Bioorganic & Medicinal Chemistry Letters
New homoisoflavonoid analogues protect cells by regulating autophagy
Li-She Gan a, Lin-Wei Zeng a, Xiang-Rong Li b, Chang-Xin Zhou a, Jie Li b,
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a College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou 310058, China
b School of Medicine, Zhejiang University City College, 48 Huzhou Road, Hangzhou 310015, China
a r t i c l e i n f o
a b s t r a c t
Article history:
As a special group of naturally occurring flavonoids, homoisoflavonoids have been discovered as active
components of several traditional Chinese medicines for nourishing heart and mind. In this study, twenty
homoisoflavonoid analogues, including different substitution groups on rings A and B, as well as
heteroaromatic B ring, were synthesized and evaluated for their cardioprotective and neuroprotective
activities. In a H2O2-induced H9c2 cardiomyocytes injury assay, nine homoisoflavonoid analogues
showed promising activities in the same level as the positive control, diazoxide. Six cardioprotective
compounds with representative structure diversities were then evaluated for their neuroprotective
effects on MPP+ induced SH-SY5Y cell injury model. Furthermore, autophagy inducing monodansylcadav-
erine (MDC) fluorescence staining methods and molecular docking studies indicated the action mecha-
nism of these compounds may involve autophagy regulating via class I PI3K signaling pathway.
Ó 2017 Elsevier Ltd. All rights reserved.
Received 14 November 2016
Revised 19 January 2017
Accepted 27 January 2017
Available online xxxx
Keywords:
Homoisoflavonoid
Synthesis
Cardioprotection
Neuroprotection
Autophagy
Homoisoflavonoids are a special group of naturally occurring
flavonoids with an additional carbon between the B and C rings
on the isoflavonoid skeleton.1 Up to date, over 200 homoisoflavo-
noids have been isolated from plant genus of Ophiopogon,
Polygonatum, Caesalpinia, Muscari, Eucomis, etc.2,3 and some of
these plants, such as O. japonicas, P. odoratum and P. cyrtonema,
were frequently used in TCM for nourishing heart and mind.
Accordingly, these structures have demonstrated biological activi-
ties including anti-inflammation,4 antioxidation,5 anti-pathogen,6
antitumor,7 and cardiovascular protection.8 In our previous stud-
ies, a series of homoisoflavonoids were isolated from O. japonicas9
and P. cyrtonema10 and their cytotoxic, myocardial protective, and
antioxidative activities were evaluated. These minor components
have demonstrated promising bioactivity while their contents in
plants are very low. Therefore, synthetic approaches have been
tried for homoisoflavonoid skeletons by several groups since
1980s and more than twenty homoisoflavonoid derivatives have
been reported.11–14
activities and representative structure diversities were evaluated
for their neuroprotective effects by MPP+ induced SH-SY5Y cell
injury model. The action mechanism of these compounds was
studied by autophagy inducing monodansylcadaverine (MDC) flu-
orescence staining methods together with molecular docking mod-
eling. Regulating effects of these compounds on autophagy via
class I PI3K signaling pathway have been revealed.
Schemes 1–3 summarized procedures for preparing three series
of homoisoflavonoid analogues. Synthesis of homoisoflavonoid
derivatives 6a–f were depicted in Scheme 1A. Friedel-Craft’s acyla-
tion of phloroglucinol with acetonitrile in the presence of phospho-
rus oxychloride and boron trifluoride gave ketone 1.15 Ketone 1
was then protected as benzyl ether 2 by using standard condi-
tions.16 Subsequently, condensation of compound 2 with substi-
tuted benzaldehyde 3a–f resulted in chalcones 4a–f, which were
then hydrogenated under the catalysis of palladium/carbon to
afford 5a–f and the benzyl protecting groups were removed simul-
taneously.17,18 Finally, cyclization of 5a–f with methanesulfonyl
chloride in the presence of the catalytic boron trifluoride provided
homoisoflavonoids 6a–f.19 For the syntheses of homoisoflavonoid
10a–d, compounds 7a and 7b were chosen as the starting materi-
als (Scheme 1B). After protection of the hydroxy group of 7 with
benzyl group, chalcones 9a–d were obtained in high yields
(80–83% in two steps) by condensation with p-anisicaldehyde
and o-anisaldehyde, respectively. With the key intermediates
9a–d in hand, homoisoflavonoid derivatives 10a–d were prepared
by applying the same reduction/cyclization sequence as 6 series.
In the current study, twenty homonisoflavonoid derivatives
Fig. 1, including different substitution groups on rings A and B, as
well as heteroaromatic B ring analogues, were synthesized respec-
tively from phloroglucinol, 2,4-dihydroxyacetophenone, and 2,6-
dihydroxyacetophenone. Myocardial protective activities of all
compounds were evaluated by H2O2-induced H9c2 cardiomy-
ocytes injury model. Furthermore, six compounds with promising
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Corresponding author.
0960-894X/Ó 2017 Elsevier Ltd. All rights reserved.