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

Lattmann, Eric, Ayuko, Washington O., Kinchinaton, Derek, Langley, Chris A., Singh, Harjit, Karimi, Leila and Tisdale, Michael J. (2003). Synthesis and evaluation of 5-arylated 2(5H)-furanones and 2-arylated pyridazin-3(2H)-ones as anti-cancer agents. Journal of Pharmacy and Pharmacology, 55 (9), pp. 1259-1265.

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.

Publication DOI: https://doi.org/10.1211/0022357021756
Divisions: Life & Health Sciences > Pharmacy
Life & Health Sciences
Uncontrolled 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,Pharmacology,Pharmaceutical Science
Full Text Link: http://onlinelibrary.wiley.com/doi/10.1211/0022357021756/abstract
Related URLs: http://www.scopus.com/inward/record.url?scp=0141459482&partnerID=8YFLogxK (Scopus URL)
Published Date: 2003-09
Authors: Lattmann, Eric
Ayuko, Washington O.
Kinchinaton, Derek
Langley, Chris A. ( 0000-0002-0178-3778)
Singh, Harjit
Karimi, Leila
Tisdale, Michael J.

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