Eric J. Gilbert

RebG- and RebM-catalyzed indolocarbazole diversification

Rebeccamycin and staurosporine represent two broad classes of indolocarbazole glycoside natural products with antitumor properties. Based upon previous sequence annotation and in vivo studies, rebG encodes for the rebeccamycin N‐glucosyltransferase, and rebM for the requisite 4′‐O‐methyltransferase. In the current study, an efficient in vivo biotransformation system for RebG was established in both Streptomyces lividans and Escherichia coli. Bioconversion experiments revealed RebG to glucosylate a set of indolocarbazole surrogates, the products of which could be further modified by in vitro RebM‐catalyzed 4′‐O‐methylation. Both RebG and RebM displayed substrate promiscuity, and evidence for a remarkable lack of RebG regioselectivity in the presence of asymmetric substrates is also provided. In the context of the created indolocarbazole analogues, cytotoxicity assays also highlight the importance of 4′‐O‐methylation for their biological activity.

Cyclizations of unsymmetrical bis-1,2-(3-indolyl)ethanes: Synthesis of (−)-tjipanazole F1

Abstract The inter- and intramolecular dimerization of 3-substituted indoles was studied. The rate and extent of dimerization depends on the indole substituents. The intramolecular dimerization of unsymmetrical bis-1,2-(3-indolyl)ethanes could be controlled using either thermodynamic reaction conditions (neat trifluoroacetic acid) or kinetic conditions (2 equiv acid/chloroform). This control of regiochemistry has been applied to an efficient synthesis of (−)-tjipanazole F1.

Discovery of Chromane Propionic Acid Analogues as Selective Agonists of GPR120 with in Vivo Activity in Rodents

GPR120 (FFAR4) is a fatty acid sensing G protein coupled receptor (GPCR) that has been identified as a target for possible treatment of type 2 diabetes. A selective activator of GPR120 containing a chromane scaffold has been designed, synthesized, and evaluated in vivo. Results of these efforts suggest that chromane propionic acid 18 is a suitable tool molecule for further animal studies. Compound 18 is selective over the closely related target GPR40 (FFAR1), has a clean off-target profile, demonstrates suitable pharmacokinetic properties, and has been evaluated in wild-type/knockout GPR120 mouse oGTT studies.