Discovery and preclinical evaluation of 7-benzyl-N-(substituted)-pyrrolo[3,2-d]pyrimidin-4-amines as single agents with microtubule targeting effects along with triple-acting angiokinase inhibition as antitumor agents

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• 作者：Roheeth Kumar Pavana^a ; Shruti Choudhary^a ; Anja Bastian^b ; Michael A. Ihnat^c ; Ruoli Bai^d ; Ernest Hamel^d ; Aleem Gangjee^a ; ^{gangjee@duq.edu}
• 关键词：AA ; antiangiogenic agents ; MTA ; microtubule targeting agents ; VEGFR-2 ; vascular endothelial growth factor receptor-2 ; PDGFR-β ; platelet-derived growth factor receptor-β ; CAM ; chorioallantoic membrane ; CA ; combretastatin A-4 ; Pgp ; P-glycoprotein ; EGFR ; epidermal growth factor receptor ; TBS ; Tris-buffered saline ; HRP ; horseradish peroxidase ; PY ; phosphotyrosine
• 刊名：Bioorganic & Medicinal Chemistry
• 出版年：2017
• 出版时间：15 January 2017
• 年：2017
• 卷：25
• 期：2
• 页码：545-556
• 全文大小：2101 K
• 卷排序：25

文摘

The utility of cytostatic antiangiogenic agents (AA) in cancer chemotherapy lies in their combination with cytotoxic chemotherapeutic agents. Clinical combinations of AA with microtubule targeting agents (MTAs) have been particularly successful. The discovery, synthesis and biological evaluations of a series of 7-benzyl-N-substituted-pyrrolo[3,2-d]pyrimidin-4-amines are reported. Novel compounds which inhibit proangiogenic receptor tyrosine kinases (RTKs) including vascular endothelial growth factor receptor-2 (VEGFR-2), platelet-derived growth factor receptor-β (PDGFR-β) and epidermal growth factor receptor (EGFR), along with microtubule targeting in single molecules are described. These compounds also inhibited blood vessel formation in the chicken chorioallantoic membrane (CAM) assay, and some potently inhibited tubulin assembly (with activity comparable to that of combretastatin A-4 (CA)). In addition, some of the analogs circumvent the most clinically relevant tumor resistance mechanisms (P-glycoprotein and β-III tubulin expression) to microtubule targeting agents (MTA). These MTAs bind at the colchicine site on tubulin. Two analogs displayed two to three digit nanomolar GI50 values across the entire NCI 60 tumor cell panel and one of these, compound 7, freely water soluble as its HCl salt, afforded excellent in vivo antitumor activity against an orthotopic triple negative 4T1 breast cancer model and was superior to doxorubicin.