Mono- and bis-aspidosperma indole alkaloid natural products have been shown to be cytotoxic against various cancer cell lines and are potential leads in therapeutics against diabetes and neurodegenerative diseases. Tabersonine, a monoterpene indole alkaloid isolated from the family Apocynaceae, was known to be the bio-synthetic precursor of its mono and dimeric analogs, including vindoline, conophylline, and vinblastine. The first synthesis of bis-aspidosperma indole alkaloid (–)-melodinine K was achieved in a chemoenzymatic fashion, featuring the T16H hydroxylation and the biomimetic dimerization via the Polonovski-Potier reaction. Moreover, eight tabersonine derivatives bearing one or two hydroxy or methoxy groups at C15-C17 were synthesized up to grams scale via a halogenation/borylation/oxidation sequence. These analogs exhibited potent inhibitory activities against cancer cells with GI50 values in the single digit micromolar level. This research on aspidosperma indole alkaloids could help guide the development of future cancer therapeutics as well as elucidate their biosynthetic pathways.Histone deacetylases (HDACs), regulating gene expression and multiple cellular activities, are important biomarkers and potential therapeutic targets. In this project, a group of fluorescent S-acetamidomethyl homocysteine-containing molecules were designed and synthesized to monitor HDAC’s activity and elucidate the temporal and spatial dynamics of HDACs in live cells. The free thiol warhead, released from the probe upon deacetylation by HDACs, would trigger an intramolecular Michael Addition to the coumarin-derived fluorophore and induce a blue shift for the fluorescence, which could be applied to the quantitative ratiometric study of HDACs. It provides a modular platform for discovering and developing class-/isoform-specific HDAC probes and future therapeutic lead compounds through modifications of fluorophores, C-terminal amino acids, and the capping acyl groups. / Chemistry
| Identifer | oai:union.ndltd.org:TEMPLE/oai:scholarshare.temple.edu:20.500.12613/10635 |
| Date | 08 1900 |
| Creators | Kang, Jinfeng, 0000-0002-9408-4799 |
| Contributors | Wang, Rongsheng, Schafmeister, Christian, Sieburth, Scott McNeill, Cannon, Kevin C. |
| Publisher | Temple University. Libraries |
| Source Sets | Temple University |
| Language | English |
| Detected Language | English |
| Type | Thesis/Dissertation, Text |
| Format | 344 pages |
| Rights | IN COPYRIGHT- This Rights Statement can be used for an Item that is in copyright. Using this statement implies that the organization making this Item available has determined that the Item is in copyright and either is the rights-holder, has obtained permission from the rights-holder(s) to make their Work(s) available, or makes the Item available under an exception or limitation to copyright (including Fair Use) that entitles it to make the Item available., http://rightsstatements.org/vocab/InC/1.0/ |
| Relation | http://dx.doi.org/10.34944/dspace/10597, Theses and Dissertations |
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