14-(β-D-2-脱氧-吡喃核糖基)-萘并[2,1-_]吡咯[3,4-c]咔唑-5,7(6H,12H)-二酮的合成、细胞毒与细胞周期抑制活性研究.docVIP

  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