Organic & Biomolecular Chemistry
Communication
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4
previously described synthesis of ascr#81 (2). Gratuitously,
bioassays demonstrated that probe D retained biological activity
matching that of unmodified ascr#8 (Fig. 2B and S1†).
2 A. B. Artyukhin, J. J. Yim, J. Srinivasan, Y. Izrayelit, N. Bose,
S. H. von Reuss, Y. Jo, J. M. Jordan, L. R. Baugh,
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P.-Y. Jeong, M. Jung, Y.-H. Yim, H. Kim, M. Park, E. Hong,
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41–545.
S. H. von Reuss and F. C. Schroeder, Nat. Prod. Rep., 2015,
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Together, these results suggest multiple avenues for testing
and development of ascaroside receptor probes. The presence
of the hydroxyl groups on the ascarylose sugar appears to be
essential for maintaining ascaroside activity (Fig. 2, 10, 11).
Introduction of an alkyne moiety at the ω-position of the side
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6
R. A. Butcher, Nat. Prod. Rep., 2017, 34, 472–477.
A. H. Ludewig, Y. Izrayelit, D. Park, R. U. Malik,
A. Zimmermann, P. Mahanti, B. W. Fox, A. Bethke,
F. Doering, D. L. Riddle and F. C. Schroeder, Proc. Natl.
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5
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chain is well tolerated in the case of ascr#8. Except for ascr#5
(
3), all ascarosides for which biological activity has been
demonstrated in C. elegans feature an ω-methyl group in the
side chain, suggesting that alkyne introduction at this position
could be used for probing receptor interactions of biosynthesis
of diverse ascarosides in C. elegans. However, in other nema-
tode species, modification of the ω-methyl may be less well tol-
erated; for example, in Caenorhabditis nigoni, hydroxylation of
the ω-side chain carbon was found to abolish the attraction of
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8
9
A. H. Ludewig, A. B. Artyukhin, E. Z. Aprison,
P. R. Rodrigues, D. C. Pulido, R. N. Burkhardt, O. Panda,
Y. K. Zhang, P. Gudibanda, I. Ruvinsky and F. C. Schroeder,
Nat. Chem. Biol., 2019, 15, 838–845.
J. Srinivasan, S. H. von Reuss, N. Bose, A. Zaslaver,
P. Mahanti, M. C. Ho, O. G. O’Doherty, A. S. Edison,
P. W. Sternberg and F. C. Schroeder, PLos Biol., 2012, 10,
e1001237.
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8
C. nigoni males to ascr#3 (8).
In the case of ascr#8, use of commercially available 2-(3-
but-3-yn-1-yl)-3H-diazirin-3-yl)ethan-1-amine, as in probe D
12), allowed for inclusion of both the photo-reactive group
A. Choe, S. H. von Reuss, D. Kogan, R. B. Gasser,
E. G. Platzer, F. C. Schroeder and P. W. Sternberg, Curr.
Biol., 2012, 22, 772–780.
(
(
and bioorthogonal reactive group with relative ease. However,
activity of many other ascarosides requires the presence of an
unmodified carboxy terminus, and therefore installation of the
alkyne at the ω-position of the side chain may be preferable,
though a suitable location for the diazirine moiety remains to
be found. For the identification of the receptor of ascr#8, our
efforts are directed at crosslinking probe D with putative recep-
tor candidates in heterologous expression systems.
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Conflicts of interest
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1
3 A. H. Ludewig and F. C. Schroeder, WormBook, 2013, 1–22,
DOI: 10.1895/wormbook.1.155.1.
4 A. B. Artyukhin, Y. K. Zhang, A. E. Akagi, O. Panda,
P. W. Sternberg and F. C. Schroeder, J. Am. Chem. Soc.,
There are no conflicts to declare.
2
018, 140, 2841–2852.
5 S. H. von Reuss and F. C. Schroeder, Nat. Prod. Rep., 2015,
2, 994–1006.
Acknowledgements
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The strain of C. elegans used in this study, CB4088 (him-5
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(e1490)), was provided by the CGC, which is funded by NIH
Office of Research Infrastructure Programs (P40 OD010440).
This work was supported in part by the NIH (R01GM113692
and R35GM131877 to F.C.S., and R01DC016058 to JS) and
startup funds from WPI to JS. We would also like to thank
Elizabeth DiLoreto in the Srinivasan Lab for providing com-
ments and edits to early versions of this manuscript.
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Notes and references
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C. Pungaliya, J. Srinivasan, B. W. Fox, R. U. Malik,
A. H. Ludewig, P. W. Sternberg and F. C. Schroeder, Proc.
Natl. Acad. Sci. U. S. A., 2009, 106, 7708–7713.
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