DOI: 10.1002/chem.201805420
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Natural Products
Synthesis of the seco-Limonoid BCD Ring System Identifies a
Hsp90 Chaperon Machinery (p23) Inhibitor
David M. Pinkerton,[a] Sharon Chow,[a] Nada H. Eisa,[b, c] Kashish Kainth,[b]
within this group. For example the Hsp90 inhibitor diacetylvila-
sinin (1)[8] maintains an intact ABCD limonoid ring skeleton,
Abstract: D-Ring-seco-limonoids (tetranortriterpenoids),
such as gedunin and xylogranin B display anti-cancer ac-
tivity, acting via inhibition of Hsp90 and/or associated
chaperon machinery (e.g., p23). Despite this, these natural
products have received relatively little attention, both in
terms of an enabling synthetic approach (which would
allow access to derivatives), and as a consequence their
structure–activity relationship (SAR). Disclosed herein is a
generally applicable synthetic route to the BCD ring
system of the seco-D-ring double bond containing limo-
noids. Furthermore, cell based assays revealed the first
skeletal fragment that exhibited inhibition of the p23
enzyme at a level which was equipotent to that of gedu-
nin, despite being much less structurally complex.
whereas Hsp90 inhibition was also observed with the C-ring
seco-limonoid deacetylsalannin (2),[8] the A,D-ring seco-limo-
noid 7a-limonylacetate (3),[9] and kotschyin A (4) [and D (5)],[10]
which are members of the B,D-ring seco class (Figure 1). Mem-
bers of this later B,D-seco class also include andirolide N (6),[11]
which inhibits sphingomyelin biosynthesis,[12] and xylogranin B
(7) that affects Wnt signaling,[13] whereas the A,D-seco-limonoid
deoxylimonin (8) displays anti-tumor activity;[14] however, these
three examples (i.e., 6–8) all contain a double bond in the D
ring (Figure 1). The most prominent limonoid in the anti-
cancer/Hsp90 space is the D-ring seco member gedunin (9),[15]
which has an additional E-ring epoxide moiety also seen in 3
(Figure 1). Interestingly, gedunin was originally identified
through a connectivity map to exert antiproliferative activity
through Hsp90.[16] Shortly after this disclosure, gedunin was de-
termined to engage Hsp90 through a mechanism unrelated to
competitive inhibition of adenosine triphosphate (ATP).[17] In-
stead, gedunin and close relative 7-oxo-gedunin (10) (Figure 1)
were found to inactivate the Hsp90 co-chaperone enzyme
p23.[18] During this time only gedunin (9) has undergone exten-
sive medicinal chemistry development, but these studies have
concentrated on the peripheral functional groups in the pur-
suit of identifying more active inhibitors and understanding
the key pharmacophore of the molecule.[19,20]
Heat shock protein 90 (Hsp90),[1] and the Hsp90 co-chaperone
machinery,[2] are molecular targets that are currently being clin-
ically evaluated for their effectiveness in cancer therapy.[3] Nat-
ural products have been found to inhibit both the N- and C-
terminus domains of this suite of enzymes.[4,5] Within this
arena various tetranortriterpenoids (limonoids[6]) have been
identified as Hsp90 and/or co-chaperone inhibitors. Further-
more, they display significant anti-cancer activity.[7]
Attempting to understand structure–activity relationships
amongst the limonoids, however, has been complicated by the
wide variety of highly oxidized and rearranged skeletal classes
In terms of accessing skeletal fragments of the limonoid
skeleton, the total syntheses of only a few limonoids have
been reported [e.g., andirolide N (6) by Newhouse,[21] limonin
(11) by Yamashita,[22] and mexicanolide (12) by our group,[23]],
along with methodological studies (e.g., Fernꢀndez-Mateos,[24]
Lhommet,[25] and by our group[26]),[27] but these efforts did not
include biological evaluation against cancer cell lines nor
Hsp90 machinery. This unfortunate situation has resulted in a
lack of general understanding as to the potential active phar-
macophore of these molecules. Inspired by this circumstance,
we explored the seco-limonoid BCD ring system, focusing on
developing and understanding a structure activity relationship
(SAR) around the Hsp90 co-chaperone enzyme p23, with the
aim of unearthing less complex inhibitors.
[a] Dr. D. M. Pinkerton, Dr. S. Chow, T. J. Vanden Berg, Dr. J. M. Burns,
Assoc. Prof. L. W. Guddat, Prof. C. M. Williams
School of Chemistry and Molecular Biosciences
University of Queensland, Brisbane, 4072, Queensland (Australia)
[b] N. H. Eisa, K. Kainth, Prof. A. Chadli
Georgia Cancer Center, Molecular Oncology Program
Augusta University, Augusta, GA, 30912 (USA)
[c] N. H. Eisa
Biochemistry Department, Faculty of Pharmacy
Mansoura University, Mansoura (Egypt)
[d] Dr. G. P. Savage
Before SAR could be performed, a general and flexible syn-
thetic route to the BCD ring system was required. This aspect
was achieved, albeit with numerous unforeseen challenges, by
drawing on our previous synthetic experiences with mexicano-
lide (12)[23] and gedunin (9)[26] (Scheme 1).
CSIRO Manufacturing, Ian Wark Laboratory
Melbourne, 3168, Victoria (Australia)
Supporting information and the ORCID identification number(s) for the
author(s) of this article can be found under:
Chem. Eur. J. 2018, 24, 1 – 6
1
ꢁ 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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