[5]-Helistatins: Tubulin-Binding Helicenes with Antimitotic Activity.

Helicenes are high interest synthetic targets with unique conjugated helical structures that have found important technological applications. Despite this interest, helicenes have had limited impact in chemical biology. Herein, we disclose a first-in-class antimitotic helicene, helistatin 1 (HA-1), where the helicene scaffold acts as a structural mimic of colchicine, a known antimitotic drug. The synthesis proceeds via sequential Pd-catalyzed coupling reactions and a π-Lewis acid cycloisomerization mediated by PtCl2. HA-1 was found to block microtubule polymerization in both cell-free and live cell assays. Not only does this demonstrate the feasibility of using helicenes as bioactive scaffolds against protein targets, but also suggests wider potential for the use of helicenes as isosteres of biaryls or cis-stilbenes-themselves common drug and natural product scaffolds. Overall, this study further supports future opportunities for helicenes for a range of chemical biological applications.

Glycosylated Nanoparticles Derived from RAFT Polymerization for Effective Drug Delivery to Macrophages.

The functional group tolerance and simplicity of reversible addition fragmentation chain transfer (RAFT) polymerization enable its use in the preparation of a wide range of functional polymer architectures for a variety of applications, including drug delivery. Given the role of tumor-associated macrophages (TAMs) in cancer and their dependence on the tyrosine kinase receptor FMS (CSF-1R), the key aim of this work was to achieve effective delivery of an FMS inhibitor to cells using a polymer delivery system. Such a system has the potential to exploit biological features specific to macrophages and therefore provide enhanced selectivity. Building on our prior work, we have prepared RAFT polymers based on a poly(butyl methacrylate-co-methacrylic acid) diblock, which were extended with a hydrophilic block, a cross-linker, and a mannose-based monomer scaffold, exploiting the abundance of macrophage mannose receptors (MMRs, CD206) on the surface of macrophages. We demonstrate that the prepared polymers can be assembled into nanoparticles and are successfully internalized into macrophages, in part, via the MMR (CD206). Finally, we showcase the developed nanoparticles in the delivery of an FMS inhibitor to cells, resulting in inhibition of the FMS receptor. As such, this study lays the groundwork for further drug-delivery studies aimed at specifically targeting TAMs with molecularly targeted therapeutics.