title: Chemoenzymatic synthesis and antileukemic activity of novel C9- and C14-functionalized parthenolide analogs.
abstract: Parthenolide is a naturally occurring terpene with promising anticancer properties, particularly in the context of acute myeloid leukemia (AML). Optimization of this natural product has been challenged by limited opportunities for the late-stage functionalization of this molecule without affecting the pharmacologically important α-methylene-γ-lactone moiety. Here, we report the further development and application of a chemoenzymatic strategy to afford a series of new analogs of parthenolide functionalized at the aliphatic positions C9 and C14. Several of these compounds were determined to be able to kill leukemia cells and patient-derived primary AML specimens with improved activity compared to parthenolide, exhibiting LC50 values in the low micromolar range. These studies demonstrate that different O-H functionalization chemistries can be applied to elaborate the parthenolide scaffold and that modifications at the C9 or C14 position can effectively enhance the antileukemic properties of this natural product. The C9-functionalized analogs 22a and 25b were identified as the most interesting compounds in terms of antileukemic potency and selectivity toward AML versus healthy blood cells.
authors.affiliation: Department of Chemistry, University of Rochester, Rochester, NY 14627, United States.
authors.forename: Vikas
authors.initials: V
authors.lastname: Tyagi
authors.affiliation: Department of Chemistry, University of Rochester, Rochester, NY 14627, United States.
authors.forename: Hanan
authors.initials: H
authors.lastname: Alwaseem
authors.affiliation: Department of Hematology/Oncology, University of Rochester, Rochester, NY 14627, United States.
authors.forename: Kristen M
authors.initials: KM
authors.lastname: O'Dwyer
authors.affiliation: Division of Hematology, University of Colorado, Aurora, CO 80045, United States; Division of Toxicology, University of Colorado, Aurora, CO 80045, United States.
authors.forename: Jessica
authors.initials: J
authors.lastname: Ponder
authors.affiliation: Department of Chemistry, University of Rochester, Rochester, NY 14627, United States.
authors.forename: Qi Ying
authors.initials: QY
authors.lastname: Li
authors.affiliation: Division of Hematology, University of Colorado, Aurora, CO 80045, United States.
authors.forename: Craig T
authors.initials: CT
authors.lastname: Jordan
authors.affiliation: Department of Chemistry, University of Rochester, Rochester, NY 14627, United States. Electronic address: rfasan@ur.rochester.edu.
authors.forename: Rudi
authors.initials: R
authors.lastname: Fasan
mesh_terms: D000215:Acylation; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity; D001410:Bacillus megaterium; D001426:Bacterial Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004926:Escherichia coli; D006801:Humans; D007938:Leukemia / Q000188:drug therapy; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism; D009251:NADPH-Ferrihemoprotein Reductase / Q000378:metabolism; D010648:Phenylacetates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D012717:Sesquiterpenes / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity; D013237:Stereoisomerism
chemical_list: D000970:Antineoplastic Agents; D001426:Bacterial Proteins; D010648:Phenylacetates; D012717:Sesquiterpenes; C000622599:benzyl 2-((6,9alpha-dimethyl-3-methylene-2-oxo-2,3,3alpha,4,5,8,9,9a,10alpha,10beta-decahydrooxireno (2',3':9,10)cyclodeca(1,2-b)furan-5-yl)oxy)-2-phenylacetate; C000622598:ethyl 2-((6,9alpha-dimethyl-3-methylene-2-oxo-2,3,3alpha,4,5,8,9,9alpha,10alpha,10beta-decahydrooxireno (2',3':9,10)cyclodeca(1,2-b)furan-5-yl)oxy)-2-(4-(trifluoromethyl) phenyl)acetate; D003577:Cytochrome P-450 Enzyme System; D009247:NADH, NADPH Oxidoreductases; D009251:NADPH-Ferrihemoprotein Reductase; C052423:flavocytochrome P450 BM3 monoxygenases; C429539:NAD phosphite oxidoreductase
keywords: Anticancer activity; Chemoenzymatic synthesis; Enzymatic hydroxylation; Late-stage C–H functionalization; Leukemia; Parthenolide