Synthesis and antitumor activity of some indeno[1,2-b]quinoline-based bis carboxamides

Bioorg Med Chem. 2000 May;8(5):977-84. doi: 10.1016/s0968-0896(00)00039-0.

Abstract

A series of bis(11-oxo-11H-indeno[1,2-b]quinoline-6-carboxamides) linked through the 6-carboxamides were prepared by coupling the requisite acid imidazolides with various diamines. Compounds with mono-cationic linker chains were more potent cytotoxins than the corresponding monomer in a panel of rodent and human cell lines, while those with the dicationic linker chains (CH2)2NR(CH2)2NR(CH2)2 and (CH2)2NR(CH2)3NR(CH2)2 showed extraordinarily high potencies (for example, IC50s of 0.18-1.4 nM against human Jurkat leukemia; up to 1000-fold more potent than the parent monomer). As seen previously in the monomeric series, small, lipophilic 4-substituents significantly increased potency in cell culture. The dimeric compounds were all slightly to significantly more potent in the mutant JL(A) and JL(D) cell lines that under-express topo II, suggesting that this enzyme is not their primary target. An 11-imino-linked dimer was much less active, and an asymmetric indeno[1,2-b]quinoline-6-carboxamide/naphthalimide dimer was less active than the comparable symmetric bis(indeno[1,2-b]quinoline-6-carboxamide). Selected analogues were active against sub-cutaneously implanted colon 38 tumors in mice, giving growth delays comparable to that of the clinical topo I inhibitor irinotecan at up to 10-fold lower doses. These compounds form an interesting new class of putative topo I inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amides / chemical synthesis*
  • Amides / pharmacology*
  • Animals
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / pharmacology*
  • Drug Screening Assays, Antitumor
  • Humans
  • Magnetic Resonance Spectroscopy
  • Mass Spectrometry
  • Mice
  • Quinolines / chemistry*
  • Tumor Cells, Cultured

Substances

  • Amides
  • Antineoplastic Agents
  • Quinolines