title: The synthesis and evaluation of the antiproliferative activity of deacidified GEX1A analogues.
abstract: GEX1A/herboxidiene (1) is a natural product isolated from Streptomyces sp. and has been reported to target the pre-mRNA splicing process. Although 1 was shown to have antitumor activity in vivo, weight loss was observed in mice when 1 was consecutively administered. We assumed that the carboxylic acid moiety was one of the causes of this toxicity. In this study, a series of amide, carbamate and urea analogues of 1 were synthesized and their antiproliferative activity was evaluated in vitro. The synthesis of urea analogues featured Curtius rearrangement following amine treatment with the one-pot procedure from 1. Furthermore, a structure-activity relationship study of the urea analogues revealed that the pharmacologically preferable basic side chains were acceptable and that compound 9g was equipotent to parent 1. These basic urea analogues would be promising leads for the development of novel antitumor agents.
authors.affiliation: Chemical Research Laboratories, R&D Division, Kyowa Hakko Kirin, Shizuoka, Japan.
authors.forename: Takamichi
authors.initials: T
authors.lastname: Imaizumi
authors.affiliation: Chemical Research Laboratories, R&D Division, Kyowa Hakko Kirin, Shizuoka, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nakagawa
authors.affiliation: Oncology Research Laboratories, R&D Division, Kyowa Hakko Kirin, Shizuoka, Japan.
authors.forename: Ran
authors.initials: R
authors.lastname: Hori
authors.affiliation: Oncology Research Laboratories, R&D Division, Kyowa Hakko Kirin, Shizuoka, Japan.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Watanabe
authors.affiliation: Oncology Research Laboratories, R&D Division, Kyowa Hakko Kirin, Shizuoka, Japan.
authors.forename: Shiro
authors.initials: S
authors.lastname: Soga
authors.affiliation: Chemical Research Laboratories, R&D Division, Kyowa Hakko Kirin, Shizuoka, Japan.
authors.forename: Kyoichiro
authors.initials: K
authors.lastname: Iida
authors.affiliation: Chemical Research Laboratories, R&D Division, Kyowa Hakko Kirin, Shizuoka, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Onodera
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002219:Carbamates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D015195:Drug Design; D005233:Fatty Alcohols / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D011714:Pyrans / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014508:Urea / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000577:Amides; D000970:Antineoplastic Agents; D002219:Carbamates; D005233:Fatty Alcohols; D011714:Pyrans; C076087:herboxidiene; D014508:Urea