroolivaceus SB3033, which lacks the 1,3-dioxo-1,2-dithiolane moiety. Here we report the chemical synthesis of 8,4'-dideshydroxy-LNM (5) from 2 and determination of the cytotoxicity of 5 against selected cancer cell lines in comparison with 1; 5 exhibits comparable activity as 1 with the EC50 values between 8.21 and 275 nM. This work reveals new insight into the structure-activity relationship of LNM and highlights the synergy between metabolic pathway engineering and medicinal chemistry for natural product drug discovery.
authors.affiliation: Division of Pharmaceutical Sciences, University of Wisconsin-Madison, Madison, WI 53705, USA.
authors.forename: Tao
authors.initials: T
authors.lastname: Liu
authors.affiliation: Department of Chemistry, The Scripps Research Institute, 130 Scripps Way, #3A1, Jupiter, FL 33458, USA.
authors.forename: Ming
authors.initials: M
authors.lastname: Ma
authors.affiliation: Department of Chemistry, The Scripps Research Institute, 130 Scripps Way, #3A1, Jupiter, FL 33458, USA.
authors.forename: Hui-Ming
authors.initials: HM
authors.lastname: Ge
authors.affiliation: Department of Cancer Biology, The Scripps Research Institute, Jupiter, FL 33458, USA.
authors.forename: Chunying
authors.initials: C
authors.lastname: Yang
authors.affiliation: Department of Cancer Biology, The Scripps Research Institute, Jupiter, FL 33458, USA.
authors.forename: John
authors.initials: J
authors.lastname: Cleveland
authors.affiliation: Division of Pharmaceutical Sciences, University of Wisconsin-Madison, Madison, WI 53705, USA; Department of Chemistry, The Scripps Research Institute, 130 Scripps Way, #3A1, Jupiter, FL 33458, USA; Department of Molecular Therapeutics, The Scripps Research Institute, 130 Scripps Way, #3A1, Jupiter, FL 33458, USA; Natural Products Library Initiative, The Scripps Research Institute, 130 Scripps Way, #3A1, Jupiter, FL 33458, USA. Electronic address: shenb@scripps.edu.
authors.forename: Ben
authors.initials: B
authors.lastname: Shen
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001688:Biological Products / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007769:Lactams / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008968:Molecular Conformation; D013302:Streptomyces / Q000737:chemistry; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C000608351:8,4'-dideshydroxy-leinamycin; D000903:Antibiotics, Antineoplastic; D001688:Biological Products; D007769:Lactams; D013844:Thiazoles
keywords: Antitumor antibiotic; DNA alkylation; Leinamycin; Metabolic pathway engineering; Structure–activity relationship