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

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 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.

Cytotoxicity of 3,4-dihalogenated 2(5H)-furanones

“…The amide 11, which is the azaanalogue of mucochloric acid, depicted a 10-time higher cytotoxicity than the parent compound, the mucochloric acid 1a. As reported (Lattmann et al 2003), 1a produced a good inhibition of cell growth in-vivo and further studies of this novel aza-analogue are in due course.…”

Utilization of Cyanoacetohydrazide and Oxadiazolyl Acetonitrile in the Synthesis of Some New Cytotoxic Heterocyclic Compounds

“…There are numerous reports available in the literature, which indicate the potential anticancer effects of pyridazinones. 6-(4-Hydroxy-2-methylphenyl)-2-(p-sulfamylphenyl)-4,5-dihydropyridazine-3(2H)-one [10] showed high activity against HL-60 (TB) (leukemia), SR (leukemia), NCIH522 (non-small-cell lung cancer), and BT-549 (breast cancer), the p-methoxydichloropyridazone [11] displayed a good inhibition of tumour growth in mice for the resistant MAC16 cell line. Some diphenylpyridazine derivatives [12] (particularly NSC 351478) were effective in the treatment of P388 leukemia in mice.…”

Vitamin B12: An efficient type catalyst for the one-pot synthesis of 3,4,5-trisubstituted furan-2(5 H )-ones and N -aryl-3-aminodihydropyrrol-2-one-4-carboxylates

“…[13,14]. 5H-Furan-2-onederivatives exhibit many pharmacological and biological activities including antifungal, antibacterial, antioxidants, anti-inflammatory, anti-microbial and anti-cancer agents [15][16][17][18][19]. Due to this wide range of abundance and applicability, various approaches toward substituted butenolides have been developed, which involve the use of organo-lithium [20], boronic acids [21,22], transition-metal catalysts such as Pd(OAc) 2 [23], Ru [24], Cu(II) [25], AuCl [26], and secondary amines [27].…”