Tao, S., Tillotson, J., Wijeratne, E. M., Xu, Y., Kang, M., Wu, T., Lau, E. C., Mesa, C., Mason, D. J., Brown, R. V., La Clair, J. J., Gunatilaka, A. A., Zhang, D. D., & Chapman, E. (2015). Withaferin A Analogs That Target the AAA+ Chaperone p97. ACS chemical biology, 10(8), 1916-1924.
Understanding the mode of action (MOA) of many natural products can be puzzling with mechanistic clues that seem to lack a common thread. One such puzzle lies in the evaluation of the antitumor properties of the natural product withaferin A (WFA). A variety of seemingly unrelated pathways have been identified to explain its activity, suggesting a lack of selectivity. We now show that WFA acts as an inhibitor of the chaperone, p97, both in vitro and in cell models in addition to inhibiting the proteasome in vitro. Through medicinal chemistry, we have refined the activity of WFA toward p97 and away from the proteasome. Subsequent studies indicated that these WFA analogs retained p97 activity and cytostatic activity in cell models, suggesting that the modes of action reported for WFA could be connected by proteostasis modulation. Through this endeavor, we highlight how the parallel integration of medicinal chemistry with chemical biology offers a potent solution to one of natures' intriguing molecular puzzles.
Gunatilaka, L. -., Liu, X., Qi, W., Cooke, L. S., Wijeratne, E. M., Marron, M. T., & Mahadevan, D. (2011). An analog of withaferin A activates the MAPK and glutathione stress pathways and inhibits pancreas cancer cell proloferation. Cancer Investigation, 29, 668-675.
Yuquan, X. u., Espinosa-Artiles, P., Schubert, V., Xu, Y., Zhang, W., Lin, M., Gunatilaka, A. L., Süssmuth, R., & Molnár, I. (2013). Characterization of the biosynthetic genes for 10,11- dehydrocurvularin, a heat shock response-modulating anticancer fungal polyketide from Aspergillus terreus. Applied and Environmental Microbiology, 79(6), 2038-2047.
PMID: 23335766;PMCID: PMC3592213;Abstract:
10,11-Dehydrocurvularin is a prevalent fungal phytotoxin with heat shock response and immune-modulatory activities. It features a dihydroxyphenylacetic acid lactone polyketide framework with structural similarities to resorcylic acid lactones like radicicol or zearalenone. A genomic locus was identified from the dehydrocurvularin producer strain Aspergillus terreus AH-02- 30-F7 to reveal genes encoding a pair of iterative polyketide synthases (A. terreus CURS1 [AtCURS1] and AtCURS2) that are predicted to collaborate in the biosynthesis of 10,11-dehydrocurvularin. Additional genes in this locus encode putative proteins that may be involved in the export of the compound from the cell and in the transcriptional regulation of the cluster. 10,11-Dehydrocurvularin biosynthesis was reconstituted in Saccharomyces cerevisiae by heterologous expression of the polyketide synthases. Bioinformatic analysis of the highly reducing polyketide synthase AtCURS1 and the nonreducing polyketide synthase AtCURS2 highlights crucial biosynthetic programming differences compared to similar synthases involved in resorcylic acid lactone biosynthesis. These differences lead to the synthesis of a predicted tetraketide starter unit that forms part of the 12-membered lactone ring of dehydrocurvularin, as opposed to the penta- or hexaketide starters in the 14-membered rings of resorcylic acid lactones. Tetraketide N-acetylcysteamine thioester analogues of the starter unit were shown to support the biosynthesis of dehydrocurvularin and its analogues, with yeast expressing AtCURS2 alone. Differential programming of the product template domain of the nonreducing polyketide synthase AtCURS2 results in an aldolcondensation with a different regiospecificity than that of resorcylic acid lactones, yielding the dihydroxyphenylacetic acid scaffold characterized by an S-type cyclization pattern atypical for fungal polyketides. © 2013, American Society for Microbiology.
A., A., Gopichand, Y., Schmitz, F. J., & Djerassi, C. (1981). Minor and trace sterols in marine invertebrates. 26. Isolation and structure elucidation of nine new 5α,8α-epidioxy sterols from four marine organisms. Journal of Organic Chemistry, 46(19), 3860-3866.
Abstract:
Sixteen 5α,8α-epidioxy Δ6 and Δ6,9(11) sterols, of which nine are new, have been isolated from the marine organisms Ascidia nigra, Dendrogyra cylindrus, Thalysias juniperina, and Aplysia dactylomela by reverse-phase high-performance liquid chromatography and characterized by high-resolution mass spectrometry and 360-MHz proton NMR spectroscopy. Attention is drawn to some unusual concentration-dependent NMR shifts of methyl signals. The probable biological significance of these epidioxy sterols is discussed with special reference to sterol biosynthesis. © 1981 American Chemical Society.
Harrigan, G. G., S.Bolzani, V. d., Gunatilaka, A. L., & Kingston, D. G. (1994). Kaurane and trachylobane diterpenes from Xylopia aethiopica. Phytochemistry, 36(1), 109-113.
Abstract:
Phytochemical investigation of Xylopia aethiopica (Annonaceae) has resulted in the isolation of two novel diterpenes, 15-oxo-(-)-trachyloban-19-oic acid and (-)-kaur-15-en-17-al-19-oic acid. Also encountered were the known compounds 15-hydroxy-(-)-trachyloban-19-oic acid, 15β-hydroxy-(-)-kaur-16-en-19-oic acid (as an inseperable mixture), 15-oxo-(-)-kaur-16-en-19-oic acid and sitosterol glucoside. 13C NMR assignments of 15-hydroxy-(-)- trachyloban-19-oic acid and the assignment of the configuration of its hydroxyl group at C-15 have been carried out for the first time. © 1994.
