title: Synthesis of dual-action parthenolide prodrugs as potent anticancer agents.
abstract: 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 IC50values ranging from 0.2 to 5.2μM, higher than those of parthenolide and anticancer drugs (cytarabine and melphalan).
authors.affiliation: Department of Chemistry, Faculty of Science, University of Birjand, P.O. Box 97175-615, Birjand, Iran.
authors.forename: Akram
authors.initials: A
authors.lastname: Taleghani
authors.affiliation: Department of Chemistry, Faculty of Science, University of Birjand, P.O. Box 97175-615, Birjand, Iran.
authors.forename: Mohammad Ali
authors.initials: MA
authors.lastname: Nasseri
authors.affiliation: Department of Pharmcognosy, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran; Biotechnology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran. Electronic address: Iranshahim@mums.ac.ir.
authors.forename: Mehrdad
authors.initials: M
authors.lastname: Iranshahi
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002384:Catalysis; D045744:Cell Line, Tumor; D060326:Chemistry Techniques, Synthetic; D003561:Cytarabine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology; D006801:Humans; D007783:Lactones / Q000737:chemistry; D008558:Melphalan / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology; D009369:Neoplasms / Q000188:drug therapy; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D012717:Sesquiterpenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D007783:Lactones; D011355:Prodrugs; D012717:Sesquiterpenes; C416683:methylene-lactone; D003561:Cytarabine; C002669:parthenolide; D008558:Melphalan
keywords: Cytarabine; Cytotoxic activity; Melphalan; Parthenolide; aza-Michael addition