Single agents with designed combination chemotherapy potential: synthesis and evaluation of substituted pyrimido[4,5-b]indoles as receptor tyrosine kinase and thymidylate synthase inhibitors and as antitumor agents.
Single agents with designed combination chemotherapy potential: synthesis and evaluation of substituted pyrimido[4,5-b]indoles as receptor tyrosine kinase and thymidylate synthase inhibitors and as antitumor agents.
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DOI：
10.1021/jm9011142
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发表时间：
2010-02-25
影响因子：
7.3
通讯作者：
Kisliuk, Roy L.
中科院分区：
文献类型：
--
作者：
Gangjee, Aleem;Zaware, Nilesh;Raghavan, Sudhir;Ihnat, Michael;Shenoy, Satyendra;Kisliuk, Roy L.
抗血管生成剂（AA）与细胞毒性剂的组合具有 显示出显著的前景，目前有几个这样的临床试验 正在进行中我们设计、合成并评估了两种化合物， 抑制血管内皮生长因子受体-2（VEGFR-2）和血小板 用于抗血管生成的衍生生长因子受体-β（PDGFR-β） 并抑制人胸苷酸合酶（hTS）的细胞毒性作用 在单一代理人。这些化合物的合成涉及亲核反应， 共同中间体置换 5-氯-9H-嘧啶并[4，5-B]吲哚-2，4-二胺 与适当的苯硫酚。这两种单药的抑制效力 针对VEGFR-2、PDGFR-β和hTS的药物优于或接近于 标准在C科洛-205异种移植小鼠模型中，一种类似物显著降低了小鼠的存活率。 肿瘤生长减少（35 mg/kg时TGI = 76%），肝脏 与标准药物和对照相比， 因此显示出有效的肿瘤生长抑制、转移抑制 和体内抗血管生成作用。这些化合物提供组合 在单一药剂中的化疗潜力。
Combinations of antiangiogenic agents (AAs) with cytotoxic agents have shown significant promise and several such clinical trials are currently underway. We have designed, synthesized and evaluated two compounds that each inhibit vascular endothelial growth factor receptor-2 (VEGFR-2) and platelet derived growth factor receptor-beta (PDGFR-β) for antiangiogenic effects and also inhibit human thymidylate synthase (hTS) for cytotoxic effects in single agents. The synthesis of these compounds involved the nucleophilic displacement of the common intermediate 5-chloro-9H-pyrimido[4,5-b]indole-2,4-diamine with appropriate benzenethiols. The inhibitory potency of both these single agents against VEGFR-2, PDGFR-β and hTS is better than or close to standards. In a COLO-205 xenograft mouse model one of the analogs significantly decreased tumor growth (TGI = 76% at 35 mg/kg), liver metastases and tumor blood vessels compared to a standard drug and to control and thus demonstrated potent tumor growth inhibition, inhibition of metastasis and antiangiogenic effects in vivo. These compounds afford combination chemotherapeutic potential in single agents.
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影响因子：
50.3
作者：
Casanovas, O;Hicklin, DJ;Hanahan, D
通讯作者：
Hanahan, D
影响因子：
3.5
作者：
Gangjee, Aleem;Namjoshi, Ojas A.;Warnke, Linda A.
通讯作者：
Warnke, Linda A.
影响因子：
3
作者：
Clamp, A. R.;Schoeffski, P.;Jayson, G. C.
通讯作者：
Jayson, G. C.
DOI：
10.1107/s0907444903014963
发表时间：
2003-09-01
期刊：
ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY
影响因子：
--
作者：
Cody, V;Luft, JR;Gangjee, A
通讯作者：
Gangjee, A
影响因子：
2.9
作者：
DAVIES, JF;DELCAMP, TJ;KRAUT, J
通讯作者：
KRAUT, J