Bioorganic & Medicinal Chemistry Letters
Analogues of the Inhoffen–Lythgoe diol with anti-proliferative
activity
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Albert M. DeBerardinis, Steven Lemieux, M. Kyle Hadden
Department of Pharmaceutical Sciences, University of Connecticut, 69 N Eagleville Rd, Unit 3092, Storrs, CT 06269-3092, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The anti-proliferative activity of a series of ester- and amide-linked Inhoffen–Lythgoe side chain ana-
logues is reported. Whereas the Inhoffen–Lythgoe diol was inactive in these studies, a number of aro-
matic and aliphatic ester-linked side chains demonstrated modest in vitro growth inhibition in two
human cancepar cell lines, U87MG (glioblastoma) and HT-29 (colorectal adenocarcinoma). Structure–
activity relationship (SAR) studies demonstrated the most active aromatic (13) and aliphatic (25 and
29) substituted analogues were approximately equipotent in U87MG and HT-29 cells. Further evaluation
of 13, 25, and 29 indicated these analogues do not activate canonical vitamin D signaling nor antagonize
Hedgehog (Hh) signaling. Thus, the cellular mechanism(s) that govern the anti-proliferative activity for
this class of truncated vitamin D-based structures appears to be different from classical mechanisms pre-
viously identified for these scaffolds.
Received 10 June 2013
Revised 19 July 2013
Accepted 24 July 2013
Available online 31 July 2013
Keywords:
Vitamin D
Inhoffen–Lythgoe diol
Vitamin D receptor
Colon cancer
Ó 2013 Elsevier Ltd. All rights reserved.
Glioblastoma
Recent years have seen a marked increase in research aimed at
the potential preventative and therapeutic anti-cancer effects of
demonstrated significantly reduced activity against HT-29 cells
(GI50 values = 66.5 17.9 and 49.7 13.9 M, respectively), a colo-
l
vitamin D.1–3 Much of this interest has focused on
1
a
,25-
,25(OH)2D3, calcitriol)], generally
acknowledged as the hormonally active form of vitamin
(Fig. 1). Administration of 1 ,25(OH)2D3 or its analogues results
rectal adenocarcinoma cell line that is commonly utilized as an
in vitro model system for evaluating the anti-proliferative activity
of vitamin D and related analogues. Interestingly, the Inhoffen-
Lythgoe (IL) diol, 5, was inactive against both cell lines. Taken to-
gether, these data suggest that modifications to the side chain re-
gion for truncated analogues of the vitamin D scaffold can yield
analogues that maintain anti-proliferative activity while complete
removal of the alkyl chain is detrimental to activity.
Additional experiments designed to identify the cellular mech-
anisms that govern the anti-proliferative activity of 3 and 4 dem-
onstrated that their in vitro activity was not mediated through
VDR activation, suggesting truncated analogues will not be prone
to the known detrimental side effects associated with the intact
vitamin D scaffold.6,7 With this in mind, we prepared and evalu-
ated the side chain benzoate of the IL diol, 6. This compound exhib-
ited modest anti-proliferative activity against both HT-29 and
U87MG cell lines (Table 1) and was intriguing as the first com-
pound in our studies demonstrating comparable activity against
both cell lines. In addition, the anti-proliferative activity of 6 was
not a result of activation of canonical VDR signaling. With this pre-
liminary data in hand, 6 served as the lead structure for a series of
truncated ‘northern’ region analogues of vitamin D, the synthesis
and in vitro evaluation of which is reported herein.
dihydroxyvitamin D3 [1
a
D
a
in significant in vitro and in vivo anti-cancer effects in prostate,
ovary, breast, and colon cancers.3,4 These effects are primarily
mediated through the vitamin D receptor (VDR), a nuclear receptor
that acts as a transcription factor to regulate apoptosis, prolifera-
tion, and differentiation.4 To date, the development of vitamin D
analogues as anti-cancer chemotherapeutics has proven largely
unsuccessful due to detrimental side effects associated with the
integral role of VDR signaling in calcium regulation, bone growth,
and neuromuscular function.
While each region of the vitamin D scaffold has been exten-
sively modified to identify analogues with improved anti-prolifer-
ative activity, the majority of these compounds retain the intact
vitamin D structure (A-, seco-B-, and CD-rings and the side
chain).1,5 To date, the evaluation of truncated forms of calcitriol
or vitamin D3 (VD3, 2) for their anti-proliferative activity has not
been explored. A recent study in our laboratory identified Grund-
mann’s alcohol, 3, and the related ‘northern’ region of vitamin
D2, 4, as having modest anti-proliferative activity against the glio-
blastoma cell line U87MG (GI50 values = 5.7 1.4 and
19.0 5.0
l
M, respectively).6 By contrast, both
3
and
4
Initially, we prepared 6 by directly coupling the IL diol with
benzoic acid using standard conditions (Scheme 1a). While this
route provided a modest yield of the desired analogue (55% yield),
it also resulted in significant formation of the dibenzoate ester 7
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