C O M M U N I C A T I O N S
Scheme 1 a
product (Figure 4g-i). On the other hand, compound 12, lacking
the perhydroindane motif, had no effect on Golgi membranes (data
not shown), attesting to the importance of the norrisolide core in
Golgi localization and structure.
In conclusion, we have dissected the chemical origins of the
cellular phenotype of norrisolide using a variety of synthetic
analogues. We found that this natural product induces an irreversible
vesiculation of the Golgi complex in intact cells by binding to the
Golgi membranes. This binding is attributed exclusively to the
presence of the perhydroindane core that acts as the recognition
element. Attachment of this core to a γ-lactone-γ-lactol side chain
or similar motifs, such as in 11, leads to a reversible Golgi
vesiculation. This vesiculation becomes irreversible when the side
chain is armed with electrophilic functionalities, such as the C19
acetyl group of 1 or the bisepoxide motif of 10. The latter
modification attests to the potential of the epoxide group for the
development of affinity probes for protein labeling.12,13 Moreover,
compound 10 induces an identical phenotype to that of norrisolide,
suggesting that it may be used to isolate the biological target of
this natural product.
a Reagents and conditions: (a) BnBr (2.5 equiv), K2CO3 (4.0 equiv),
acetone, reflux, 6 h, 95%; (b) NaOH (1 N), THF, 50 °C, 4 h, 99%; (c) 8
(1.7 equiv), 9 (1.0 equiv), EDC (1.7 equiv), DMAP (1.7 equiv), CH2Cl2,
25 °C, 24 h, 92%; (d) 10% Pd/C (0.1 equiv), H2 (1 atm), EtOAc, 25 °C, 6
h, 92%; (e) epi-bromohydrin (4.0 equiv), CsCO3 (4.0 equiv), DMF, 25 °C,
12 h, 75%.
Acknowledgment. Dedicated to Professor K. C. Nicolaou on
the occasion of his 60th birthday. Financial support by the NIH
(CA 086079 to E.A.T., and GM 46224 and GM 53747 to V.M.) is
gratefully acknowledged.
Supporting Information Available: Procedures for the synthesis,
characterization and cellular evaluation, and immunofluorescence
processing of all compounds. This material is available free of charge
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