title: Toward synthesis of third-generation spin-labeled podophyllotoxin derivatives using isocyanide multicomponent reactions.
abstract: Spin-labeled podophyllotoxins have elicited widespread interest due to their far superior antitumor activity compared to podophyllotoxin. To extend our prior studies in this research area, we synthesized a new generation of spin-labeled podophyllotoxin analogs via isocyanide multicomponent reactions and evaluated their cytotoxicity against four human cancer cell lines (A-549, DU-145, KB and KBvin). Most of the compounds exhibited potent cytotoxic activity against all four cell lines, notably against the drug resistant KBvin cancer cell line. Among the new analogs, compounds 12e (IC50: 0.60-0.75 μM) and 12h (IC50: 1.12-2.03 μM) showed superior potency to etoposide (IC50: 2.03 to >20 μM), a clinically available anticancer drug. With a concise efficient synthesis and potent cytotoxic profiles, compounds 12e and 12h merit further development as a new generation of epipodophyllotoxin-derived antitumor clinical trial candidates.
authors.affiliation: School of Pharmacy, Lanzhou University, Lanzhou 730000, PR China.
authors.forename: Liang
authors.initials: L
authors.lastname: Kou
authors.affiliation: School of Pharmacy, Lanzhou University, Lanzhou 730000, PR China.
authors.forename: Mei-Juan
authors.initials: MJ
authors.lastname: Wang
authors.affiliation: Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Li-Ting
authors.initials: LT
authors.lastname: Wang
authors.affiliation: School of Pharmacy, Lanzhou University, Lanzhou 730000, PR China.
authors.forename: Xiao-Bo
authors.initials: XB
authors.lastname: Zhao
authors.affiliation: School of Pharmacy, Lanzhou University, Lanzhou 730000, PR China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Nan
authors.affiliation: Environmental and Municipal Engineering School, Lanzhou Jiaotong University, Lanzhou 730000, PR China.
authors.forename: Liu
authors.initials: L
authors.lastname: Yang
authors.affiliation: School of Pharmacy, Lanzhou University, Lanzhou 730000, PR China; Xinjiang Production & Construction Corps Key Laboratory of Protection and Utilization of Biological Resources in Tarim Basin, PR China. Electronic address: yqliu@lzu.edu.cn.
authors.forename: Ying-Qian
authors.initials: YQ
authors.lastname: Liu
authors.affiliation: Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Susan L
authors.initials: SL
authors.lastname: Morris-Natschke
authors.affiliation: Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA; Chinese Medicine Research and Development Center, China Medical University and Hospital, Taichung, Taiwan. Electronic address: khlee@email.unc.edu.
authors.forename: Kuo-Hsiung
authors.initials: KH
authors.lastname: Lee
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003486:Cyanides / Q000138:chemical synthesis / Q000737:chemistry; D004354:Drug Screening Assays, Antitumor; D005047:Etoposide / Q000494:pharmacology; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy; D011034:Podophyllotoxin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013113:Spin Labels / Q000138:chemical synthesis*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D003486:Cyanides; D013113:Spin Labels; D005047:Etoposide; D011034:Podophyllotoxin
keywords: C-4 position; Cytotoxic activity; Isocyanide multicomponent reactions; Podophyllotoxin; Spin labeled