Anticancer activity profiling of parthenolide analogs generated via P450-mediated chemoenzymatic synthesis. Issue 7 (1st April 2018)

• Record Type: Journal Article
• Authors: Alwaseem, Hanan; Frisch, Benjamin J.; Fasan, Rudi
• Is Part Of: Bioorganic & medicinal chemistry. Volume 26:Issue 7(2018)
• Page Start: 1365
• Page End: 1373
• Publication Date: 2018-04-01
• Subjects: PTL parthenolide -- AML acute myelogenous leukemia -- CSCs cancer stem cells -- DMAPT dimethylamino-parthenolide -- PTDH phosphite dehydrogenase -- NADPH nicotinamide adenine dinucleotide phosphate (reduced) -- IPTG β-d-1-thiogalactopyranoside -- δ-ALA δ-aminolevulinic acid -- TB terrific broth -- DMSO dimethylsulfoxide -- DBTDL dibutyltin laurate; Parthenolide -- Sesquiterpene lactones -- Anticancer activity -- Chemoenzymatic synthesis -- Cytochrome P450BM3 -- Enzymatic hydroxylation -- Late-stage C–H functionalization; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2017.08.009
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: The plant-derived sesquiterpene lactone parthenolide (PTL) was recently found to possess promising anticancer activity but elaboration of this natural product scaffold for optimization of its pharmacological properties has proven challenging via available chemical methods. In this work, P450-catalyzed C–H hydroxylation of positions C9 and C14 in PTL was coupled to carbamoylation chemistry to yield a panel of novel carbamate-based PTL analogs ('parthenologs'). These compounds, along with a series of other C9- and C14-functionalized parthenologs obtained via O–H acylation, alkylation, and metal-catalyzed carbene insertion, were profiled for their cytotoxicity against a diverse panel of human cancer cell lines. These studies led to the discovery of several parthenologs with significantly improved anticancer activity (2–14-fold) compared to the parent molecule. Most interestingly, two PTL analogs with high cytotoxicity (LC50 ∼ 1–3 μM) against T cell leukemia (Jurkat), mantle cell lymphoma (JeKo-1), and adenocarcinoma (HeLa) cells as well as a carbamate derivative with potent activity (LC50 = 0.6 μM) against neuroblastoma cells (SK-N-MC) were obtained. In addition, these analyses resulted in the identification of parthenologs featuring both a broad spectrum and tumor cell-specific anticancer activity profile, thus providing valuable probes for the future investigation of biomolecular targets that can affect cell viability across multiple as well as specific types of human cancers. Altogether, these results highlight the potential of P450-mediated chemoenzymatic C–H functionalization toward tuning and improving the anticancer activity of the natural product parthenolide.