Tukov, F. F., Anand, S., Sarma, R., A., A., Matthews, J. C., & Rimoldi, J. M. (2004). Inactivation of the cytotoxic activity of repin, a sesquiterpene lactone from Centaurea repens. Chemical Research in Toxicology, 17(9), 1170-1176.
PMID: 15377150;Abstract:
Prolonged ingestion of Yellow Starthistle (Centaurea solstitialis) and Russian Knapweed (Centaurea repens) by horses has been shown to result in a fatal neurodegenerative disorder called equine nigropallidal encephalomalacia (ENE). Bioassay-guided fractionation of extracts from Centaurea species using the PC12 cell line have led to the identification of one of several putative agents, which may contribute to ENE, namely, the sesquiterpene lactone (SQL) repin (1), previously linked to ENE due to its abundance in C. repens. To characterize the molecular basis of repin-induced neurotoxicity, the present study was designed to identify reactive functional groups that may contribute overall to its toxicity. The reaction of repin (1) with glutathione (GSH) led to the exclusive addition of GSH to the α-methylenebutyrolactone affording a GSH conjugate (3b) that lacked toxicity in the PC12 cell assay, while selective reduction of the α-methylenebutyrolactone double bond of 1 also resulted in an analogue (2) that was devoid of toxicity relative to the parent compound. Unlike repin, analogue 2 failed to decrease cellular dopamine levels in PC12 cells, further substantiating the requirement of the α- methylenebutyrolactone group. Results from this study are suggestive that GSH depletion by the SQL repin may be a primary event in the etiology of ENE, increasing the susceptibility to oxidative damage.
Gunatilaka, L., Xu, Y., Wijeratne, K., Babyak, A. L., Brooks, A. D., Tewary, P., Marks, H. R., Xuan, L., Wang, W., & Sayers, T. J. (2017). Withanolides from Aeroponically Grown Physalis peruviana and Their Selective Cytotoxicity to Prostate Cancer and Renal Carcinoma Cells. Journal of Natural Products, 80, 1981-1991. doi:10.1021/acs.jnatprod.6b01129
Gunatilaka, A. L., Shekhar-Guturja, T., Gunaherath, G. B., Wijeratne, E. K., Lambert, J., Averette, A. F., Bahn, Y., Tripodi, F., Ammar, R., Sanglard, D., Andes, D., Nislow, C., Coccetti, P., Gingras, A., Heitman, J., & Cowen, L. E. (2016). Dual Action Small Molecule Potentiates Antifungal Efficacy, Blocks the Evolution of Drug Resistance, and Renders Resistant Pathogens Responsive to Therapy via Modulation of Multidrug Efflux and TOR Signaling. Nature Chemical Biology, 12, 867-875.
Gunatilaka, A. L., Berger, J. M., Evans, R., Miller, J. S., Wisse, J. H., Neddermann, K. M., Bursuker, I., & G., D. (2001). Isolation, synthesis, and structure - Activity relationships of bioactive benzoquinones from Miconia lepidota from the suriname rainforest. Journal of Natural Products, 64(1), 2-5.
PMID: 11170656;Abstract:
Bioactivity-directed fractionation of an EtOAc extract from the leaves of Miconia lepidota afforded the two benzoquinones 2-methoxy-6-heptyl-1,4-benzoquinone (1) and 2-methoxy-6-pentyl-1,4-benzoquinone (primin) (2). This is the first reported isolation of 1. Both quinones 1 and 2 exhibited activity toward mutant yeast strains based on Saccharomyces cerevisiae, indicative of their cytotoxicity and potential anticancer activity. A number of previously synthesized and new analogues were prepared and tested in the same strains. Compounds 1, 2, 2-methoxy-6-butyl-1,4-benzoquinone (5), and 2-methoxy-6-decyl-1,4-benzoquinone (6) were tested in two cytotoxicity assays. In the M109 tumor cell lines, quinones 1, 2, and 6 had an IC50 value of 10 μg/mL. In the A2780 cell line, compounds 1, 2 and 5 had IC50 values of 7.9, 2.9, and 3.2/ μg/mL, respectively.
Santagata, S., Xu, Y., M., E., Kontnik, R., Rooney, C., Perley, C. C., Kwon, H., Clardy, J., Kesari, S., Whitesell, L., Lindquist, S., & A., A. (2012). Using the heat-shock response to discover anticancer compounds that target protein homeostasis. ACS Chemical Biology, 7(2), 340-349.
PMID: 22050377;PMCID: PMC3291478;Abstract:
Unlike normal tissues, cancers experience profound alterations in protein homeostasis. Powerful innate adaptive mechanisms, especially the transcriptional response regulated by Heat Shock Factor 1 (HSF1), are activated in cancers to enable survival under these stressful conditions. Natural products that further tax these stress responses can overwhelm the ability to cope and could provide leads for the development of new, broadly effective anticancer drugs. To identify compounds that drive the HSF1-dependent stress response, we evaluated over 80,000 natural and synthetic compounds as well as partially purified natural product extracts using a reporter cell line optimized for high-throughput screening. Surprisingly, many of the strongly active compounds identified were natural products representing five diverse chemical classes (limonoids, curvularins, withanolides, celastraloids, and colletofragarones). All of these compounds share the same chemical motif, an α,β- unsaturated carbonyl functionality, with strong potential for thiol-reactivity. Despite the lack of a priori mechanistic requirements in our primary phenotypic screen, this motif was found to be necessary albeit not sufficient, for both heat-shock activation and inhibition of glioma tumor cell growth. Within the withanolide class, a promising therapeutic index for the compound withaferin A was demonstrated in vivo using a stringent orthotopic human glioma xenograft model in mice. Our findings reveal that diverse organisms elaborate structurally complex thiol-reactive metabolites that act on the stress responses of heterologous organisms including humans. From a chemical biology perspective, they define a robust approach for discovering candidate compounds that target the malignant phenotype by disrupting protein homeostasis. © 2011 American Chemical Society.
