title: Isolation, Structure Elucidation, and (Bio)Synthesis of Haprolid, a Cell-Type-Specific Myxobacterial Cytotoxin.
abstract: Myxobacteria are well-established sources for novel natural products exhibiting intriguing bioactivities. We here report on haprolid (1) isolated from Byssovorax cruenta Har1. The compound exhibits an unprecedented macrolactone comprising four modified amino acids and a polyketide fragment. As configurational assignment proved difficult, a bioinformatic analysis of the biosynthetic gene cluster was chosen to predict the configuration of each stereocenter. In-depth analysis of the corresponding biosynthetic proteins established a hybrid polyketide synthase/nonribosomal peptide synthetase origin of haprolid and allowed for stereochemical assignments. A subsequent total synthesis yielded haprolid and corroborated all predictions made. Intriguingly, haprolid showed cytotoxicity against several cell lines in the nanomolar range whereas other cells were almost unaffected by treatment with the compound.
authors.affiliation: Helmholtz Center for Infection Research (HZI), Department Microbial Drugs, Inhoffenstrasse 7, 38124, Braunschweig, Germany.
authors.forename: Heinrich
authors.initials: H
authors.lastname: Steinmetz
authors.affiliation: Institute for Organic Chemistry, Gottfried Leibniz Universität Hannover.|Centre of Biomolecular Drug Research (BMWZ), Schneiderberg 1B, 30167, Hannover, Germany.|Helmholtz Center for Infection Research (HZI), Inhoffenstrasse 7, 38124, Braunschweig, Germany.
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.affiliation: Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Center for Infection Research and Pharmaceutical Biotechnology, Saarland University, Campus Building E8.1, 66123, Saarbrücken, Germany.
authors.forename: Chengzhang
authors.initials: C
authors.lastname: Fu
authors.affiliation: Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Center for Infection Research and Pharmaceutical Biotechnology, Saarland University, Campus Building E8.1, 66123, Saarbrücken, Germany.
authors.forename: Nestor
authors.initials: N
authors.lastname: Zaburannyi
authors.affiliation: Helmholtz Center for Infection Research (HZI), Department Microbial Drugs, Inhoffenstrasse 7, 38124, Braunschweig, Germany.
authors.forename: Birgitte
authors.initials: B
authors.lastname: Kunze
authors.affiliation: Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Center for Infection Research and Pharmaceutical Biotechnology, Saarland University, Campus Building E8.1, 66123, Saarbrücken, Germany.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Harmrolfs
authors.affiliation: Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Center for Infection Research and Pharmaceutical Biotechnology, Saarland University, Campus Building E8.1, 66123, Saarbrücken, Germany.
authors.forename: Viktoria
authors.initials: V
authors.lastname: Schmitt
authors.affiliation: Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Center for Infection Research and Pharmaceutical Biotechnology, Saarland University, Campus Building E8.1, 66123, Saarbrücken, Germany.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Herrmann
authors.affiliation: Helmholtz Center for Infection Research (HZI), Inhoffenstrasse 7, 38124, Braunschweig, Germany.
authors.forename: Hans
authors.initials: H
authors.lastname: Reichenbach
authors.affiliation: Helmholtz Center for Infection Research (HZI), Inhoffenstrasse 7, 38124, Braunschweig, Germany.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Höfle
authors.affiliation: Institute for Organic Chemistry, Gottfried Leibniz Universität Hannover. markus.kalesse@oci.uni-hannover.de.|Centre of Biomolecular Drug Research (BMWZ), Schneiderberg 1B, 30167, Hannover, Germany. markus.kalesse@oci.uni-hannover.de.|Helmholtz Center for Infection Research (HZI), Inhoffenstrasse 7, 38124, Braunschweig, Germany. markus.kalesse@oci.uni-hannover.de.
authors.forename: Markus
authors.initials: M
authors.lastname: Kalesse
authors.affiliation: Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Center for Infection Research and Pharmaceutical Biotechnology, Saarland University, Campus Building E8.1, 66123, Saarbrücken, Germany. Rolf.Mueller@helmholtz-hzi.de.
authors.forename: Rolf
authors.identifier: 0000-0001-6571-6630
authors.initials: R
authors.lastname: Müller
mesh_terms: D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003603:Cytotoxins / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007783:Lactones / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D018942:Macrolides / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D015394:Molecular Structure; D009231:Myxococcales / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D003603:Cytotoxins; D007783:Lactones; D018942:Macrolides; C000628195:haprolid
keywords: cell-line-selective cytotoxin; haprolid; polyketide (bio)synthesis; retrosynthesis; structure elucidation