TY - JOUR

T1 - Post Polyketide Synthase Carbon-Carbon Bond Formation in Type-II PKS-Derived Natural Products from Streptomyces venezuelae

AU - Robertson, Andrew W

AU - MacLeod, Jeanna M

AU - MacIntyre, Logan W

AU - Forget, Stephanie M

AU - Hall, Steven R

AU - Bennett, Leah G

AU - Correa, Hebelin

AU - Kerr, Russell G

AU - Goralski, Kerry B

AU - Jakeman, David L

PY - 2018/2/16

Y1 - 2018/2/16

N2 - Polyketide synthase (PKS) derived natural products are biosynthesized by head-to-tail addition of acetate and malonate extender units resulting in linear extended-polyketide chains. Despite the well-documented structural diversity associated with PKS-derived natural products, C-C chain branching deviating from the usual linear pattern is relatively rare. Herein, type-II PKS angucyclic natural products containing a hemiaminal functionality were identified and proposed as the parent of a series of C-C-branched analogues. These C-C linked acetate or pyruvate branching units were located at the α-positions on the extended polyketide chains of jadomycins incorporating 3- and 4-aminomethylbenzoic acids. Labeling studies utilizing [1-13C]-d-glucose provided mechanistic evidence that the C-C bond formation occurred as a result of a previously unidentified post-PKS processing, additional to the enzymes encoded within the biosynthetic gene cluster. Selected compounds were evaluated in cytotoxic or antimicrobial assays.

AB - Polyketide synthase (PKS) derived natural products are biosynthesized by head-to-tail addition of acetate and malonate extender units resulting in linear extended-polyketide chains. Despite the well-documented structural diversity associated with PKS-derived natural products, C-C chain branching deviating from the usual linear pattern is relatively rare. Herein, type-II PKS angucyclic natural products containing a hemiaminal functionality were identified and proposed as the parent of a series of C-C-branched analogues. These C-C linked acetate or pyruvate branching units were located at the α-positions on the extended polyketide chains of jadomycins incorporating 3- and 4-aminomethylbenzoic acids. Labeling studies utilizing [1-13C]-d-glucose provided mechanistic evidence that the C-C bond formation occurred as a result of a previously unidentified post-PKS processing, additional to the enzymes encoded within the biosynthetic gene cluster. Selected compounds were evaluated in cytotoxic or antimicrobial assays.

KW - Animals

KW - Antineoplastic Agents/chemistry

KW - Biological Products/chemistry

KW - Carbon/chemistry

KW - Cell Line, Tumor

KW - Cell Proliferation/drug effects

KW - Cell Survival/drug effects

KW - Chlorocebus aethiops

KW - Drug Screening Assays, Antitumor

KW - Fibroblasts/drug effects

KW - Gram-Positive Bacteria/drug effects

KW - Humans

KW - Microbial Sensitivity Tests

KW - Molecular Structure

KW - Polyketide Synthases/chemistry

KW - Streptomyces/metabolism

KW - Vero Cells

U2 - 10.1021/acs.joc.7b02823

DO - 10.1021/acs.joc.7b02823

M3 - Journal article

C2 - 29313335

VL - 83

SP - 1876

EP - 1890

JO - Journal of Organic Chemistry

JF - Journal of Organic Chemistry

SN - 0022-3263

IS - 4

ER -