Bacherikov Valeriy A, Chou Ting-Chao, Dong Hua-Jin, Chen Ching-Huang, Lin Yi-Wen, Tsai Tsong-Jen, Su Tsann-Long
Laboratory of Bioorganic Chemistry, Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan.
Bioorg Med Chem Lett. 2004 Sep 20;14(18):4719-22. doi: 10.1016/j.bmcl.2004.06.080.
A series of 9-anilinoacridine N-mustard derivatives, in which the alkylating N-mustard residue was linked to the C-3' or C-4' position of the anilino ring with an O-ethylene spacer, was synthesized and evaluated for cytotoxicity against human lymphoblastic leukemic cells (CCRF-CEM) in culture. The results showed that all of the new compounds exhibited potent cytotoxicity with IC(50) values ranging from 0.002 to 0.7 microM, which were as potent or significantly more potent than 3-(9-acridinylamino)-5-hydroxymethylaniline (AHMA). Compound 9 did not exhibit cross-resistance against both vinblastine-resistant (CCRF-CEM/VBL) and taxol-resistant (CCRF-CEM/taxol) cells. Additionally, compound 9 demonstrated potent antitumor effect in nude mice bearing human breast carcinoma MX-1 xenografts, resulting in complete tumor remission in two out of three mice at the maximal dose of 1-2mg/kg (Q3Dx7) or 3mg/kg (Q4Dx5) via intravenous injection.
合成了一系列9-苯胺基吖啶N-芥子气衍生物，其中烷基化N-芥子气残基通过O-乙烯间隔基连接到苯胺环的C-3'或C-4'位置，并对其在培养物中对人淋巴细胞白血病细胞（CCRF-CEM）的细胞毒性进行了评估。结果表明，所有新化合物均表现出强效细胞毒性，IC50值在0.002至0.7微摩尔之间，与3-(9-吖啶基氨基)-5-羟甲基苯胺（AHMA）一样有效或明显更有效。化合物9对长春碱耐药（CCRF-CEM/VBL）和紫杉醇耐药（CCRF-CEM/紫杉醇）细胞均未表现出交叉耐药性。此外，化合物9在携带人乳腺癌MX-1异种移植瘤的裸鼠中显示出强效抗肿瘤作用，通过静脉注射，在最大剂量为1-2mg/kg（每3天一次，共7次）或3mg/kg（每4天一次，共5次）时，三只小鼠中有两只实现了肿瘤完全缓解。
