Taleghani Akram, Nasseri Mohammad Ali, Iranshahi Mehrdad
Department of Chemistry, Faculty of Science, University of Birjand, P.O. Box 97175-615, Birjand, Iran.
Department of Pharmcognosy, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran; Biotechnology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
Bioorg Chem. 2017 Apr;71:128-134. doi: 10.1016/j.bioorg.2017.01.020. Epub 2017 Feb 1.
Cancer stem cells are responsible for the failure of a large number of cancer treatments and the re-emergence of cancer in patients. Parthenolide is a potent anticancer sesquiterpene lactone that is also able to kill cancer stem cells. The main problem with this compound is its poor solubility in water. To solve this problem, medicinal chemists have tried to prepare amino-derivatives of parthenolide, however, most amino-derivatives have less potency than that of parthenolide. In this paper, we proposed a new approach to synthesize parthenolide derivatives with better solubility and higher potency. We prepared novel parthenolide derivatives through the aza-Michael addition of nitrogen-containing anticancer drug molecules (cytarabine and melphalan) to the α-methylene-γ-lactone group of parthenolide. Different types of catalysts were used to catalyze the aza-Michael addition. Among all the used catalysts, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) was found to have the highest catalytic activity. In addition, we examined the effects of parthenolide-anticancer drug hybrids on the growth and proliferation of three cancer cell lines (MCF-7, LNcaP, Hep G2) and CHO. The parthenolide prodrugs showed potent cytotoxic property with IC values ranging from 0.2 to 5.2μM, higher than those of parthenolide and anticancer drugs (cytarabine and melphalan).
癌症干细胞是导致大量癌症治疗失败以及患者癌症复发的原因。小白菊内酯是一种有效的抗癌倍半萜内酯，也能够杀死癌症干细胞。这种化合物的主要问题是其在水中的溶解度较差。为了解决这个问题，药物化学家尝试制备小白菊内酯的氨基衍生物，然而，大多数氨基衍生物的效力都低于小白菊内酯。在本文中，我们提出了一种合成具有更好溶解性和更高效力的小白菊内酯衍生物的新方法。我们通过含氮抗癌药物分子（阿糖胞苷和美法仑）与小白菊内酯的α-亚甲基-γ-内酯基团进行氮杂迈克尔加成反应制备了新型小白菊内酯衍生物。使用了不同类型的催化剂来催化氮杂迈克尔加成反应。在所有使用的催化剂中，发现1,8-二氮杂双环[5.4.0]十一碳-7-烯（DBU）具有最高的催化活性。此外，我们研究了小白菊内酯-抗癌药物杂化物对三种癌细胞系（MCF-7、LNcaP、Hep G2）和CHO细胞生长和增殖的影响。小白菊内酯前药表现出强大的细胞毒性，IC值范围为0.2至5.2μM，高于小白菊内酯和抗癌药物（阿糖胞苷和美法仑）。
