Griffin Carly, Sharda Natasha, Sood Divya, Nair Jerald, McNulty James, Pandey Siyaram
Department of Chemistry and Biochemistry, University of Windsor, Windsor, Ontario, Canada.
Department of Chemistry, McMaster University, Hamilton, Ontario, Canada.
Cancer Cell Int. 2007 Jun 5;7:10. doi: 10.1186/1475-2867-7-10.
Pancratistatin (PST), a compound extracted from an Amaryllidaceae (AMD) family plant, has been shown to specifically induce apoptosis in cancer cells with no/minimal toxic effect on normal cells. A systematic synthetic approach has indicated that the minimum cytotoxic pharmacophore comprises the trans-fused b/c-ring system containing the 2, 3, 4-triol unit in the C-ring. To further explore the structure-activity relationship of this group of compounds we have investigated the anti-cancer efficacy and specificity of two PST-related natural compounds, AMD4 and AMD5. Both of these compounds lack the polyhydroxylated lycorane element of PST instead having a methoxy-substituted crinane skeleton.
Our results indicate that AMD5 has efficacy and selectivity similar to PST, albeit at a 10-fold increased concentration. Interestingly AMD4 lacks apoptotic activity.
Our results indicate that the phenanthridone skeleton in natural Amaryllidaceae alkaloids may be a significant common element for selectivity against cancer cells; furthermore, the configuration of the methoxy-side groups is responsible for higher binding affinity to the target protein/s thus making for a more efficient anti-cancer agent.
pancratistatin（PST）是一种从石蒜科（AMD）植物中提取的化合物，已被证明能特异性诱导癌细胞凋亡，对正常细胞无/极小毒性作用。一种系统的合成方法表明，最小细胞毒性药效团包括在C环中含有2,3,4 - 三醇单元的反式稠合b/c环系统。为了进一步探索这类化合物的构效关系，我们研究了两种与PST相关的天然化合物AMD4和AMD5的抗癌疗效和特异性。这两种化合物都缺乏PST的多羟基化石蒜碱元素，取而代之的是具有甲氧基取代的水仙环素骨架。
我们的结果表明，AMD5具有与PST相似的疗效和选择性，尽管浓度增加了10倍。有趣的是，AMD4缺乏凋亡活性。
我们的结果表明，天然石蒜科生物碱中的菲啶酮骨架可能是对癌细胞选择性的一个重要共同元素；此外，甲氧基侧基的构型导致与靶蛋白有更高的结合亲和力，从而成为一种更有效的抗癌剂。
