title: Total Synthesis and Biological Evaluation of Hybrubin A.
abstract: Here, we report the first total synthesis of hybrubin A, a bipyrrole tetramic acid alkaloid representing a new carbon framework derived from convergent (truncated red cluster and exogenous hbn cluster) biosynthetic pathways. A highly convergent synthesis was developed, employing 4-methoxy-1,5-dihydro-2H-pyrrol-2-one (13) as a single starting material to provide hybrubin A in three steps from 13 and 20.8% overall yield. As no biological activity was prescribed to hybrubin A except for a lack of cytotoxicity, we further profiled this unique alkaloid across panels of discrete molecular targets. Interestingly, hybrubin A was found to be a ligand for a variety of GPCRs with a propensity for potent binding across therapeutically relevant adenosine receptors (A1, A2a, and A3) as well as a potent activity at a kinase, FLT3. This pattern of biological activity is distinct from other related prodigiosin natural and unnatural products and is even more intriguing in the absence of cytotoxicity.
authors.affiliation: Department of Chemistry, Vanderbilt Institute of Chemical Biology, Vanderbilt University , Nashville, Tennessee 37232-6600, United States.
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Jeffries
authors.affiliation: Department of Chemistry, Vanderbilt Institute of Chemical Biology, Vanderbilt University , Nashville, Tennessee 37232-6600, United States.|Department of Pharmacology, Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University , Nashville, Tennessee 37232-6600, United States.
authors.forename: Craig W
authors.identifier: 0000-0003-0168-1445
authors.initials: CW
authors.lastname: Lindsley
mesh_terms: D004305:Dose-Response Relationship, Drug; D045325:HCT116 Cells; D006801:Humans; D008024:Ligands; D015394:Molecular Structure; D011353:Prodigiosin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D008024:Ligands; D047428:Protein Kinase Inhibitors; C000608276:hybrubin A; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3; D011353:Prodigiosin