Abstract
Dehydroleucodine is a bioactive sesquiterpene lactone. Herein, four dehydroleucodine amino derivatives were synthesized using the amines proline, piperidine, morpholine, and tyramine, and spectroscopic methods and single-crystal X-ray diffraction unambiguously established their structures. The cytotoxic activity of these compounds was evaluated against eight acute myeloid leukemia cell lines, and their toxicity to peripheral blood mononuclear cells was also determined. The proline adduct was the most active compound, it showed anti-leukemic activity, upregulated heme oxygenase 1 (HMOX1) and the primary stress-inducible isoform of the heath shock 70 kDa protein 1 (HSPA1A), and downregulated NFkB1 transcription, it was also found to be about 270 times more water soluble than dehydroleucodine.
Highlights
Sesquiterpene lactones (SLs) are a large and diverse group of biologically active plant chemicals, mainly distributed in the Asteraceae family
Compound 2 is a white powder with a molecular formula of C20 H25 NO5 based on high-resolution mass spectroscopy (HRMS) (m/z 360.1823 [M + H]+ ) data
5, a nuclear Overhauser effect (NOE) correlation was observed between H-9 and H-12 protons indicating that they are on the same face, this is supported by moderate nuclear Overhauser enhancement spectroscopy (NOESY) correlations between H-8 and both H-13 protons
Summary
Sesquiterpene lactones (SLs) are a large and diverse group of biologically active plant chemicals, mainly distributed in the Asteraceae family. Parthenolide has been evaluated in different biological systems, including the inhibition of acute myeloid leukemia (AML) stem and progenitor cells [1]. In order to mitigate this limitation, an amino-prodrug strategy has been reported This strategy utilizes the masking of exocyclic methylene in the lactone ring by reaction with primary or secondary amines. SLs have shown intracellular effects in various cancer cell lines, including inhibition of nuclear factor-κB (NF-κB), inhibition of sarco/endoplasmic reticulum calcium ATPase (SERCA) pump, iron-dependent free radical generation, blocking of the signal transducer and activator of transcription. NF-κB has an important role in the regulation of cell cycle progression, proliferation, and apoptosis It can be formed by homodimers and heterodimers of a p50 and a p65 subunit. We report the synthesis and chemical characterization of four amino derivatives of dehydroleucodine, as well as their evaluation against several AML cell lines
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