Cytotoxic 5-aryl-1-(4-nitrophenyl)-3-oxo-1,4-pentadienes mounted on alicyclic scaffolds

European Journal of Medicinal Chemistry

et al. 2009

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This study demonstrated that replacement of the axial protons on the C2 and C6 atoms of various 1-methyl-3,5-bis(benzylidene)-4-piperidones 3 by a dimethylene bridge leading to series 2 lowered cytotoxic potencies. Four compounds 2a and 3a-c emerged as lead molecules based on their toxicity towards different neoplasms and their selective toxicity for malignant rather than normal cells. Some possible reasons for the disparity between the IC 50 values in the two series of compounds are presented based on molecular modeling, log P values and respiration in rat liver mitochondria.

Section: Introductionmentioning

confidence: 99%

The cytotoxic properties and preferential toxicity to tumour cells displayed by some 2,4-bis(benzylidene)-8-methyl-8-azabicyclo[3.2.1] octan-3-ones and 3,5-bis(benzylidene)-1-methyl-4-piperidones

Pati

European Journal of Medicinal Chemistry

et al. 2009

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“…Recently a small number of 2,6-bis(benzylidene) cyclohexanones were prepared in which the substituents in each of the aryl rings differed in their electronic properties. 7,8 In these molecules, the charges on the olefinic carbon atoms are predicted to be divergent thereby enhancing sequential reactions.…”

Section: Introductionmentioning

confidence: 99%

“…Second, the original series consisted of a small group of compounds which possessed widely differing potencies in the Molt 4/C8, CEM, and L1210 bioassays. 8 Hence expansion of the cluster of compounds was indicated in order to draw meaningful conclusions pertaining to those structural features which contribute to cytotoxicity.…”

Section: Introductionmentioning

confidence: 99%

E,E-2-Benzylidene-6-(nitrobenzylidene)cyclohexanones: Syntheses, cytotoxicity and an examination of some of their electronic, steric, and hydrophobic properties

Doroudi

Bioorganic & Medicinal Chemistry

et al. 2008

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Three series of structurally isomeric 2-benzylidene-6-(nitrobenzylidene) cyclohexanones 1-3 were prepared and evaluated against human Molt/C8 and CEM T-lymphocytes as well as murine L1210 cells. The IC 50 values of the majority of compounds are less than 10 μM and in some assays, the figures for 1d and 1e are submicromolar. Correlations were discerned between cytotoxic potencies and the atomic charges on one of the olefinic carbon atoms, the torsion angles between an aryl ring, and the adjacent unsaturated group as well as logP values. Three representative compounds were examined for their effect on respiration in rat liver mitochondria.

“…Compounds containing the 1,5-diaryl-3-oxo-1,4-pentadienyl group were synthesized at the College of Pharmacy and Nutrition, University of Saskatchewan using reported procedures [2,[6][7][8][9]14]. Tris (tris(hydroxymethyl)aminomethane) and HPLC grade acetonitrile were purchased from Fisher Scientific (Ottawa, ON, Canada).…”

Section: Chemicals and Reagentsmentioning

confidence: 99%

“…1) [4]. The literature refers to this pharmacophore as a curcumin analogue [5], and a substantial number of these compounds have excellent antineoplastic properties [2,[6][7][8][9][10]. Other laboratories are also examining the biological potential of this pharmacophore [5,[11][12][13].…”

Section: Introductionmentioning

confidence: 99%

A general HPLC–UV method for the quantitative determination of curcumin analogues containing the 1,5-diaryl-3-oxo-1,4-pentadienyl pharmacophore in rat biomatrices

Singh

Journal of Chromatography B

Dimmock

et al. 2010

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Curcumin and its derivatives generally display favorable cytotoxic activities against a number of cancer cell types. We focus our rational antineoplastic drug design program on curcumin analogues containing the 1,5-diaryl-3-oxo-1,4-pentadienyl pharmacophore. Favorable outcomes from pharmacological screens of this series demanded further pharmacokinetic evaluations to determine their suitability as effective compounds in vivo. To allow such evaluations and to provide a general, sensitive, rapid and simple method for the analysis of compounds containing the 1,5-diaryl-3-oxo-pentadienyl scaffold, we developed an HPLC method with ultraviolet detection for their detection in various biological matrices of a relevant preclinical species, i.e. the rat. Our HPLC method is specific for the analysis of many members in this series in rat blood, plasma, serum and hepatic microsomes following liquid-liquid extraction with TBME (1:30, v/v). The assay procedure involves chromatographic separation on a Zorbax-Eclipse C-18 column under isocratic conditions with the mobile phase consisting of acetonitrile and ammonium acetate buffer (pH 5.0, 10 mM) in different ratios depending upon the compound. The method was validated for NC 2083 in rat serum and rat liver microsomes, a potential lead compound, to demonstrate its applicability. The standard curve was linear (r 2 ≥ 0.997) from 50 to 5000 ng/mL. Intra-and interday precision and accuracy of the method were within USFDA specified limits. The stability of NC 2083 was established in an auto-injector, on bench-top, during freeze-thaw cycles and longterm stability at −80 °C for 40 days. The method is suitable for a number of compounds containing the 1,5-diaryl-3-oxo-pentadienyl scaffold with divergent log P values with only minor adjustments in the buffer to acetonitrile ratio of the mobile phase.