Synthesis and evaluation of 5-arylated 2(5H)-furanones and 2-arylated pyridazin-3(2H)-ones as anti-cancer agents

Eric Lattmann*, Washington O. Ayuko, Derek Kinchinaton, Chris A. Langley, Harjit Singh, Leila Karimi, Michael J. Tisdale

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Bis-cyclic butenolides, 5-arylated 2(5H)-furanones 6a-c, 7a, b and the 3(2H)-pyridazones 9a-d were prepared by using the aldehyde form of muco halogen acids in electrophilic substitution reactions and in an aldol-like condensation reaction. The cytotoxicity of these simple and bis-cyclic butenolides have been evaluated in tissue culture studies on MAC 13 and MAC 16 murine colon cancer cell lines. The butyl furanone 3 displayed the highest cytotoxicity of 3 μM, as one selected example of a series of dichlorinated pseudoesters. The 5-arylated 2(5H)-furanones 6 and 7 did not show a structure-activity relationship (SAR) depending on the substitution pattern of the aromatic system. An IC50 (concentration inhibiting growth by 50%) was found within a range of 30-50 and 40-50 μM for the MAC 13 and MAC 16 cell lines, respectively. The pyridazine series 9 showed a maximum in-vitro activity for the p-methoxydrivative 9b, having an IC50 of 17 in MAC 13 and 11 μM in MAC 16 cell lines. Selected examples of each series and further novel 2(5H)-furanones such as the hydrazone 5 and the hydantoin 8 have been screened in-vivo in mice and the data are presented. For the pyridazines 9a-d, the in-vitro cytotoxicity correlated with an in-vivo inhibition of tumour growth. The ring expansion of the 5-membered 2(5H)-furanone ring system such as 6a into the 6-membered 3(2H)-pyridazone 9b led to an agent with improved antineoplastic properties. On the resistant MAC 16 cell line the pyridazone 9b displayed 52% tumour inhibition in mice at a dose of 50 mg kg-1 compared with 27% for the 5-FU standard.

Original languageEnglish
Pages (from-to)1259-1265
Number of pages7
JournalJournal of Pharmacy and Pharmacology
Volume55
Issue number9
DOIs
Publication statusPublished - Sep 2003

Keywords

  • Bis-cyclic butenolides
  • 5-arylated 2(5H)-furanones
  • 3(2H)-pyridazones 9a–d
  • aldehyde form
  • muco halogen acids
  • electrophilic substitution reactions
  • aldol-like condensation reaction
  • cytotoxicity
  • butenolides
  • tissue culture studies
  • murine colon cancer cell lines
  • tumour growth
  • antineoplastic properties

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