title: Formal synthesis of (-)-englerin A and cytotoxicity studies of truncated englerins.
abstract: An efficient formal synthesis of (-)-englerin A (1) is reported. The target molecule is a recently isolated guaiane sesquiterpene that possesses highly potent and selective activity against renal cancer cell-lines. Our enantioselective strategy involved the construction of the BC ring system of compound 1 through a Rh(II)-catalyzed [4+3] cycloaddition reaction followed by subsequent attachment of the A ring through an intramolecular aldol condensation reaction. As such, this strategy allows the synthesis of truncated englerins. Evaluation of these analogues with the A498 renal cancer cell-line suggested that the A ring of englerin is crucial to its antiproliferative activity. Moreover, evaluation of these analogues led to the identification of potent growth-inhibitors of CEM cells with GI(50) values in the range 1-3 μM.
authors.affiliation: Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, MC: 0358, La Jolla, CA 92093-0358, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Xu
authors.forename: Eduardo J E
authors.initials: EJ
authors.lastname: Caro-Diaz
authors.forename: Ayse
authors.initials: A
authors.lastname: Batova
authors.forename: Steven D E
authors.initials: SD
authors.lastname: Sullivan
authors.forename: Emmanuel A
authors.initials: EA
authors.lastname: Theodorakis
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002384:Catalysis; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D003500:Cyclization; D006801:Humans; D020128:Inhibitory Concentration 50; D007680:Kidney Neoplasms / Q000188:drug therapy; D008958:Models, Molecular; D029803:Phyllanthus / Q000737:chemistry*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy; D012238:Rhodium / Q000737:chemistry; D045789:Sesquiterpenes, Guaiane / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D045789:Sesquiterpenes, Guaiane; C534971:englerin A; D012238:Rhodium