11H-Pyrido[3′,2′:4,5]pyrrolo[3,2-c]cinnoline and Pyrido[3′,2′:4,5]pyrrolo[1,2-c][1,2,3]benzotriazine: Two New Ring Systems with Antitumor Activity

被引：53

作者：

Parrino, Barbara ^{[1
]}

Carbone, Anna ^{[1
]}

Muscarella, Marina ^{[1
]}

Spano, Virginia ^{[1
]}

Montalbano, Alessandra ^{[1
]}

Barraja, Paola ^{[1
]}

Salvador, Alessia ^{[2
]}

Vedaldi, Daniela ^{[2
]}

Cirrincione, Girolamo ^{[1
]}

Diana, Patrizia ^{[1
]}

机构：

[1] Univ Palermo, Dipartimento Sci & Tecnol Biol Chim & Farmaceut S, I-90123 Palermo, Italy

[2] Univ Padua, Dipartimento Sci Farmaco, I-35121 Padua, Italy

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2014年 / 57卷 / 22期

关键词：

MARINE ALKALOID NORTOPSENTIN; TYROSINE KINASE INHIBITORS; ANTIPROLIFERATIVE ACTIVITY; TOPOISOMERASE-I; ANTICANCER AGENTS; POTENT ANTITUMOR; ANALOGS; DERIVATIVES; APOPTOSIS; BENZOTRIAZINES;

D O I：

10.1021/jm501244f

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Derivatives of new ring systems 11H-pyrido[3′,2′:4,5]pyrrolo[3,2-c]cinnoline and pyrido[3′,2′:4,5]pyrrolo[1,2-c][1,2,3]benzotriazine have been prepared from the key intermediates 2-(1H-pyrrolo[2,3-b]pyridin-2-yl)anilines in excellent yields (94-99%) and screened by the National Cancer Institute (Bethesda, MD) on about 60 human tumor cell lines derived from nine cancer cell types. The tested compounds exhibited antiproliferative activity against all the human cell lines, showing comparable MG-MID (mean graph midpoint) values in the range of 0.74-1.15 μM. A particular efficacy was observed against the leukemia subpanel (GI50 = 0.73-0.0090 μM). Flow cytometric analysis of the cell cycle demonstrated an increase in the percentage of cells in the G2/M phase. The compounds caused apoptosis of the cells, mitochondrial depolarization, generation of reactive oxygen species, and activation of caspase-3, caspase-8, and caspase-9. Moreover, they acted as topoisomerase I inhibitors. © 2014 American Chemical Society.

引用

页码：9495 / 9511

页数：17

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