To identify an agent with specific activity against leukemic stem cells (LSCs), we evaluated compounds that targeted hepatic leukemia factor (HLF), a gene implicated in hematopoietic stem cell (HSCs) regulation, that we found overexpressed in LSCs. Cantharidin, a natural toxin from blister beetles, used as medicinal agent since antiquity, has been described to modulate the HLF competitor NFIL3 and is under clinical evaluation as an antitumor and antimetastatic agent. The molecule is not a substrate for multidrug resistant pumps and does not cause myelosuppression, and therefore it represents a promising compound for selective ablation of LSCs. Cantharidin and norcantharidin, a derivative with reduced toxicity, decreased HLF protein levels and induced apoptosis in the AML cell line MV4‐11 by modulating the expression of several molecules that govern survival pathway, including HLF, SLUG, NFIL3 and c‐myc, thereby inducing p53 and the mitochondrial caspase cascade. In vitro, cantharidin readily targeted primary AML stem and progenitor cells in contrast to conventional chemotherapeutic agents, such as Ara‐C and daunorubicin, that mainly targeted more differentiated leukemic cells. In vitro the compound did not exhibit a therapeutic window, being equally toxic to normal HSCs and LSCs. In vivo cantharidin did not produce myelosuppression. Because of dose‐limiting toxicity in vivo, neither cantharidin nor norcantharidin proved therapeutical benefit in AML xenograft models as a single agent. However, its potent in vitro LSC activity and pathway targeting may still be exploited clinically with a new generation of cantharidin derivatives or formulations and with appropriate drug combinations. © 2008 Wiley‐Liss, Inc.

The right way round: Peribysin E, a naturally occurring adhesion inhibitor, has been synthesized and, as a result, its absolute configuration reassigned. The natural and nonnatural enantiomers can be reached starting from (R)‐ or (S)‐carvone, respectively. A key step is the ring contraction of 1 to 2 (see scheme, TBS=tert‐butyldimethylsilyl, TES=triethylsilyl).

Richtig herum: Der natürliche Adhäsionsinhibitor Peribysin E wurde synthetisiert, und als eine Folge davon wurde seine absolute Konfiguration neu festgelegt. Das natürliche und das nichtnatürliche Enantiomer sind ausgehend von (R)‐ bzw. (S)‐Carvon zugänglich. Ein Schlüsselschritt ist die Ringkontraktion von 1 zu 2 (siehe Schema, TBS=tert‐Butyldimethylsilyl, TES=Triethylsilyl).

Terpenes U 0200Total Synthesis of Peribysin E Necessitates Revision of the Assignment of Its Absolute Configuration. -Naturally occurring peribysin E has the absolute configuration represented by structure (I), whereas the previously reported structure corresponds to the enantiomer. -(ANGELES, A. R.; DORN, D. C.; KOU, C. A.; MOORE, M. A. S.; DANISHEFSKY*, S.