Synthesis and evaluation of 5-arylated 2(5H)-furanones and 2-arylated pyridazin-3(2H)-ones as anti-cancer agents.
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 microM, 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 microM 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 microM 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.
Lattmann
Eric
E
The School of Pharmacy, Aston University, Aston Triangle, Birmingham, UK. e.lattmann@aston.ac.uk
Ayuko
Washington O
WO
Kinchinaton
Derek
D
Langley
Christopher A
CA
Singh
Harjit
H
Karimi
Leila
L
Tisdale
Michael J
MJ
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001835:Body Weight / Q000187:drug effects; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000473:pathology; D004354:Drug Screening Assays, Antitumor / Q000379:methods*; D005663:Furans / Q000138:chemical synthesis* / Q000494:pharmacology; D051379:Mice; D008815:Mice, Inbred Strains; D009368:Neoplasm Transplantation / Q000379:methods; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D005663:Furans