Department of Chemistry, University of Puerto Rico at Humacao, PR 00791, USA.
Eur J Pharm Sci. 2011 Sep 18;44(1-2):21-6. doi: 10.1016/j.ejps.2011.04.013. Epub 2011 May 13.
Three different series of N-hydroxyethyl aza-podophyllotoxin derivatives containing (i) a five-membered methylenedioxy ring (7a-f), (ii) a five-membered ring with no heteroatom (8a-f) or (iii) a six membered ethylenedioxy ring (9a-f) as ring A were synthesized using a convenient one-pot multi-component reaction. Further variation on ring E was done by decorating it with methoxy and hydroxy groups at different positions. Calculation of logP values of these compounds indicates them to be better soluble than corresponding non-hydroxy derivatives. These novel aza-podophyllotoxin derivatives were screened for their cytostatic and cytotoxic activities on National Cancer Institute's 60 human tumor cell lines to study the structure activity relationship. The overall anticancer activity of these compounds was in the order of 8a-f>9a-f>7a-f. Furthermore, the compounds having 3'-methoxy and 3',4',5'-trimethoxy substitution at ring E were the most active within the series. The cytotoxicity of all the active compounds was low, while their antiproliferative (or cytostatic) activity was high, providing a wide therapeutic window for their potential application as anticancer drugs.
采用方便的一锅多组分反应，合成了三个不同系列的含 N-羟乙基氮杂鬼臼毒素衍生物，分别为：（i）含五元亚甲二氧基环的（7a-f），（ii）不含杂原子的五元环（8a-f）或（iii）六元亚乙基二氧基环的（9a-f）作为环 A。进一步对环 E 进行了修饰，在不同位置上引入了甲氧基和羟基。这些化合物的 logP 值计算表明，它们比相应的非羟基衍生物具有更好的溶解性。对这些新型氮杂鬼臼毒素衍生物进行了细胞生长抑制和细胞毒性活性筛选，以研究构效关系。这些化合物的整体抗癌活性顺序为 8a-f>9a-f>7a-f。此外，在环 E 上具有 3'-甲氧基和 3'，4'，5'-三甲氧基取代的化合物在该系列中最为活跃。所有活性化合物的细胞毒性均较低，而其抗增殖（或细胞生长抑制）活性较高，为其作为抗癌药物的潜在应用提供了广阔的治疗窗口。
