Chemoenzymatic synthesis and antileukemic activity of novel C9- and C14-functionalized parthenolide analogs

• Published in: Bioorganic & medicinal chemistry 2016-09, Vol.24 (17), p.3876-3886
• Main Authors: Tyagi, Vikas, Alwaseem, Hanan, O’Dwyer, Kristen M., Ponder, Jessica, Li, Qi Ying, Jordan, Craig T., Fasan, Rudi
• Format: Article
• Language: English
• Subjects: Acylation; Anticancer activity; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - pharmacology; Antineoplastic Agents - toxicity; Bacillus megaterium; Bacterial Proteins - metabolism; Cell Line, Tumor; Chemoenzymatic synthesis; Cytochrome P-450 Enzyme System - metabolism; Enzymatic hydroxylation; Escherichia coli; Humans; Late-stage C–H functionalization; Leukemia; Leukemia - drug therapy; NADH, NADPH Oxidoreductases - metabolism; NADPH-Ferrihemoprotein Reductase - metabolism; Parthenolide; Phenylacetates - chemical synthesis; Phenylacetates - chemistry; Phenylacetates - pharmacology; Sesquiterpenes - chemical synthesis; Sesquiterpenes - pharmacology; Sesquiterpenes - toxicity; Stereoisomerism
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2016.06.028

[Display omitted] 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.