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首页> 外文OA文献 >Anticancer pharmacology of natural and semi-synthetic lignansfrom Larrea tridentata (Moc and Sess) cov. (Zygophyllaceae)
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Anticancer pharmacology of natural and semi-synthetic lignansfrom Larrea tridentata (Moc and Sess) cov. (Zygophyllaceae)

机译：天然和半合成木脂素的抗癌药理作用。 （y科）

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摘要

The objective of this dissertation was to isolate, identify, modify, and pharmacologically characterize lignans from Larrea tridentata (Zygophyllaceae) which possessed antitumor activity. Seven lignans including the novel 3,4'-dihydroxy-3 ',4-dimethoxy-6,7'-cyclolignan ( 3), and one flavanone were isolated. Although 1-(3-hydroxy-4-methoxyphenyl)-4-(3-methoxy-4-acetoxyphenyl)2,3-dimethylbutane (1) was previously reported, the spectroscopic data is reported here for the first time. Eight acyl and alkyl derivatives of nordihydroguaiaretic acid (NDGA) were prepared to determine the effect of additions to the catechol hydroxyl on tumor cell cytotoxicity. All of the compounds were assessed for their cytotoxicity in human tumor cell lines. NDGA and compounds 1--14 had IC₅₀ values ranging from 6--60 μM in all cell lines. Compounds 2 and 15 were active only against human breast cancer cells. There appeared to be a positive correlation between the number of O-methyl substitutions on the NDGA molecule and potency against breast cancer cells. NDGA and tetra-O-methylnordihydroguaiaretic acid (M₄N) were chosen for further study based on cytotoxicity results and compound availability. Both compounds inhibited DNA synthesis, but only M₄N demonstrated antitumor activity in vivo. M₄N induced cell cycle arrest in the G₀/G₁ and the G₂/M phases and induced apoptosis in melanoma cells. Myeloma cells with decreased topoisomerase IIα levels exhibited increased sensitivity to M₄N, although M₄N inhibited neither topoisomerase IIα or topoisomerase I in a cell-free system. In cells with decreased topoisomerase IIβ levels, the increased sensitivity to M₄N was ablated. This suggests topoisomerase IIβ partially mediates M₄N cytotoxicity. NDGA was hepatotoxic both in vitro and in vivo (LD₅₀ = 75 mg/kg (i.p.) in the mouse). M₄N was non-toxic in vivo and did not alter hepatic enzymes. This demonstrates the importance of the catechol hydroxyls in causing hepatotoxicity. NDGA (i.v.) exhibited two-compartment pharmacokinetics with a distribution half-life of 30 min and a terminal half-life of 135 min in mice. The peak plasma concentration was 14.7 μg/mL and the clearance was 201.9 mL/(min*kg). Overall, several new compounds were identified from L. tridentata that have an improved therapeutic index, compared with NDGA, against human cancer cells. This growth inhibition may involve topoisomerase II inhibition leading to cell cycle arrest and impaired DNA synthesis.
机译：本论文的目的是从具有抗肿瘤活性的Larrea tridentata（Zygophyllaceae）中分离，鉴定，修饰和药理鉴定木脂素。分离出包括新颖的3,4'-二羟基-3'，4-二甲氧基-6,7'-环木脂素（3）在内的7种木脂素和1种黄烷酮。尽管先前曾报道过1-（3-羟基-4-甲氧基苯基）-4-（3-甲氧基-4-乙酰氧基苯基）2,3-二甲基丁烷（1），但光谱数据首次在此报道。制备了八种去氢二氢愈创木酸（NDGA）的酰基和烷基衍生物，以确定儿茶酚羟基添加物对肿瘤细胞毒性的影响。评估所有化合物在人肿瘤细胞系中的细胞毒性。 NDGA和化合物1--14在所有细胞系中的IC₅₀值在6--60μM之间。化合物2和15仅对人乳腺癌细胞有活性。 NDGA分子上的O-甲基取代数量与抗乳腺癌细胞的功效之间似乎存在正相关。根据细胞毒性结果和化合物的可用性，选择了NDGA和四-O-甲基去甲二氢愈创木酸（M₄N）进行进一步研究。两种化合物均抑制DNA合成，但只有M₄N表现出体内抗肿瘤活性。 M₄N诱导细胞周期停滞在G₀/G₁和G2 / M期，并诱导黑素瘤细胞凋亡。拓扑异构酶IIα水平降低的骨髓瘤细胞对M₄N的敏感​​性增加，尽管M₄N在无细胞系统中既不抑制拓扑异构酶IIα也不抑制拓扑异构酶I。在拓扑异构酶IIβ水平降低的细胞中，对M₄N的敏感​​性增加被消除。这表明拓扑异构酶IIβ部分介导M₄N细胞毒性。 NDGA在体外和体内均具有肝毒性（小鼠的LD 50 ＝ 75mg / kg（腹腔））。 M₄N在体内无毒，不会改变肝酶。这证明了儿茶酚羟基在引起肝毒性中的重要性。 NDGA（i.v.）在小鼠中表现出两室药代动力学，分布半衰期为30分钟，终末半衰期为135分钟。血浆峰值浓度为14.7μg/ mL，清除率为201.9 mL /（min * kg）。总体而言，从三齿线虫中鉴定出几种新化合物，与NDGA相比，它们对人癌细胞的治疗指数更高。这种生长抑制可能涉及拓扑异构酶II抑制，从而导致细胞周期停滞和DNA合成受损。

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    Lambert Joshua David;

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  • 年度 2001
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