Bioorganic & Medicinal Chemistry Letters
Synthesis and cytotoxicity of novel imidazo[4,5-d]azepine compounds
derived from marine natural product ceratamine A
a
a
⇑
Xuan Pan , Lulu Tao , Ming Ji, Xiaoguang Chen, Zhanzhu Liu
State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical
Sciences, Beijing 100050, PR 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 novel imidazo[4,5-d]azepine compounds derived from marine natural product ceratamine A
were designed and synthesized in 7 steps. Most compounds exhibited comparable cytotoxicity against
five human cancer cell lines (HCT-116, HepG2, BGC-823, A549 and A2780) to natural product ceratamine
A. Compound 1k, bearing methoxy group at C-14, C-15 and C-16, showed the best in vitro cytotoxicity,
which was better than ceratamine A. The structure and activity relationships study showed that the ben-
zyloxymethyl group on N-3 played an important role on the cytotoxicity.
Received 21 December 2017
Revised 1 February 2018
Accepted 2 February 2018
Available online xxxx
Keywords:
Ó 2018 Elsevier Ltd. All rights reserved.
Ceratamine A
Microtubule
Heck reaction
Anticancer
Over the past 30 years, marine natural products have gained a
1
lot of attention as an important source of drug candidates. Several
anticancer drugs derived from marine natural products have
2
achieved great successes in clinic. This trend indicates that marine
natural products would continue to play a key role in anticancer
3
drug discovery.
Ceratamine A (Fig. 1) is a heterocyclic alkaloid isolated from
marine sponge Pseudoceratina sp., which displayed potent antimi-
totic activity through promoting tubulin polymerization. The fact
that ceratamine A has a totally different binding site on micro-
tubule from paclitaxel makes it a promising lead compound in
anticancer drug discovery.4 However, the lack of availability from
natural source brings huge difficulty in its further biological
evaluation.
Fig. 1. Marine natural product ceratamine A.
(
HCT-116, HepG2, BGC-823 and A2780) to ceratamine A and better
cytotoxicity against A549 than ceratamine A (Fig. 2). Because the
synthesis of intermediate 1a was apparently easier than cer-
atamine A and its analogues, we attempted to synthesize some
derivatives with the imidazo[4,5-d]azepine skeleton in order to
discover potential anticancer candidate with simpler structure.
In this paper, a series of analogues of compound 1a as cer-
atamine A simplified derivatives were synthesized in 7 steps as
depicted in Scheme 1. The synthetic route generally follows that
In our previous work, we have reported an efficient approach to
synthesize ceratamine A5 and its analogues.6 Some analogues
exhibited slight increases in cytotoxicity compared with cer-
atamine A, and a preliminary structure and activity relationship
was obtained. It was found that the introduction of bulky groups
at C-14 and C-16 could increase the cytotoxity, and that the sub-
stituents on N-7 played a significant role on high potency. During
the evaluation of cytotoxicity, we were pleased to find that the
6
reported by us previously. The key step was to employ Heck reac-
6
intermediate 1a with the imidazo[4,5-d]azepine skeleton exhib-
7
tion to construct the imidazo[4,5-d]azepine core. Firstly, amine 5
was easily prepared from commercially available histamine dihy-
ited comparable cytotoxicity against four human cancer cell lines
drochloride over 4 steps. Treatment of amine 5 with substituted
cinnamic acids
6
generated by Knoevenagel condensation8
⇑
These authors contributed equally.
afforded compounds 7a-d in satisfying yields. Benzylation of 7a-
d with NaH afforded amides 8a-n. The target compounds 1a-n
a
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