Approaches to the Chemical Synthesis of the Chlorosulfolipids

[Image: see text] Since the initial discovery of the chlorosulfolipids in 1969, the chemical synthesis community largely ignored these compounds for nearly four decades, perhaps because they contain a high density of chlorine atoms that suggested that these molecules and any projected synthetic intermediates might be unstable. Beginning in 2008, a sudden flurry of synthesis activity by several research groups, including our own, appeared in the literature. In this Account, we highlight our work from the last several years on the chemical synthesis of the chlorosulfolipids. Our work in this area began with attempts to stereoselectively generate the abundant dichloroalcohol functional group arrangements in these natural targets. In these early studies, we learned that many polychlorinated intermediates were far more stable than anticipated. We also developed a method for the diastereoselective dichlorination of allylic alcohol derivatives that permitted access to the syn,syn-dichloroalcohol stereotriad found in several chlorosulfolipids. Concurrently, we investigated an approach to mytilipin A that included multiple intermediates bearing β-chloroaldehyde functional group arrangements, but this route proved intractable. However, we leveraged what we had learned from this approach into our first success in this area: we synthesized danicalipin A via a route that introduced all of the polar functional groups using alkene oxidation reactions. By adapting this relatively general strategy, we completed an enantioselective synthesis of malhamensilipin A. This body of work also resulted in the full stereochemical elucidation of danicalipin A and the structural revision of malhamensilipin A. Finally, with the advent of Z-selective alkene cross metathesis, we developed a second-generation synthesis that featured this strategy in place of a poorly performing Wittig olefination that plagued our first approach. In addition to this new convergent step, we developed a reliable protocol for diastereoselective addition to highly sensitive α,β-dichloroaldehydes and a method for kinetic resolution of complex vinyl epoxides. Altogether, these advances led to a synthesis of enantioenriched mytilipin A in only eight steps. In the context of this work, we discovered a number of highly stereoselective reactions that might offer new, broadly applicable lessons in acyclic stereocontrol. Moreover, this research testifies to the stability of polychlorinated molecules and should inspire confidence in the use of aliphatic chlorides in other applications, including in discovery chemistry

Cellular Delivery of Nanoparticles Revealed with Combined Optical and Isotopic Nanoscopy.

Direct polymerization of an oxaliplatin analogue was used to reproducibly generate amphiphiles in one pot, which consistently and spontaneously self-assemble into well-defined nanoparticles (NPs). Despite inefficient drug leakage in cell-free assays, the NPs were observed to be as cytotoxic as free oxaliplatin in cell culture experiments. We investigated this phenomenon by super-resolution fluorescence structured illumination microscopy (SIM) and nanoscale secondary ion mass spectrometry (NanoSIMS). In combination, these techniques revealed NPs are taken up via endocytic pathways before intracellular release of their cytotoxic cargo. As with other drug-carrying nanomaterials, these systems have potential as cellular delivery vehicles. However, high-resolution methods to track nanocarriers and their cargo at the micro- and nanoscale have been underutilized in general, limiting our understanding of their interactions with cells and tissues. We contend this type of combined optical and isotopic imaging strategy represents a powerful and potentially generalizable methodology for cellular tracking of nanocarriers and their cargo

Synthesis and Biological Evaluation of Dimeric Furanoid Macroheterocycles: Discovery of New Anticancer Agents

A recently developed dimerization/macrocyclization was employed to synthesize a series of macroheterocycles which were biologically evaluated, leading to the discovery of a number of potent cytotoxic agents (e.g., <b>27</b>: GI₅₀ = 51 nM against leukemia CCRF-CEM cell line; <b>29</b>: GI₅₀ = 99 nM against melanoma MDA-MB-435 cell line). Further biological studies support an apoptosis mechanism of action for these compounds involving deregulation of the tricarboxylic acid cycle activity and suppression of mitochondrial function in cancer cells

Cellular Delivery of Nanoparticles Revealed with Combined Optical and Isotopic Nanoscopy

Direct polymerization of an oxaliplatin analogue was used to reproducibly generate amphiphiles in one pot, which consistently and spontaneously self-assemble into well-defined nanoparticles (NPs). Despite inefficient drug leakage in cell-free assays, the NPs were observed to be as cytotoxic as free oxaliplatin in cell culture experiments. We investigated this phenomenon by super-resolution fluorescence structured illumination microscopy (SIM) and nanoscale secondary ion mass spectrometry (NanoSIMS). In combination, these techniques revealed NPs are taken up <i>via</i> endocytic pathways before intracellular release of their cytotoxic cargo. As with other drug-carrying nanomaterials, these systems have potential as cellular delivery vehicles. However, high-resolution methods to track nanocarriers and their cargo at the micro- and nanoscale have been underutilized in general, limiting our understanding of their interactions with cells and tissues. We contend this type of combined optical and isotopic imaging strategy represents a powerful and potentially generalizable methodology for cellular tracking of nanocarriers and their cargo