Format

Send to

Choose Destination
Angew Chem Int Ed Engl. 2016 Aug 16;55(34):10113-7. doi: 10.1002/anie.201603288. Epub 2016 Jul 12.

Isolation, Structure Elucidation, and (Bio)Synthesis of Haprolid, a Cell-Type-Specific Myxobacterial Cytotoxin.

Author information

1
Helmholtz Center for Infection Research (HZI), Department Microbial Drugs, Inhoffenstrasse 7, 38124, Braunschweig, Germany.
2
Institute for Organic Chemistry, Gottfried Leibniz Universität Hannover.
3
Centre of Biomolecular Drug Research (BMWZ), Schneiderberg 1B, 30167, Hannover, Germany.
4
Helmholtz Center for Infection Research (HZI), Inhoffenstrasse 7, 38124, Braunschweig, Germany.
5
Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Center for Infection Research and Pharmaceutical Biotechnology, Saarland University, Campus Building E8.1, 66123, Saarbrücken, Germany.
6
Institute for Organic Chemistry, Gottfried Leibniz Universität Hannover. markus.kalesse@oci.uni-hannover.de.
7
Centre of Biomolecular Drug Research (BMWZ), Schneiderberg 1B, 30167, Hannover, Germany. markus.kalesse@oci.uni-hannover.de.
8
Helmholtz Center for Infection Research (HZI), Inhoffenstrasse 7, 38124, Braunschweig, Germany. markus.kalesse@oci.uni-hannover.de.
9
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.

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.

KEYWORDS:

cell-line-selective cytotoxin; haprolid; polyketide (bio)synthesis; retrosynthesis; structure elucidation

PMID:
27404448
DOI:
10.1002/anie.201603288
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Wiley
Loading ...
Support Center