The first active aza analogue of narciclasine was synthesized from a pentasubstituted derivative of nicotinic acid. The key features of the synthesis include a halogen dance of bromopyridine and an intramolecular Heck reaction with a conduramine derived chemoenzymatically from bromobenzene. 10-Aza-narciclasine was found to have reasonable activity against several cancer cell lines.

Hydrogels containing sugar and oxaborole residues with remarkable self-healing properties were synthesized by free-radical polymerization in a facile and one pot process. The strong covalent interactions between the oxaborole residues and free adjacent hydroxyl groups of the pendent sugar residues of the glycopolymer allowed the in situ formation of hydrogels achievable under either neutral or alkaline conditions. These hydrogels showed excellent self-healing and injectability behaviors in aqueous conditions and were found to be responsive to both pH and the presence of free sugars (such as glucose) in solution. Furthermore, these hydrogels can easily be reconstructed from their lyophilized powder into any desired three-dimensional scaffold. Additionally, the hydrogels can be designed to have very low cytotoxicity and hence can be used as a scaffold for cell encapsulation. With these unique properties, these biocompatible, biodegradable, rebuildable, and self-healable hydrogels offer great potential in many biomedical applications.

Enhanced mitochondrial stability and decreased dependence on oxidative phosphorylation confer an acquired resistance to apoptosis in cancer cells, but may present opportunities for therapeutic intervention. The compound pancratistatin (PST) has been shown to selectively induce apoptosis in cancer cells. However, its low availability in nature has hindered its clinical advancement. We synthesized PST analogs and a medium-throughput screen was completed. Analogs SVTH-7, -6, and -5 demonstrated potent anti-cancer activity greater than PST and several standard chemotherapeutics. They disrupted mitochondrial function, activated the intrinsic apoptotic pathway, and reduced growth of tumor xenografts in vivo. Interestingly, the pro-apoptotic effects of SVTH-7 on cancer cells and mitochondria were abrogated with the inhibition of mitochondrial complex II and III, suggesting mitochondrial or metabolic vulnerabilities may be exploited by this analog. This work provides a scaffold for characterizing distinct mitochondrial and metabolic features of cancer cells and reveals several lead compounds with high therapeutic potential.

The synthesis of two C-1 analogues of pancratistatin has been accomplished in 17 steps from bromobenzene. The key steps involved the enzymatic dihydroxylation, regioselective opening of epoxyaziridine 9 with the alane derived from 8, a solid-state silica-gel-catalyzed intramolecular opening of aziridine to produce phenanthrene 13 whose oxidative cleavage and recyclization provided the full skeleton of the Amaryllidaceae constituents. The new analogues 5 and 6 exhibited promising activity in several human cancer cell lines.

Several unnatural derivatives of narciclasine were prepared in which the C-7 carbon was replaced with nitrogen. The 7-aza derivative and its N-oxide were prepared by the coupling of iodopicolinic acid with a conduramine unit derived chemoenzymatically from bromobenzene. Intramolecular Heck reaction was used to construct the carbostyryl ring system. The compounds were submitted to biological screening against cancer cell lines. Full experimental and spectra data are provided for all new compounds.