Crystal Structures and Human Leukemia Cell Apoptosis Inducible Activities of Parthenolide Analogues Isolated from Piptocoma rufescens

Abstract

The molecular structures of three parthenolide analogues, (-)-goyazensolide (1), (-)-15-deoxygoyazensolide (2), and (-)-ereglomerulide (3), isolated from the leaves of Piptocoma rufescens in a previous study were determined by X-ray analysis, and the absolute configuration of (-)-goyazensolide (1) was confirmed crystallographically using Cu Kα radiation at low temperature. Compounds 1-3, (+)-rufesolide A (4), and commercial parthenolide were found to be growth inhibitory toward MOLM-13 and EOL-1 human acute myeloid leukemia cells using PKC412 (midostaurin) as the positive control, with 1-3 being more active than parthenolide. Also, compounds 1-4 exhibited synergistic effects when tested with PKC412, but parthenolide did not show this type of activity. At a concentration lower than 2.0 μM, both 1 and 2 induced approximately 50% of the cells to become apoptotic at a late stage of the cell cycle, but no similar apoptotic effects were observed for 3, 4, or parthenolide. Leukemia cell apoptosis was induced by these compounds through the activation of caspase-3 and the inhibition of NF-κB, as indicated by immunoblotting analysis, and compounds 1 and 2 seem to be promising leads for development as potential antileukemic agents.

Potential Anticancer Agents Characterized from Selected Tropical Plants

“…This determination has been confirmed by single-crystal X-ray diffraction analysis for (−)-goyazensolide ( 74 ), with the data collected at 90 K, using Cu Kα radiation. Both the Flack parameter, refined to a value of −0.04(13), and the Hooft y parameter, determined as −0.03(4), after refinement by analysis of the Bijvoet pairs, indicated a (6 R ,7 R ,8 S ,10 R ) absolute configuration for (−)-goyazensolide ( 74 ) …”

Cytotoxic Activity of Germacrane-Type Sesquiterpene Lactones from Dimerostemma aspilioides

“…An analogue of compound 1 , parthenolide, with a methyl group at C-10 and lacking the side chain at C-8, caused cell cycle arrest in the G 2 /M phase in the U373 glioblastoma cell line, while no apoptosis was observed at 16 μM . Nor was this mechanism of death observed against the leukemia cells MOLM-13 and EOL-1 at 4.0 μM . However, it was seen in a series of acute and chronic myelogenous and lymphoblastic leukemia cells at 5.0–7.5 μM and also in in vivo assays …”

“…31 Nor was this mechanism of death observed against the leukemia cells MOLM-13 and EOL-1 at 4.0 μM. 32 However, it was seen in a series of acute and chronic myelogenous and lymphoblastic leukemia cells at 5.0−7.5 μM and also in in vivo assays. 33 To determine the toxic effect of compound 1 against normal cells and thus show its selectivity for leukemia cells, an MTT assay was performed against peripheral blood mononuclear cells (PBMC).…”

Identification of a Covalent Importin-5 Inhibitor, Goyazensolide, from a Collective Synthesis of Furanoheliangolides

“…There is clear evidence that goyazensolide inhibits the expression of genes under the control of c-myb , a proto-oncogenic transcription factor; however, its exact mode of action remains undefined. 15-Deoxygoyazensolide ( 3 , Figure ) was found to be slightly more cytotoxic than goyazensolide, suggesting that small modifications can enhance activity. 15-Deoxygoyazensolide was also found to be active in a number of quantitative-cell-based reporter assays …”