Kim D K, Kim G, Gam J, Cho Y B, Kim H T, Tai J H, Kim K H, Hong W S, Park J G
Life Science Research Center, Sunkyong Industries, Kyungski-Do, Korea.
J Med Chem. 1994 May 13;37(10):1471-85. doi: 10.1021/jm00036a013.
The synthesis, physical properties, antitumor activity, structure-activity relationships, and nephrotoxicity of a series of [2-substituted-4,5-bis(aminomethyl)-1,3-dioxolane]platinum(II) complexes are described. The 42 platinum(II) complexes having a seven-membered ring structure in this series have been prepared and characterized by 1H NMR, 13C NMR, IR, FAB-MS, and elemental analysis. All members of the series were designed to have a 1,3-dioxolane ring moiety in their carrier ligands to increase water solubility. The solubility of platinum complexes was related to the nature of leaving ligands and 2-substituents in the 4,5-bis(aminomethyl)-1,3-dioxolane carrier ligands. In general, compounds having two different R1 and R2 substituents in the 4,5-bis(aminomethyl)-1,3-dioxolane moiety were more water-soluble than those having the same substituents. Most members of this series showed the excellent antitumor activity against murine L1210 leukemia cells transplanted in mice and were superior to cisplatin and carboplatin. The (4R,5R)-stereoisomer 1a-h exhibited the higher antitumor activity than the corresponding (4S,5S)-stereoisomer 2a-h in the (1,1-cyclobutanedicarboxylato)platinum(II) complexes. The (glycolato)-platinum(II) complexes were highly cytotoxic toward four human stomach cancer cell lines, SNU-1, SNU-5, SNU-16, and NCI-N87, and among them, complexes 3d-g were even more cytotoxic than cisplatin. The (malonato)platinum(II) complex 1m and the (glycolato)platinum(II) complexes 3d-g were selected for further studies based on the greater in vivo and in vitro antitumor activity and desirable physical properties. The complexes 3e-g were almost equally cytotoxic to cisplatin toward human stomach cancer cell lines, KATO-III and MKN-45, and a human non-small cell lung cancer cell line, PC14. In contrast with cisplatin and carboplatin, five complexes selected significantly increased in life span in mice transplanted with cisplatin-resistant L1210 cells. Nephrotoxicity studies in ICR mice indicated that serum BUN and creatinine levels were not elevated when five complexes were given at a dose equal to 1.5 times the optimal dose determined in the in vivo L1210 screening system.
描述了一系列[2-取代-4,5-双(氨甲基)-1,3-二氧戊环]铂(II)配合物的合成、物理性质、抗肿瘤活性、构效关系和肾毒性。该系列中具有七元环结构的42种铂(II)配合物已通过1H NMR、13C NMR、IR、FAB-MS和元素分析进行了制备和表征。该系列的所有成员在其载体配体中均设计有1,3-二氧戊环环部分以增加水溶性。铂配合物的溶解度与4,5-双(氨甲基)-1,3-二氧戊环载体配体中离去配体和2-取代基的性质有关。一般来说，在4,5-双(氨甲基)-1,3-二氧戊环部分具有两个不同R1和R2取代基的化合物比具有相同取代基的化合物更易溶于水。该系列的大多数成员对移植到小鼠体内的小鼠L1210白血病细胞显示出优异的抗肿瘤活性，并且优于顺铂和卡铂。在(1,1-环丁烷二羧酸根)铂(II)配合物中，(4R,5R)-立体异构体1a-h比相应的(4S,5S)-立体异构体2a-h表现出更高的抗肿瘤活性。(乙醇酸根)铂(II)配合物对四种人胃癌细胞系SNU-1、SNU-5、SNU-16和NCI-N87具有高度细胞毒性，其中配合物3d-g甚至比顺铂具有更高的细胞毒性。基于更大的体内和体外抗肿瘤活性以及理想 的物理性质，选择了(丙二酸根)铂(II)配合物1m和(乙醇酸根)铂(II)配合物3d-g进行进一步研究。配合物3e-g对人胃癌细胞系KATO-III和MKN-45以及人非小细胞肺癌细胞系PC14的细胞毒性与顺铂几乎相同。与顺铂和卡铂相反，所选的五种配合物显著延长了移植有顺铂耐药L1210细胞的小鼠的寿命。对ICR小鼠的肾毒性研究表明，当以等于体内L1210筛选系统中确定的最佳剂量的1.5倍的剂量给予五种配合物时，血清BUN和肌酐水平没有升高。
