SYNTHESIS OF METHOTREXATE ANTIBODY CONJUGATES BY REGIOSPECIFIC COUPLING AND ASSESSMENT OF DRUG AND ANTITUMOR ACTIVITIES
SYNTHESIS OF METHOTREXATE ANTIBODY CONJUGATES BY REGIOSPECIFIC COUPLING AND ASSESSMENT OF DRUG AND ANTITUMOR ACTIVITIES
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DOI：
10.1021/jm00131a003
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发表时间：
1989-11-01
影响因子：
7.3
通讯作者：
GHOSE, T
中科院分区：
文献类型：
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作者：
KRALOVEC, J;SPENCER, G;GHOSE, T
为了增加药物活性的保留，使用区域特异性偶联来合成甲氨蝶呤 (MTX,1) 与正常兔 IgG (NRG) 和小鼠抗人肾癌单克隆 IgG (Dal K-20) 的缀合物。 MTXγ-甲酯(4)通过MTX的选择性酯化或通过4-氨基-4-脱氧-N10-甲基蝶酸(2)与合适的谷氨酸衍生物的偶联来制备。然后将MTXγ-甲酯(4)转化为相应的酰肼6。当通过使用亚硝酸叔丁酯或三氟乙醛将MTXγ-酰肼(6)转化为反应性酰化物质7时，形成酰胺连接的缀合物，其与天然IgG中的亲核中心(推测为ε-氨基)反应。当MTX-γ-酰肼(6)直接与首先被高碘酸盐氧化形成多醛IgG的IgG反应时，形成腙连接的缀合物。与对照非区域特异性缀合物相比，区域特异性合成的缀合物在二氢叶酸还原酶和人肾癌细胞(Caki-1)细胞集落形成的体外是更有效的抑制剂。
In order to increase the retention of drug activity, regiospecific coupling has been used to synthesize conjugates of methotrexate (MTX,1) with normal rabbit IgG (NRG) and a mouse anti-human renal cancer monoclonal IgG (Dal K-20). MTX .gamma.-methyl ester (4) was produced either by selective esterification of MTX or by coupling of 4-amino-4-deoxy-N10-methylpteroic acid (2) with suitable glutamic acid derivatives. The MTX .gamma.-methyl ester (4) was then converted to the corresponding hydrazide 6. An amide-linked conjugates was formed when the MTX .gamma.-hydrazide (6) was converted to reactive acylating species 7 by using tert-butyl nitrite or trifluoracetaldehyde, which were reacted with nucleophilic centers, presumably .epsilon.-amino groups, in native IgG. A hydrazone-linked conjugate was formed when MTX-.gamma.-hydrazide (6) was reacted directly with IgG that had first been oxidized with periodate to form polyaldehyde IgG. The regiospecifically synthesized conjugates were somewhate more effective inhibitors in vitro of dihydrofolate reductase and of colony formation by human renal cancer (Caki-1) cells than were control nonregiospecific conjugates.