P-17 The Synthesis and Evaluation of the Antiproliferative Activity of Deacidified GEX1A analogues

DOI

Bibliographic Information

Other Title
  • P-17 酸性構造を回避した GEX1A 誘導体の合成と構造活性相関

Abstract

GEX1A (1, herboxidiene) and its analogues are natural products produced by Streptomyces sp. GEX1 strain. These polyketides induce cell cycle arrest at G1 and G2/M phases against cancer cells and inhibit the pre-mRNA splicing process by binding to SAP155, a subunit of SF3b in the splicesome. Although 1 was exhibited to have antitumor activity in vivo, weight loss was observed in mice when administered consecutively. Since we assumed that the carboxylic acid moiety in 1 was one of the causes of the toxicity, we aimed to evaluate the tolerability of deacidified analogues of 1. Series of analogues with biologically stable linkers, such as amide, carbamate and urea, were prepared from 1 isolated from bacteria. Among them, the urea linker was selected for further examination because of their remaining antiproliferative activity against HeLa S3 cells. The synthesis of the urea linker analogues were efficiently achieved by the one-pot two-step procedure from 1 featuring Curtius rearrangement following amine treatment. Finally we found that the pharmacologically preferable basic side chains were acceptable and that compound 9c was equipotent to 1 against various cancer cell lines. These basic urea analogues would be promising leads for the development of novel antitumor agents.

Journal

Details 詳細情報について

  • CRID
    1390285697597702144
  • NII Article ID
    130007906403
  • DOI
    10.24496/tennenyuki.59.0_327
  • ISSN
    24331856
  • Text Lang
    ja
  • Data Source
    • JaLC
    • CiNii Articles
  • Abstract License Flag
    Disallowed

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