Epigenetic mechanisms play a critical role in the regulation of gene expression, and how such regulation becomes aberrant in cancer. Along with DNA methyltransferases (DNMTs) and histone deacetylases (HDACs), histone methyltransferases (HKMTs) have recently appeared as new promising drug targets for epigenetic cancer therapies. While several HDAC and DNMT inhibitors have been clinically validated, to date only few HKMT inhibitors have been reported. Chaetocin, a fungal metabolite belonging to the 3,6-epidithio-diketopiperazine (ETP) class was first described as a specific inhibitor of the histone methyltransferase SU(VAR)3–9.(1) Like other fungal metabolites of the ETP class however, it exhibits a broad range of antibacterial and cytostatic activity, including a remarkable cytotoxicity against HeLa cells. Since the broad cytotoxicity of the ETPs is due to the presence of the disulfide bridge of the 3,6-epidithio-diketopiperazine (causing protein crosslinking, reactive oxygen species generation, or zinc chelation), we reasoned that access to semi-synthetic derivatives devoid of such functionality, would provide valuable insight into the chemical biology of this natural product, particularly its reported HKMT activity. We developed conditions to extract and purify the natural product culture (Chaetomium virescens var. thielavioideum), followed several semi-synthetic approaches to obtain chaetocin analogues. Comparison of experimental and computationally simulated chiroptical spectroscopy allowed unambiguous structural characterization of our products. Evaluation of our compounds in a number of in vitro HKMT assays revealed a total loss in inhibitory potency upon modification of the disulfide bridge. These studies thus demonstrate the ETP functionality of chaetocin to be responsible for its reported HKMT activity. In conclusion, we have synthetically prepared distinct and novel chaetocin analogues from the natural product and explored their HKMT activity, implicating the ETP functionality as the active pharmacophore.


1. Greiner, D.; Bonaldi, T.; Eskeland, R.; Roemer, E.; Imhof, A. Nat. Chem. Biol. 2005, 1, 143.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B165.