Synthesis and biological evaluation of conformationally constrained analogs of the antitumor agents XK469 and SH80. Part 5

Bioorg Med Chem. 2006 Apr 1;14(7):2462-7. doi: 10.1016/j.bmc.2005.11.036. Epub 2005 Dec 5.

Abstract

Conformational restriction of bioactive molecules offers the possibility of generating structures of increased potency. To this end, a synthesis has been achieved of (R,S)-2-[(8-chlorobenzofurano[2,3-b]quinolinyl)oxy]propionic acid (12a), a highly rigidified, polycyclic analog of 2-[4-[(7-chloro-2-quinoxalinyl)oxy]phenoxy]propionic acid (2a, XK469). Efforts to effect the same synthesis of the corresponding 8-bromo-derivative led to a mixture of intermediate, 8-chloro (9a), and 8-bromo-2-hydroxybenzofurano[2,3-b]quinoline (9b), generated by halogen-exchange, via an aromatic S(RN)1(A(RN)1) reaction of precursor, 8b, with pyridine hydrochloride. The presumption that conformational restriction of 1b-12a might enhance the antitumor potency of the latter has not been sustained. In fact, 12a proved to be significantly less active than 1b. However, it is apparent that virtually all of the spatial and steric properties of 12a, necessary for improved activity, including the disposition of the 2-oxypropionic acid side chain remain to be identified.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Benzofurans / chemical synthesis*
  • Benzofurans / chemistry
  • Benzofurans / pharmacology*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Crystallography, X-Ray
  • Drug Screening Assays, Antitumor
  • Humans
  • In Vitro Techniques
  • Mice
  • Models, Molecular
  • Molecular Structure
  • Propionates / chemical synthesis*
  • Propionates / chemistry
  • Propionates / pharmacology*
  • Quinolines / chemical synthesis*
  • Quinolines / chemistry
  • Quinolines / pharmacology*
  • Quinoxalines / chemical synthesis*
  • Quinoxalines / chemistry
  • Quinoxalines / pharmacology*
  • Structure-Activity Relationship

Substances

  • (R,S)-2-((8-chlorobenzofurano(2,3-b)quinolinyl)oxy)propionic acid
  • 2-(4-((7-bromo-2-quinolinyl)oxy)phenoxy)propionic Acid
  • Antineoplastic Agents
  • Benzofurans
  • Propionates
  • Quinolines
  • Quinoxalines
  • XK 469