血管新生抑制劑對癌細胞轉移之活性評估

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Title:	血管新生抑制劑對癌細胞轉移之活性評估
Authors:	呂玉玲
Contributors:	藥學系
Date:	2006
Issue Date:	2008-05-19 15:34:45 (UTC+8)
Publisher:	台南縣：嘉南藥理科技大學藥學系
Abstract:	為阻止惡性腫瘤細胞藉由新生血管增生作用，突破原來的生長區域、擴張生長，而使癌症一直擴展而蔓延到其他部位。近年來，抑制新血管增生成為治療癌症的新策略。研究惡性腫瘤時發現了各種不同的血管新生因子，其中以VEGF (vascular endothelial growth factor) 可由腫瘤細胞或巨噬細胞分泌，是促進內皮細胞增生；移動及存活的誘導因子，在腫瘤新血管生成過程中扮演最重要的角色。藉由抑制VEGF調控訊息的抗新血管增生之治療模式，對癌症病人而言，應是安全且副作用少的治療方式。為此抑制腫瘤細胞的新血管生成，VEGF接受器成為藥物設計的新標的。最近，應用小分子(anilinoquinazoline類衍生物) 來抑制KDR之tyrosine kinase的活性，它們能干擾VEGF接受器之RTK的活性，結果顯示，此小分子可有效抑制血管新生作用。本計劃以anilinoquinazoline類衍生物當模型，將quinazoline與aniline之連接方式以sulfonylamide (-SO2NH-)取代-NH-，以人類VEGFR2 (KDR)的 X光結晶構形ATP 結合中心當作docking region，以ZD6474 及sulfonylamide analog 5, 利用Autodock的過程作研究，發現sulfonylamide analog之sulfonyl基團可與ATP 結合中心之胺基酸有額外的氫鍵結合機會。 Pathological angiogenesis has been associated with a variety of disease states including diabetic retinopathy, psoriasis, cancer, rheumatoid arthritis, atheroma, Kaposi’s sarcoma, and haemangioma. Recently evidence indicates that VEGF (vascular endothelial growth factor) is an important stimulator of both normal and pathological angiogenesis. VEGF has been shown to be secreted by human tumor cell lines in culture. Moreover, VEGF protein has been identified for VEGF receptor FlK-1/KDR in primary tumors of breast, colon, and renal origin. Blockade of VEGF signal transduction by sequestration of VEGF with antibody has been shown to prevent tumor growth. VEGF RTKs must, therefore, be viewed as attractive therapeutic targets for the development of novel agents to treat angioproliferative diseases such as cancer. Recently, a series of substituted 4-anilinoquinazolines have potential inhibitors of VEGF receptor (Flt and KDR) tyrosine kinase activity. In this report, we replaced linkage of 4-anilinoquinazolines by sulfonamide link. To evaluated quinazoline phenyl sulfonamide derivatives for KDR by Autodock program. The results showed hydrogen binding between sulfonylamide analog 5 and ATP binding site of KDR.
Relation:	計畫編號 : CNPH9510
Appears in Collections:	[Dept. of Pharmacy] CNU Project

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