Bioorganic & Medicinal Chemistry Letters
Synthesis and hypoglycemic activity of 9-O-(lipophilic group
substituted) berberine derivatives
Shanshan Zhang a, Xiaohong Wang a, Weicheng Yin b, Zhenbao Liu c, Mi Zhou b, Daipeng Xiao a,
Yanfei Liu a, , Dongming Peng b,
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a Department of Pharmaceutical Engineering, School of Chemistry and Chemical Engineering, Central South University, Changsha 410083, China
b Department of Medicinal Chemistry, School of Pharmacy, Hunan University of Chinese Medicine, Changsha 410208, China
c Department of Pharmaceutics, School of Pharmaceutical Sciences, Central South University, Changsha 410013, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of 9-O-(lipophilic group substituted) berberine derivatives were synthesized and evaluated for
their cytotoxicity and hypoglycemic activity against HepG2 cells. All the results indicated that most of
the synthesized compounds exhibited lower cytotoxicity and a certain degree of hypoglycemic activity.
Especially the compounds 5g and 5h displayed dramatically increased hypoglycemic activity compared
with berberine, and the cytotoxicity maintained or even lower than berberine, indicating that they are
potential candidates for new anti-type 2 diabetes mellitus drugs.
Received 6 June 2016
Revised 28 July 2016
Accepted 10 August 2016
Available online 11 August 2016
Keywords:
Berberine derivatives
Synthesis
Ó 2016 Elsevier Ltd. All rights reserved.
Cytotoxicity
Hypoglycemic activity
Structure–activity analysis
Diabetes, one of the most common chronic metabolic disorder
diseases in the world, has been characterized with high glucose
concentration in the blood, which is termed hyperglycemia. The
cases of diabetes are estimated to be 171 million worldwide in
2000, and it is anticipated that the number will become over two
fold by 2030.1 Diabetes can be divided into type 1 diabetes mellitus
(T1DM) and type 2 diabetes mellitus (T2DM). T2DM is the most
common one, occupying 90% of diabetics. Compared with T1DM,
which is attributed to an absolute deficiency of insulin, T2DM is
accompanied with insulin resistance and impaired insulin secre-
tion.2 T1DM is usually treated with intravenous injection of insulin,
while T2DM is treated with oral hypoglycemic agents, including
insulin secretagogues (sulfonylureas, glinides, meglitinides), incre-
tin based medicine (exenatide, dipeptidyl peptidase 4 inhibitors,
liraglutide, pramlintide, bromocriptine and insulin), insulin sensi-
tizers (biguanides and thiazolidinediones), and other medicines
(alpha-glucosidase inhibitors and sodium-glucose cotransporter 2
inhibitors) to maintain proper blood glucose level. However, cur-
rent anti-diabetic drugs usually have side effects, such as sulfony-
lureas always cause hypoglycemia and gastrointestinal reaction,
biguanides are associated with gastrointestinal complaints3 and
lactic acidosis, thiazolidinediones lead to peripheral edema, and
alpha glucosidase inhibitors cause intestinal disorder. All these dis-
advantages lead us to search therapeutic compound with enhanced
hypoglycemic activity.
Berberine (BBR, 1, Fig. 1), an isoquinoline alkaloid extracted
from a traditional Chinese herb Coptischinensis,4 has been exten-
sively used in traditional Chinese medicine and Ayurvedic.5 In
accordance with literatures, BBR has been applied in the treatment
of bacterial diarrhea6 and bacteriostasis.7 Other pharmacological
effects of BBR, such as anti-hyperlipidemic action,8 anti-inflamma-
tory,9 anticancer,10 and antileishmanial11 have also been reported.
Especially, researchers recently find that BBR is associated with
glucose homeostasis and hypoglycemic activity in T2DM.12
Although BBR shows capacity for the treatment of T2DM, its hypo-
glycemic effect is not effective enough to replace existing anti-dia-
betic agents in clinic. It is a current trend to improve hypoglycemic
effect of BBR by a variety of strategies. One of them is to improve
the bioavailability by changing the formulations. To name only a
few, Meng et al. developed an amorphous solid dispersion of BBR
with sodium caprate, which showed a superior hypoglycemic
effect compared to pure BBR.13 Lv et al. found that both BBR and
co-administration with sodium caprate orally could significantly
decrease fasting blood glucose and improve glucose tolerance in
diabetic rats.14 Pierro et al. proved that it was more effective in
reducing glycosylated hemoglobin by the association of BBR and
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Corresponding authors. Tel./fax: +86 731 88879616 (Y.L.), +86 731 85555868
(D.P.).
0960-894X/Ó 2016 Elsevier Ltd. All rights reserved.