Antitumor activity of tricyclic pyrone analogs, a new synthetic class of microtubule de-stabilizing agents, in the murine EMT-6 mammary tumor cell line in vitro
Antitumor activity of tricyclic pyrone analogs, a new synthetic class of microtubule de-stabilizing agents, in the murine EMT-6 mammary tumor cell line in vitro
复制标题
DOI：
10.1097/00001813-199807000-00008
复制
发表时间：
1998-07-01
影响因子：
2.3
通讯作者：
Perchellet, JP
中科院分区：
文献类型：
--
作者：
Perchellet, EM;Ladesich, JB;Perchellet, JP
在华的实验室中合成的新型三环吡喃酮（TP）类似物（代号H10，H14和H16）针对一系列已知的抗有丝分裂药物进行了测试，以确定其破坏微管（MT）动力学，改变有丝分裂指数，并阻止小鼠EMT-6乳腺肉瘤细胞合成DNA和体外增殖的能力。在2-10 μ M时，H10比H14更大程度地抑制DNA合成、微管蛋白聚合和肿瘤细胞生长，而H16没有作用。这些TP的抗肿瘤活性需要线性骨架，其中A环的C-3处有一个吡啶环，一个吡喃a环，并且C环的C-7处没有烷基化。由于H10模拟长春新碱（VCR）对微管蛋白聚合的作用，但不模拟紫杉醇的作用，因此TP可能代表一种新型合成MT去稳定抗癌药物。H10对微管蛋白聚合（IC 50：1.5 μ M vs 0.15 μ M）和肿瘤细胞增殖（IC 50：1.5 μ M vs 5 nM）的抑制效力低于VCR，但抑制DNA合成（IC 50：10 μ M）的效力高于除tubulozole-C外的所有其他MT破坏剂。虽然TP破坏DNA合成并可能影响细胞周期的几个阶段，但H10增加有丝分裂细胞百分比的能力表明这些新型化合物可能是用于将哺乳动物细胞阻滞在M期的细胞周期特异性抗癌药物。[(C)1998 Lippincott-Raven Publishers.
Novel tricyclic pyrone (TP) analogs synthesized in Hua's laboratory (code names H10, H14 and H16) were tested against a spectrum of known antimitotic drugs for their ability to disrupt microtubule (MT) dynamics, alter the mitotic index, and prevent murine EMT-6 mammary sarcoma cells from synthesizing DNA and proliferating in vitro. At 2-10 mu M, H10 inhibits DNA synthesis, tubulin polymerization and tumor cell growth to a greater degree than H14, whereas H16 has no effect. A linear skeleton with a pyridyl ring at C-3 of the A-ring, a pyran a-ring and no alkylation at C-7 of the C-ring is required for the antitumor activity of these TPs. Since H10 mimics the effect of vincristine (VCR), but not that of paclitaxel, on tubulin polymerization, TPs may represent a novel synthetic class of MT de-stabilizing anticancer drugs. H10 is less potent than VCR against tubulin polymerization (IC50: 1.5 mu M versus 0.15 mu M) and tumor cell proliferation (IC50: 1.5 mu M versus 5 nM) but inhibits DNA synthesis (IC50: 10 mu M) more effectively than ail other MT-disrupting agents tested, except tubulozole-C. Although TPs disrupt DNA synthesis and might affect several phases of the cell cycle, the ability of H10 to increase the percentage of mitotic cells indicates that these novel compounds may be cell cycle-specific anticancer drugs useful for arresting mammalian cells in M-phase. [(C) 1998 Lippincott-Raven Publishers.].