Bioorganic & Medicinal Chemistry Letters
Synthesis and biological activity of (±)-7,3′,4′-trihydroxyhomoisoflavan
and its analogs
,
b
,
,e
Toshiro Noshitaa *, Kentaro Fujitac, Takeru Kogac, Hidekazu Ouchid, Akihiro Taia
a Faculty of Life and Environmental Sciences, Prefectural University of Hiroshima, 5562 Nanatsuka, Shobara, Hiroshima 727-0023, Japan
b Department of Pharmacy, Gifu University of Medical Science, 4-3-3 Nijigaoka, Kani, Gifu 509-0293, Japan
c Program in Biological System Sciences, Graduate School of Comprehensive Scientific Research, Prefectural University of Hiroshima, 5562 Nanatsuka, Shobara,
Hiroshima 727-0023, Japan
d Department of Pharmacy, Faculty of Pharmacy, Kindai University, 3-4-1 Kowakae, Higashiosaka, Osaka 577-8502, Japan
e Graduate School of Technology, Industrial and Social Sciences, Tokushima University, 2-1 Minami-Josanjima, Tokushima 770-8506, Japan
A R T I C L E I N F O
A B S T R A C T
Keywords:
Acetylcholinesterase (AChE) inhibitors and neurite outgrowth promoters are thought to alleviate the symptoms
of degenerative brain disorders, such as Alzheimer’s disease. We designed and synthesized a series of homo-
isoflavonoids based on the structure of natural homoisoflavan isolated from Dracaena cambodiana dragon’s
blood. The homoisoflavonoids were then evaluated as AChE inhibitors and neurite outgrowth promoters. The
catechol structure of the homoisoflavan B rings was important for AChE inhibition, and some of the homoiso-
flavonoids significantly promoted neurite outgrowth induced by nerve growth factor (NGF).
Dragon’s blood
Homoisoflavan
AChE inhibitory activity
Neurite outgrowth promoting activity
Dracaena cambodiana
The aging of Japanese society has been accompanied by an increase
in the incidence of dementia caused by Alzheimer’s disease (AD). Ac-
cording to the New Orange Plan to promote measures against dementia,
over 4,000,000 Japanese individuals had dementia in 2012.1 The inci-
dence of dementia has since increased, so the search for new drugs and
natural compounds that can alleviate the symptoms of dementia is
becoming increasingly important. Acetylcholinesterase (AChE) in-
hibitors are promising therapeutic agents for dementia. Several AChE
inhibitors, including donepezil,2 galantamine,3 and rivastigmine,4 are
currently used to treat mild and moderate AD symptoms. Neurodegen-
erative diseases, including AD, are characterized by dysfunction of the
nervous system due to the progressive disintegration of neuronal net-
works.5 Nerve growth factor (NGF) promotes the growth and prolifer-
ation of neurons,6 so increasing NGF activity with a pharmacological
agent could relieve the symptoms of AD and other types of dementia.
Compounds that can promote neurite outgrowth are thus of great
interest.7
synthesized the natural AChE inhibitor 3 and several analogs. The
neurite outgrowth promoting activity of each compound was then
evaluated by performing an AChE bioassay.
The synthetic route for 7,3′,4′-trihydroxyhomoisoflavan (3) is shown
in Scheme 1. The homoisoflavone skeleton was synthesized using Vils-
meier reagent, which was obtained by mixing methanesulfonyl chloride
with dihydrochalcone derived from 4-benzyloxy-2-hydroxy acetophe-
none9 and 3,4-dimethoxybenzaldehyde according to the method re-
ported by Gan et al.10 The homoisoflavone was then subjected to
catalytic hydrogenation using 10% Pd on carbon (Pd/C) as a catalyst. No
homoisoflavanone was obtained after this reduction step, and we were
unable to identify reduction conditions that would generate the homo-
isoflavanone. Demethylation was performed by treating the intermedi-
ate with BBr3. Thus, the desired homoisoflavan 3 afforded in five steps,
and the overall yield is 48%. The spectral profile of synthetic compound
3 was consistent with that of 3 from natural sources. Although we ob-
tained a racemate, this was the first complete synthesis reported for
7,3′,4′-trihydroxyhomoisoflavan (3). We then synthesized analogs 3a–3f
using the same synthetic route (Scheme 2). The chemical structures of all
In 2017, Li et al. reported isolating the flavonoids (R)-7,4′-dihy-
droxy-8-methylflavan (1), (R)-7,4′-dihydroxy-6-methylflavan (2), and
(R)-7,3′,4′-trihydroxyhomoisoflavan (3) from Dracaena cambodiana
dragon’s blood (Fig. 1). Compound 3 had particularly strong AChE
inhibiting activity,8 which made it an appropriate lead compound for
the development of therapeutic drugs to treat dementia. In this study, we
1
the synthetic compounds were determined by performing H and 13C
nuclear magnetic resonance spectroscopy and high-resolution mass
spectrometry. Only the catechol-type homoisoflavans with two phenolic
hydroxy groups on their B rings exhibited potent AChE inhibition. We
* Corresponding author at: Faculty of Pharmacy, Gifu University of Medical Science, 4-3-3 Nijigaoka, Kani, Gifu 509-0293, Japan.
Received 14 September 2020; Received in revised form 26 October 2020; Accepted 1 November 2020
Available online 6 November 2020
0960-894X/© 2020 Elsevier Ltd. All rights reserved.