Totopotensamide Congeners from a Halogenase-Inactivated Mutant.

The installation of halogen atoms into aromatic and less activated polyketide substrates by halogenases is a powerful strategy to tune the bioactivity, bioavailability, and reactivity of compounds. In the biosynthetic pathway of totopotensamide A ( 1 ), the halogenase TotH was confirmed in vivo to catalyze the C-4 chlorination to form the nonproteinogenic amino acid ClMeDPG. Herein, we report the isolation, structure elucidation, and bioactivity evaluation of six new deschloro totopotensamide (TPM) congeners TPMs H2-H7 ( 5 - 10 ) from the totH -inactivated strain and the proposed absolute configuration of the polyketide chain in TPMs using 4 as a model compound by a combination of the J BCA and bioinformatic analysis. Compounds 5 , 6 , 8 , and 9 displayed cytotoxicity against the A549, PANC-1, Calu3, and BXPC3 cell lines with IC 50 values ranging from 2.3 to 9.7 μM.