title: Orthogonal chemistry for the synthesis of thiocoraline-triostin hybrids. Exploring their structure-activity relationship.
abstract: The natural compounds triostin and thiocoraline are potent antitumor agents that act as DNA bisintercalators. From a pharmaceutical point of view, these compounds are highly attractive although they present a low pharmacokinetic profile, in part due to their low solubility. Synthetically, they represent a tour de force because no robust strategies have been developed to access a broad range of these bicyclic (depsi)peptides in a straightforward manner. Here we describe solid-phase strategies to synthesize new bisintercalators, such as thiocoraline-triostin hybrids, as well as analogues bearing soluble tags. Orthogonal protection schemes (up to five from: Fmoc, Boc Alloc, pNZ, o-NBS, and Troc), together with the right concourse of the coupling reagents (HOSu, HOBt, HOAt, Oxyma, EDC, DIPCDI, PyAOP, PyBOP, HATU, COMU), were crucial to establish the synthetic plan. In vitro studies and structure-activity relationships have been shown trends in the structure-activity relationship that will facilitate the design of new bisintercalators.
authors.affiliation: Institute for Research in Biomedicine Barcelona , Baldiri Reixac 10, 08028 Barcelona, Spain.
authors.forename: Judit
authors.initials: J
authors.lastname: Tulla-Puche
authors.forename: Sara
authors.initials: S
authors.lastname: Auriemma
authors.forename: Chiara
authors.initials: C
authors.lastname: Falciani
authors.forename: Fernando
authors.initials: F
authors.lastname: Albericio
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D047630:Depsipeptides / Q000737:chemistry*; D019073:HT29 Cells; D006801:Humans; D008956:Models, Chemical; D015394:Molecular Structure; D011810:Quinoxalines / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D047630:Depsipeptides; D011810:Quinoxalines; C109005:thiocoraline; C009589:triostin C