Synthesis and biological evaluation of BU-4664L derivatives as potential anticancer agents

Bioorg Med Chem Lett. 2022 Jan 1:55:128474. doi: 10.1016/j.bmcl.2021.128474. Epub 2021 Nov 24.

Abstract

BU-4664L is a naturally occurring N-farnesylated dibenzodiazepinone with important biological activities. Herein, we report the synthesis and antitumor evaluation of two series of BU-4664L derivatives bearing different substituent patterns on the dibenzodiazepinone core and with diverse side chains. All of the derivatives displayed micromolar activity against the human prostate cancer PC-3 cells, while lower or no activity against the human lung H460 cells. The most active derivatives were 10a and 16c which exerted antiproliferative activity against PC-3 cells with GI50 values of 5.66 and 5.94 μM, respectively, and thus represent promising lead compounds for further development.

Keywords: Anticancer agents; BU-4664L; Diazepinomicin; ECO-4601; TLN-4601.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Dibenzazepines / chemical synthesis
  • Dibenzazepines / chemistry
  • Dibenzazepines / pharmacology*
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • Humans
  • Molecular Structure
  • Sesquiterpenes / chemical synthesis
  • Sesquiterpenes / chemistry
  • Sesquiterpenes / pharmacology*
  • Structure-Activity Relationship

Substances

  • 5,10-dihydro-4,6,8-trihydroxy-10-(3,7,11-trimethyl-2,6,10-dodecatrienyl)-11H-dibenzo(b,e)(1,4)diazepin-11-one
  • Antineoplastic Agents
  • Dibenzazepines
  • Sesquiterpenes