A novel class of in vivo active anticancer agents:: Achiral seco-amino- and seco-hydroxycyclopropylbenz[e]indolone (seco-CBI) analogues of the duocarmycins and CC-1065
A novel class of in vivo active anticancer agents:: Achiral seco-amino- and seco-hydroxycyclopropylbenz[e]indolone (seco-CBI) analogues of the duocarmycins and CC-1065
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DOI：
10.1021/jm050179u
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发表时间：
2005-06-02
影响因子：
7.3
通讯作者：
Lee, M
中科院分区：
文献类型：
--
作者：
Sato, A;McNulty, LA;Lee, M
设计、合成了CC-1065和倍癌霉素的一种非手性开环-羟基环丙基苯并[e]吲哚酮（seco-CBI）（12）和七种非手性开环-氨基-CBI（11 a-g）类似物，并评价了它们的DNA结合和抗癌性质。这些化合物含有核心2-氯乙基萘结构，并且它们不具有立构中心。根据热裂解凝胶分析，化合物11 a-g和12显示出与阿多来辛3和外消旋开环-CBI-TMI 4类似的共价序列特异性，以结合至5 '-AAAAA（865）-3'位点。将人（K562）和鼠（B16、L1210和P815）癌细胞系连续暴露于化合物证明了其显著的细胞毒性，IC 50值在亚微摩尔范围内。通常，乙基部分上的良好离去基团和萘基部分上的游离氨基或羟基对于活性是必需的。根据NCI的细胞毒性筛选，化合物11 a和12对源自肺、结肠、黑素瘤、肾系统和乳腺的人癌细胞系具有活性。在15和20 mg/kg的相应剂量（通过ip途径给药）下，化合物11 a和12抑制C57 BL/6小鼠中鼠B16-F0黑素瘤的生长，毒性最小，并且11 a给出显著的抗癌效果。化合物11 a的体内抗癌活性在人肿瘤异种移植研究（scid小鼠中生长的晚期SC-OVCAR-3卵巢癌）中得到证实。最后，化合物11 a在对先前报道的化合物4有毒的剂量下对培养物中的鼠骨髓细胞生长没有毒性。
One achiral seco-hydroxycyclopropylbenz[e]indolone (seco-CBI) (12) and seven achiral seco-amino-CBI (11a-g) analogues of CC-1065 and the duocarmycins were designed, synthesized and evaluated for their DNA-binding and anticancer properties. These compounds contain a core 2-chloroethylnaphthalene structure and they do not have a stereocenter. From thermal cleavage gel analyses, compounds 11a-g and 12 demonstrated similar covalent sequence specificity to adozelesin 3 and the racemic seco-CBI-TMI 4 for binding to the 5'-AAAAA(865)-3' site. Continuous exposure of human (K562) and murine (B16, L1210 and P815) cancer cell lines to the compounds demonstrated their significant cytotoxicity, with IC50 values in the sub-micromolar range. Generally, a good leaving group on the ethyl moiety and a free amino or hydroxyl group on the naphthyl moiety are essential for activity. According to NCI's cytotoxicity screen, compounds 11a and 12 were active against human cancer cell lines derived from lung, colon, melanoma, renal system, and breast. At the respective doses of 15 and 20 mg/kg (administered via an ip route), compounds 11a and 12 inhibited the growth of murine B16-F0 melanoma in C57BL/6 mice, with minimal toxicity, and 11a gave a significant anticancer effect. The in vivo anticancer activity of compound 11a was confirmed in a human tumor xenograft study (advanced stage SC-OVCAR-3 ovarian cancer growing in scid mice). Finally, compound 11a was not toxic to murine bone marrow cell growth in culture at a dose that was toxic for the previously reported compound 4.