title: Enzymatic methylation and structure-activity-relationship studies on polycarcin V, a gilvocarcin-type antitumor agent.
abstract: Polycarcin V, a polyketide natural product of Streptomyces polyformus, was chosen to study structure-activity relationships of the gilvocarcin group of antitumor antibiotics due to a similar chemical structure and comparable bioactivity with gilvocarcin V, the principle compound of this group, and the feasibility of enzymatic modifications of its sugar moiety by auxiliary O-methyltransferases. Such enzymes were used to modify the interaction of the drug with histone H3, the biological target that interacts with the sugar moiety. Cytotoxicity assays revealed that a free 2'-OH group of the sugar moiety is essential to maintain the bioactivity of polycarcin V, apparently an important hydrogen bond donor for the interaction with histone H3, and converting 3'-OH into an OCH3 group improved the bioactivity. Bis-methylated polycarcin derivatives revealed weaker activity than the parent compound, indicating that at least two hydrogen bond donors in the sugar are necessary for optimal binding.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 South Limestone Street, Lexington, Kentucky 40536-0596 (USA).
authors.forename: Jhong-Min
authors.initials: JM
authors.lastname: Chen
authors.forename: Micah D
authors.initials: MD
authors.lastname: Shepherd
authors.forename: Jamie
authors.initials: J
authors.lastname: Horn
authors.forename: Markos
authors.initials: M
authors.lastname: Leggas
authors.forename: Jürgen
authors.initials: J
authors.lastname: Rohr
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003374:Coumarins / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D006027:Glycosides / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D008745:Methylation; D009369:Neoplasms / Q000188:drug therapy; D013302:Streptomyces / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D003374:Coumarins; D006027:Glycosides; C534478:polycarcin V; C031781:gilvocarcin V
keywords: chemical biology; combinatorial enzymology; gilvocarcin; methyl transferases; polycarcin