摘要
一氧化氮 (nitricoxide ,NO)在肿瘤病理生理过程中产生多方面的生化作用 ,诸如引起的某些核苷酸碱基的羟基化 ,参与免疫系统清除肿瘤细胞 ,促进肿瘤细胞凋亡和调节血管生成等 .在此基础上 ,首次提出将NO供体 (NOdonor)或一氧化氮合酶 (nitricoxidesynthase ,NOS)抑制剂分别连接到甲氨蝶呤 (methotrexate ,MTX ,MTX本身就是NOS抑制剂 )的α或γ位羧基上的设想 ,设计并合成出 :( 1)MTX NO供体 ( 3 羟甲基 4 苯基 1,2 ,5 二唑 2 氧化物 ,属于Furoxan衍生物 ,缩写为FU) :1a (MTX α FU) ,2a (MTX γ FU) ;( 2 )MTX NOS抑制剂 (L Nω 硝基精氨酸或L Nω 硝基精氨酸甲酯 ) :1b (MTX α L Nω NO2 Arg) ,2b (MTX γ L Nω NO2 Arg) ,1c (MTX α L Nω NO2 Arg OMe) ,2c (MTX γ L Nω NO2 Arg OMe) .在生物活性测试中 ,我们选择耐MTX细胞株K 5 62 (慢性粒细胞性白血病急性病变细胞株 ) ,进行抗肿瘤活性测试 ,得到以下结果 :( 1)脂溶性差的MTX衍生物 1b ,2b抗肿瘤活性低于MTX ,其它 1a ,2a ;1c ,2c均优于MTX ;( 2 )连接有NO供体的MTX明显增强了MTX衍生物的抗肿瘤活性 ;( 3 )MTX中谷氨酸γ位组合物抗肿瘤活性均高于相应的α位异构体的活性 .以上初步结果 ,将对进一步研究NO抗肿瘤作用以及新的抗肿瘤?
Nitric oxide (NO) is an important messenger molecule with multiple biological activities in blood vessels, neurons, macrophages, and other cells. NO is a ubiquitous modulator of both physiological and pathophysiological functions that is generated endogenous by the enzyme nitric oxide synthase of which 3 isoforms are known. NO appears critical for the tumoricidal activity of the immune system, modulates apoptosis of tumors and has other effects on tumor biology, including angiogenesis and metestasis. On the basis of the multifaceted roles of NO in cancer and the fact that methotrexate (MTX) is a very active anticancer drug and one of the nitric oxide synthase (NOS) inhibitors, new conjugates of MTX with NO donors or NOS inhibitors have been synthesized hoping that MTX functions as an active carrier. Methotrexate was coupled with 3-hydroxymethyl-4-phenyl-1,2,5-oxadiazole-N-oxide (an NO donor) at the α- and γ-carboxyl groups to give 1a and 2a. Analogously reacted MTX with N-nitro-L-arginine to 1b and 2b and with N-nitro-L-arginine methyl ester to 1c and 2c. In the biological assay the MTX-conjugates were tested against K-562 human leukemia cells which are resistant to MTX. Increasing in lipiphobicity as shown by 1b and 2b reduced the activity of K-562 cell-killing in culture and contrarily, compounds 1a, 2a, 1c and 2c inhibited the growth of K-562 cells superior to MTX due to their higher lipiphilicity. In general, the MTX-NO-donors enhance tumoricidal activity significantly and the γ-substituted conjugates are more effective than the α-isomers.
出处
《化学学报》
SCIE
CAS
CSCD
北大核心
2004年第7期703-712,共10页
Acta Chimica Sinica
基金
国家自然科学基金 (No.39870 882 )资助项目