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14-β-D-2-脱氧-吡喃核糖基-萘并[2,1-_]吡咯[3,4-c]咔唑-5,76H,12H-二酮的合成、细胞毒与细胞周期抑制活性研究
Synthesis and biological evaluation of cytotoxic activity of
14-(β-D-2-deoxy-ribopyranosyl)-naphtho
[2,1-a]pyrrolo[3,4-c]carbazole-5,7(6H,12H)–dione#
5
10
15
DING Ning*
(School of Pharmacy, Fudan University)
Abstract: Naphtho[2,1-a]pyrrolo[3,4-c]carbazole-5,7(6H,12H)-dione (NPCD) is known to be a very
potent and selective cyclin D1-CDK4 inhibitors and could induce strong G1 phase arrest in breast
tumor cell lines. In this work, the synthesis and biological evaluation of cytotoxic activity of a novel
NPCD glycoside, 14-(α-L-rhamnopyranosyl)-naphtho[2,1-a]pyrrolo[3,4-c] carbazole-5,7 (6H,12H)-
dione (1) were reported. The results showed the NPCD glycoside 1 displayed strong tumor cell growth
inhibitory activities in the range of micromolar IC50 towards a broad spectrum of tumor cell lines.
Analysis of cell cycle profiles revealed that NPCD glycoside 1 arrested the cells at different phases
depending on the cell lines.)
Key words: indolocarbazole; cytotoxicity; rebeccamycin; cell-cycleglycoside
0 Introduction
Indolo[2,3-?]pyrrolo[3,4-c]carbazole alkaloids form a class of compounds
endowed with potent antitumor, antiviral, and antimicrobial activities1-2. This family
has raised considerable attention because of their central role in the regulation of cell
20
cycle
progression
and
specific
enzymatic
inhibitions3.
Recently,
several
aryl[?]pyrrolo[3,4-c]carbazole analogues have been developed as very potent CDK
(cyclin-dependent
kinases)
inhibitors4.
For
instance,
naphtho[2,1-a]pyrrolo[3,4-c]carbazole-5,7(6H,12H)-dione5 (NPCD, Fig.1), in which
one indole ring is replaced by a naphthyl ring, is a very potent and selective cyclin
25
D1-CDK4 inhibitors. The recent strong evidence on the link between D1/CDK4
activity and tumor proliferation has focused a considerable amount of interest in
CDK4 inhibitors6. Our previous work
7
has also proved that NPCD can cause
long-lasting growth arrest in G1 phase and cell death of some breast cancer cell lines
a
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