title: Total synthesis of AMF-26, an antitumor agent for inhibition of the Golgi system, targeting ADP-ribosylation factor 1.
abstract: An effective method for the total synthesis of 1 (AMF-26), a potentially promising new anticancer drug that disrupts the Golgi system by inhibiting the ADP-ribosylation factor 1 (Arf1) activation, has been developed for the first time. The construction of the chiral linear precursor (a key to the synthesis) was achieved by the asymmetric aldol reaction followed by the computer-assisted predictive stereoselective intramolecular Diels-Alder reaction. The global antitumor activity of the totally synthetic 1 against a variety of human cancer cells was assessed using a panel of 39 human cancer cell lines (JFCR39), and it was shown that the synthetic 1 strongly inhibited the growth of several cancer cell lines at concentrations of less than 0.04 μM. Biological assays of novel derivatives, 26 and 31, which have different side-chains at the C-4 positions in the Δ¹,²-octalin backbone, disclosed the importance of the suitable structure of the side-chain containing conjugated multidouble bonds.
authors.affiliation: Department of Applied Chemistry, Faculty of Science, Tokyo University of Science, 1-3 Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan. shiina@rs.kagu.tus.ac.jp
authors.forename: Isamu
authors.initials: I
authors.lastname: Shiina
authors.forename: Yuma
authors.initials: Y
authors.lastname: Umezaki
authors.forename: Yoshimi
authors.initials: Y
authors.lastname: Ohashi
authors.forename: Yuta
authors.initials: Y
authors.lastname: Yamazaki
authors.forename: Shingo
authors.initials: S
authors.lastname: Dan
authors.forename: Takao
authors.initials: T
authors.lastname: Yamori
mesh_terms: D020823:ADP-Ribosylation Factor 1 / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D006056:Golgi Apparatus / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D015394:Molecular Structure; D009284:Naphthols / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013816:Thermodynamics
chemical_list: D000970:Antineoplastic Agents; C573938:N-(pyridine-3-ylmethyl)-5-(7-hydroxy-2,6,8-trimethyl-1,2,4a,5,6,7,8,8a-octahydronaphthalene-1-yl)-2-methylpenta-2,4-dienamide; D009284:Naphthols; D011725:Pyridines; D020823:ADP-Ribosylation Factor 1