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.
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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DOI：
10.1016/j.bmc.2016.11.026
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发表时间：
2017-01-15
影响因子：
3.5
通讯作者：
Gangjee A
中科院分区：
文献类型：
--
作者：
Pavana RK;Choudhary S;Bastian A;Ihnat MA;Bai R;Hamel E;Gangjee A
细胞抑制抗血管生成药物（AA）在肿瘤化疗中的应用在于它们与细胞毒性化疗药物的联合使用。AA与微管靶向药物（mta）的临床联合治疗尤其成功。报道了一系列7-苄基n-取代吡咯[3,2-d]嘧啶-4胺的发现、合成和生物学评价。本文描述了抑制血管生成受体酪氨酸激酶（RTKs）的新化合物，包括血管内皮生长因子受体-2 （VEGFR-2）、血小板衍生生长因子受体-β (PDGFR-β)和表皮生长因子受体（EGFR），以及单分子微管靶向。在鸡绒毛膜尿囊膜（CAM）实验中，这些化合物还能抑制血管形成，一些化合物还能有效抑制微管蛋白的组装（其活性与combretastatin A-4 （CA）相当）。此外，一些类似物绕过了临床上最相关的肿瘤耐药机制（p -糖蛋白和β-III微管蛋白表达）对微管靶向药物（MTA）的抵抗。这些mta在微管蛋白上的秋水仙碱位点结合。两种类似物在整个NCI 60肿瘤细胞组中显示出两到三位数纳摩尔的GI50值，其中一种化合物7，其HCl盐可自由溶于水，对原位三阴性4T1乳腺癌模型具有出色的体内抗肿瘤活性，优于阿霉素。
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.
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DOI：
10.1016/j.jconrel.2012.04.014
发表时间：
2012-12-10
期刊：
Journal of controlled release : official journal of the Controlled Release Society
影响因子：
--
作者：
Denison TA;Bae YH
通讯作者：
Bae YH
影响因子：
7.3
作者：
Gangjee, Aleem;Zaware, Nilesh;Raghavan, Sudhir;Ihnat, Michael;Shenoy, Satyendra;Kisliuk, Roy L.
通讯作者：
Kisliuk, Roy L.
影响因子：
5.7
作者：
Bello, Ezia;Taraboletti, Giulia;Damia, Giovanna
通讯作者：
Damia, Giovanna
DOI：
10.1016/0304-4165(81)90231-2
发表时间：
1981-01-01
期刊：
BIOCHIMICA ET BIOPHYSICA ACTA
影响因子：
--
作者：
HAMEL, E;LIN, CM
通讯作者：
LIN, CM
影响因子：
2.9
作者：
HAMEL, E;LIN, CM
通讯作者：
LIN, CM