| RRC ID |
54757
|
| 著者 |
Fukuda T, Nanjo Y, Fujimoto M, Yoshida K, Natsui Y, Ishibashi F, Okazaki F, To H, Iwao M.
|
| タイトル |
Lamellarin-inspired potent topoisomerase I inhibitors with the unprecedented benzo[g][1]benzopyrano[4,3-b]indol-6(13H)-one scaffold.
|
| ジャーナル |
Bioorg Med Chem
|
| Abstract |
A new class of topoisomerase I inhibitors containing the unprecedented benzo[g][1]benzopyrano[4,3-b]indol-6(13H)-one (abbreviated as BBPI) ring system have been developed based on structure-activity relationship studies of the cytotoxic marine alkaloid lamellarin D. The pentacyclic BBPI scaffold was constructed from N-tert-butoxycarbonylpyrrole by sequential and regioselective functionalization of the pyrrole core using directed lithiation, conventional electrophilic substitution, and palladium-catalyzed cross-coupling reactions. Further N-alkylation of the scaffold followed by selective deprotection of the O-isopropyl group produced a range of N-substituted BBPI derivatives. The BBPIs thus prepared exhibited potent topoisomerase I inhibitory activity in DNA relaxation assays. The activities of BBPIs were higher than those of lamellarin D and camptothecin; they showed potent and selective antiproliferative activity in the panel of 39 human cancer cell lines established by Japanese Foundation for Cancer Research. COMPARE analyses indicated that the inhibition patterns of the BBPIs correlated well with those of the known topoisomerase I inhibitors such as SN-38 and TAS-103. The water-soluble valine ester derivative exhibited antitumor activity in vivo against murine colon carcinoma colon 26. The activity was comparable to that of the approved anticancer agent irinotecan.
|
| 巻・号 |
27(2)
|
| ページ |
265-277
|
| 公開日 |
2019-1-15
|
| DOI |
10.1016/j.bmc.2018.11.037
|
| PII |
S0968-0896(18)31523-2
|
| PMID |
30553626
|
| MeSH |
Animals
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology
Antineoplastic Agents / therapeutic use*
Cattle
Cell Line, Tumor
Cell Proliferation / drug effects
Colonic Neoplasms / drug therapy
Coumarins / chemical synthesis
Coumarins / chemistry
Coumarins / pharmacology
Coumarins / therapeutic use*
Drug Design
Drug Screening Assays, Antitumor
Humans
Indoles / chemical synthesis
Indoles / chemistry
Indoles / pharmacology
Indoles / therapeutic use*
Male
Mice, Inbred BALB C
Molecular Structure
Structure-Activity Relationship
Topoisomerase I Inhibitors / chemical synthesis
Topoisomerase I Inhibitors / chemistry
Topoisomerase I Inhibitors / pharmacology
Topoisomerase I Inhibitors / therapeutic use*
|
| IF |
2.802
|
| 引用数 |
4
|
| リソース情報 |
| ヒト・動物細胞 |
Colon-26(RCB2657) |
