Physical and biological characteristics of the antitumor drug actinomycin D analogues derivatized at N-methyl-L-valine residues.
Physical and biological characteristics of the antitumor drug actinomycin D analogues derivatized at N-methyl-L-valine residues.
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DOI：
10.1021/bi960828r
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发表时间：
1996-10
期刊：
影响因子：
2.9
通讯作者：
F. Takusagawa;L. Wen;W. Chu;Q. Li;K. T. Takusagawa;R. G. Carlson;R. F. Weaver
中科院分区：
文献类型：
--
作者：
F. Takusagawa;L. Wen;W. Chu;Q. Li;K. T. Takusagawa;R. G. Carlson;R. F. Weaver
DNA-放线菌素D（AMD）复合物的晶体结构和一个简单的分子模拟研究表明，在N-甲基-L-缬氨酸残基（AMD的环状缩酚酸肽的第五个氨基酸残基）衍生的AMD类似物可以像母体AMD一样强烈地与DNA结合。N-甲基-L-缬氨酸残基被N-甲基缬氨酸、N-甲基苏氨酸、N-甲基苯丙氨酸、N-甲基酪氨酸和N-甲基-O-甲基酪氨酸的L-和D-型取代的类似物已全部合成。用可见吸收光谱法研究了这些类似物与DNA-1 [d（TATATATGCATATATA）]、DNA-2 [d（TATATACGCGTATATA）]、DNA-3 [d（ATATATAGCTATAT）]和DNA-4 [d（ATATATGGCCATATAT）]的结合特性。由吸收光谱计算的缔合常数表明，AMD分子中N-甲基-L-缬氨酸残基的修饰确实影响类似物的DNA结合特性。除了与DNA-1（-TGCA-）结合外，L-芳香族类似物的结合略好于L-脂肪族类似物，而D-脂肪族类似物的结合始终好于D-芳香族类似物。在L型类似物中，L-Tyr类似物具有最高的总缔合常数，而D-Val类似物在D型类似物中具有最高的缔合常数。尽管取代的庞大的芳香族基团，D-芳香族类似物结合的DNA-1相当好。然而，D-芳香族类似物显着降低了它们与其他DNA的结合能力，表明D-芳香族残基的取代产生了独特的四碱基序列偏好（-TGCA-）。已使用人细胞（HeLa）检查了AMD类似物在体内的RNA聚合酶抑制活性。除L-Thr类似物外，所有AMD类似物在相对低的药物浓度下均严重抑制RNA合成。D-Val、L-OMT、L-Phe和D-Phe类似物比天然抗生素（AMD本身）更强烈地抑制RNA合成。
The crystal structure of the DNA-actinomycin D (AMD) complex and a simple molecular modeling study indicated that AMD analogues derivatized at N-methyl-L-valine residues (fifth amino acid residue in the cyclic depsipeptide of AMD) could bind to DNA as strongly as the parent AMD. The analogues in which N-methyl-L-valine residues were replaced with L- and D-forms of N-methylvalines, N-methylthreonines, N-methylphenylalanies, N-methyltyrosines, and N-methyl-O-methyltyrosines have been totally synthesized. The characteristics of binding of the analogues to various DNAs including DNA-1 [d(TATATATGCATATATA)], DNA-2 [d(TATATACGCGTATATA)], DNA-3 [d(ATATATAGCTATATAT)], and DNA-4 [d(ATATATGGCCATATAT)] have been examined by using visible absorption spectrum methods. The association constants calculated from the absorption spectra indicate that the modifications of the N-methyl-L-valine residues in the AMD molecule do affect the DNA binding characteristics of the analogues. The L-aromatic analogues bind slightly better than the L-aliphatic analogues except for binding to DNA-1 (-TGCA-), whereas the D-aliphatic analogues bind consistently better than the D-aromatic analogues. In the L-form analogues, the L-Tyr analogue has the highest overall association constant, whereas the D-Val analogue has the highest association constant among the D-form analogues. In spite of substitution of bulky aromatic groups, the D-aromatic analogues bind to the DNA-1 quite well. However, D-aromatic analogues have significantly reduced their binding capacities to the other DNAs, indicating that the substitution of the D-aromatic residues creates a unique four-base sequence preference (-TGCA-). The RNA polymerase inhibitory activities of the AMD analogues in vivo have been examined using human cells (HeLa). All AMD analogues except for the L-Thr analogues severely inhibit RNA synthesis at relatively low drug concentrations. The D-Val, L-OMT, L-Phe, and D-Phe analogues inhibit RNA synthesis more strongly than the natural antibiotic (AMD itself).