THE DEVELOPMENT AND APPLICATION OF CLICKABLE LIPID ANALOGS FOR ELUCIDATING AND HARNESSING LIPID FUNCTIONS - Click Chemistry in Glycoscience: New Developments and Strategies - page 86

which is exemplified by the production of 23 from alkynyl-glycolipid 24 and azido-
triacylglycerol analog 25 .
While advances in the synthesis of traditional carbohydrate and lipid motifs have
allowed the generation of highly complex glycolipids, click chemistry has furthered
the cause of producing functionalized analogs. A prime example pertains to the work
of Guo and coworkers in the development of 26 , a protected alkyne-tagged analog
of monophosphoryl Lipid A (Fig. 4.7) [66]. This glycolipid is of significant interest
due to the pivotal role this compound plays in endotoxicity through the activation of
the toll-like receptor 4. As a result, synthetic Lipid A conjugates have been pursued
to develop new immunostimulants to combat sepsis, although the synthesis of such
analogs is hindered by the complex structure of this glycolipid. Thus, the production of
clickable derivatives 26 shows promise for enhancing the rapid production of analogs
with useful properties. The convenient modification of this analog was demonstrated
through coupling with GM3-alkyne 27 to access conjugate 28 .
As a result of the diversity of lipid structures that have been generated using click
chemistry, it is clear that this is a generally effective strategy for the pursuit of complex
lipids for a wide range of applications. In addition, a few important concepts have
arisen from this work, including the location for tag placement and the properties of
the resulting triazoles. It has been shown that click chemistry can be effectively used
to derivatize lipids at both the headgroup and within the acyl chains. Here, the choice
of tag location will often be dependent on the particular structures and applications
that are targeted. However, the properties of the subsequent triazoles, and in particular,
their polar nature, play into this as well by affecting the physicochemical properties
of the resulting lipid analogs. These previous lessons should be considered when
developing the optimal synthetic targets in future studies.
4.4 DIRECT IN SITU LABELING AND IMAGING OF SYNTHETICALLY
TAGGED LIPID ANALOGS
Another area of study that has benefited from click-chemistry-based derivatization
involves in situ labeling and imaging of lipids within the complex environments of bio-
logical samples, which exploits the bioorthogonal nature of this reaction (Fig. 4.8a).
Lipids are dynamic biomolecules that continually undergo modification via metabolic
pathways and movement throughout cellular membranes. The localization of each
particular lipid, which is regulated in a spatial and temporal manner through pro-
cesses such as enzymatic modification and diffusion, controls important biological
activities, including fusion and signaling. Thus, the elucidation of the details of lipid
localization is necessary to fully understand subsequent biological properties. How-
ever, due to the relatively simple structures and specific properties of lipids, it is
difficult to track these molecules in a native environment without perturbing the sys-
tem. Recent advancements using click chemistry have shown promise for overcoming
these challenges.
In a recent report, Schultz and Neef used synthetic alkyne-tagged PA analogs
to image the dynamics of this lipid in both fixed and living cells (Fig. 4.8b) [67].