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PubMed2000

Interaction of cyclohexanediones with acetyl coenzyme-A carboxylase and an artificial target-site antibody mimic: a comparative molecular field analysis.

Similarities and differences between steric and electrostatic potentials of a monoclonal-antibody-based surrogate of a herbicide target-site and its in vitro enzyme target were investigated using three-dimensional quantitative structure-activity relationship comparative molecular field analysis (3D-QSAR CoMFA). Two separate, five-component, partial least squares CoMFA models were developed to compare the interaction of cyclohexanedione herbicides with their target site, acetyl coenzyme-A carboxylase (ACCase; EC 6.4.1.2) and a cyclohexanedione pharmacophore-specific monoclonal antibody (mAb A). On the basis of CoMFA models, similarities in steric and electrostatic requirements around position 2 of the binding site for the oxime functional group of the cyclohexanedione molecule appear to be crucial for interaction of the herbicide with both ACCase and mAb A. These similarities explain the observed quantitative relationship between binding of cyclohexandedione herbicides to ACCase mAb A. Furthermore, these results support the production and use of mAb-based surrogates of pesticide targets as screening tools in pesticide discovery programs.

Acetyl-CoA Carboxylase↗
PubMed2000

Enzymatic conversion of precarthamin to carthamin by a purified enzyme from the yellow petals of safflower.

Precarthamin, a yellow precursor of carthamin, was efficiently isolated from the yellow petals of safflower (Carthamus tinctorius L. ) with Sephadex LH-20 column chromatography and preparative HPLC, and identified with UV-vis and NMR spectrometry. The UV-vis spectrum of precarthamin showed lambda(max) of 238 and 406 nm in MeOH. The molar extinction coefficients of precarthamin at 406 nm in MeOH and 50 mM citrate buffer (pH 5.0) were 59 000 M(-)(1) cm(-)(1) and 45 400 M(-)(1) cm(-)(1), respectively. The isolated and structurally identified precarthamin was converted to a red pigment by a homogeneously purified enzyme from the immature petals of safflower in 50 mM citrate buffer (pH 5.0). The enzymatically converted red pigment was identified as carthamin, a red pigment of safflower by TLC, HPLC, and UV-vis spectral analysis.

Chalcone↗
PubMed2001

Synthesis of new cyclitol compounds that influence the activity of phosphatidylinositol 4-kinase isoform, PI4K230.

The synthesis, chemical derivatization, and investigation of the inhibitory properties of novel cyclitol derivatives on the phosphatidylinositol 4-kinase enzymes PI4K55 and PI4K230 involved in the phosphatidylinositol cycle are reported. Some of the prepared cyclitol derivatives (i.e. 9, 11, 12, and 14) proved to be very powerful and specific irreversible inhibitors of PI4K230 at or below a concentration of 1 mM.

Animals↗
PubMed1981

4-aryl-4-aminocyclohexanones and their derivatives, a novel class of analgesics. 3. m-Hydroxyphenyl derivates.

Derivatives of 4-aryl-4-(dimethylamino)cyclohexan-1-ones substituted by m-hydroxy groups were obtained by using as a key reaction the displacement of cyanide from the alpha-aminonitrile of 1,4-cyclohexanedione ketal, with the THP ether of m-hydroxyphenylmagnesium bromide. A number of the products show narcotic antagonist activity. Amino alcohols obtained on reaction of the free ketones with phenethyl Grignard reagents are potent analgetics, though devoid of antagonist activity. Systematic variation of the substituent on nitrogen revealed nonclassical structure-activity relationships; the dimethylamino group gives the most potent antagonist.

Analgesics↗
PubMed1981

4-amino-4-arylcyclohexanones and their derivatives: a novel class of analgesics. 2. Modification of the carbonyl function.

The effect on potency of modification of the carbonyl function of analgesics derived from 4-(dimethylamino)-4-arylcyclohexan-1-one was studied by reduction and by addition of nucleophiles. The resulting amino alcohols were separated and assigned structures on the basis of X-ray crystallography, NMR, and TLC mobility. The trans (OH and N) isomers were invariably more potent than the cis. Inclusion of flat lipophilic moieties (phenyl, cyclohexenyl) at a distance of at least two carbon atoms from the carbon bearing hydroxyl led to increases in potency by orders of magnitude. The possible significance of this on receptor interaction is discussed.

Analgesics↗
PubMed1985

Synthesis and activity of 5-(aminomethylene)-1,3-cyclohexanediones: enolic analogues of gamma-aminobutyric acid.

Eight 1,3-cyclohexanediones with an aminoalkyl side chain in the 5-position were synthesized as rigid enolic analogues of GABA (gamma-aminobutyric acid). Biochemical investigations about their abilities to displace [3H]GABA and [3H]baclofen [beta-(p-chlorophenyl)-gamma-aminobutyric acid] in binding studies or to inhibit the high-affinity sodium-dependent GABA uptake showed that these compounds were generally devoid of affinity for the two GABA receptors and for the GABA carrier. Only compound 1 exhibited a weak affinity in the GABA-A binding experiments (IC50 = 6.5 X 10(-5) M). Graphic computer modeling was applied in an attempt to explain this activity in comparison to some reference GABA agonists. Electrophysiological studies on dorsal root ganglia (DRG) also excluded agonistic or antagonistic properties on GABA-A or GABA-B receptor models but pointed out an atypical prolongation of Ca2+-dependent action potential for compound 1.

Action Potentials↗
PubMed1980

4-Amino-4-arylcyclohexanones and their derivatives, a novel class of analgesics. 1. Modification of the aryl ring.

Investigation of central nervous system activity of phenylcyclohexylamines was continued by preparation of "reversed" analogues. Following the unexpected finding of analgesic activity with 1-(dimethylamino)-1-phenylcyclohexylamine, the SAR of the series was investigated. Synthesis starts by double Michael reaction of acrylate on arylacetonitriles. Following cyclization, decarboxylation, ketalization, and saponification, the geminally substituted acid is rearranged to the isocyanate by means of (C6H5O)2PON3. Isocyanates were then converted to the title compounds. Analgesic activity is very sensitive to the nature and position of the substitutent on the aromatic ring. The most potent compounds in this series (p-CH3, p-Br) showed 50% the potency of morphine. Deletion of the ring oxygen abolishes activity.

Analgesics↗
PubMed2003

Molecular basis of the antitumor activities of 2-crotonyloxymethyl-2-cycloalkenones.

The antitumor activity of 2-crotonyloxymethyl-2-cyclohexenone (COMC-6) is not the result of the GSH conjugate (GSMC-6) formed inside tumor cells, as the diethyl ester prodrug form of GSMC-6 displays little antitumor activity with B16 melanotic melanoma in vitro (IC(50) > 460 microM) versus COMC-6 (IC(50) 0.041 microM) and its five- and seven-membered ring homologues. Antitumor activity probably results from a reactive intermediate that forms during conjugation of the COMCs with intracellular GSH.

Animals↗
PubMed2003

4-Substituted 4-hydroxycyclohexa-2,5-dien-1-ones with selective activities against colon and renal cancer cell lines.

The synthesis and antitumor evaluation of a series of new heteroaromatic- and aromatic-substituted hydroxycyclohexadienones ("quinols"), and their imine counterparts, are described. The quinols were synthesized via the addition of a lithiated aromatic moiety to a quinone ketal followed by deprotection. When the aromatic portion of the molecule is a fused heterobicyclic structure (e.g., benzothiazole derivative 7a), potent in vitro antitumor activity was observed in HCT 116 (GI50 = 40 nM) and HT 29 (GI50 = 380 nM) human colon as well in as MCF-7 and MDA 468 human breast cancer cell lines. When examined on the NCI Developmental Therapeutics Screening Program in vitro screen (60 human cancer cell lines), active compounds in this series consistently displayed a highly unusual pattern of selectivity; cytotoxicity (LC50) was concentrated in certain colon and renal cell lines only. Analogue 7a also showed in vivo antitumor activity against human RXF 944XL renal xenografts in nude NMRI mice and is the focus of further study.

Algorithms↗
PubMed2003

Fumagalone, a reversible inhibitor of type 2 methionine aminopeptidase and angiogenesis.

Fumagillin and ovalicin constitute a family of structurally related natural products that possess antiangiogenic activity. We report the synthesis of a new fumagillin analogue, fumagalone, in which the spiroepoxide group is replaced with an aldehyde. Fumagalone inhibits type 2 methionine aminopeptidase (MetAP2) with IC(50) = 8 microM and endothelial cell proliferation with IC(50) = 52 nM. With dialysis and competition assays, it was unambiguously demonstrated that binding of fumagalone to MetAP2 is reversible.

Aminopeptidases↗
PubMed2005

Quinols as novel therapeutic agents. 2.(1) 4-(1-Arylsulfonylindol-2-yl)-4-hydroxycyclohexa-2,5-dien-1-ones and related agents as potent and selective antitumor agents.

A series of substituted 4-(1-arylsulfonylindol-2-yl)-4-hydroxycyclohexa-2,5-dien-1-ones (indolylquinols) has been synthesized on the basis of the discovery of lead compound 1a and screened for antitumor activity. Synthesis of this novel series was accomplished via the "one-pot" addition of lithiated (arylsulfonyl)indoles to 4,4-dimethoxycyclohexa-2,5-dienone followed by deprotection under acidic conditions. Similar methodology gave rise to the related naphtho-, 1H-indole-, and benzimidazole-substituted quinols. A number of compounds in this new series were found to possess in vitro human tumor cell line activity substantially more potent than the recently reported antitumor 4-substituted 4-hydroxycyclohexa-2,5-dien-1-ones(1) with similar patterns of selectivity against colon, renal, and breast cell lines. The most potent compound in the series in vitro, 4-(1-benzenesulfonyl-6-fluoro-1H-indol-2-yl)-4-hydroxycyclohexa-2,5-dienone (1h), exhibits a mean GI(50) value of 16 nM and a mean LC(50) value of 2.24 muM in the NCI 60-cell-line screen, with LC(50) activity in the HCT 116 human colon cancer cell line below 10 nM. The crystal structure of the unsubstituted indolylquinol 1a exhibits two independent molecules, both participating in intermolecular hydrogen bonds from quinol OH to carbonyl O, but one OH group also interacts intramolecularly with a sulfonyl O atom. This interaction, which strengthens upon ab initio optimization, may influence the chemical environment of the bioactive quinol moiety. In vivo, significant antitumor activity was recorded (day 28) in mice bearing subcutaneously implanted MDA-MB-435 xenografts, following intraperitoneal treatment of mice with compound 1a at 50 mg/kg.

Animals↗
PubMed2005

Selective inhibition of MCF-7(piGST) breast tumors using glutathione transferase-derived 2-methylene-cycloalkenones.

Human glutathione (GSH) transferase (hGSTP1-1) catalyzes the conversion of antitumor 2-crotonyloxymethyl-2-cycloalkenones (COMCs) to highly reactive exocyclic enone alkylating agents. In vitro efficacy studies show that the cytotoxicities of the COMCs directly correlate with the level of expression of GSTP1-1 in MCF-7(piGST) versus MCF-7wt breast tumors, indicating that the exocyclic enones are the actual cytotoxic species. The COMCs are a potentially important new class of prodrugs, which can specifically target multi-drug-resistant tumors overexpressing hGSTP1-1.

Antineoplastic Agents, Alkylating↗
PubMed1999

Conformational and quantitative structure-activity relationship study of cytotoxic 2-arylidenebenzocycloalkanones.

Various 2-arylideneindanones 1, 2-arylidenetetralones 2, and 2-arylidenebenzosuberones 3 were synthesized with the aim of determining the relative orientations of the two aryl rings which favored cytotoxicity. Molecular modeling of the unsubstituted compound in each series revealed differences in the spatial arrangements of the two aryl rings, and evaluation of these compounds against P388, L1210, Molt 4/C8, and CEM cells as well as a panel of human tumor cell lines indicated that in general the order of cytotoxicity was 3 > 2 > 1. In particular 2-(4-methoxyphenylmethylene)-1-benzosuberone (3k) had the greatest cytotoxicity, possessing 11 times the potency of the reference drug melphalan when all five screens were considered. Series 3 was considered in further detail. First, excision of the aryl ring fused to the cycloheptanone moiety in series 3 led to some 2-arylidene-1-cycloheptanones 4 which had approximately one-third of the bioactivity of the analogues 3. Second, in some screens cytotoxicity was correlated negatively with the sigma values and positively with the MR constants of the substituents in the arylidene aryl ring of 3. Third, X-ray crystallography of five representative compounds (3i,k-n) revealed differences in the locations of the aryl rings which may have contributed to the variations in cytotoxicity. Finally three members of series 3 inhibited RNA and protein syntheses and induced apoptosis in human Jurkat T cells. This study has revealed that 2-arylidene-1-benzosuberones are a group of useful cytotoxic agents, and in particular 3k serves as a prototypic molecule for subsequent structural modifications.

Animals↗
PubMed2003

Stereochemical analysis by solid-state NMR: structural predictions in ambuic acid.

Relative stereochemistry is predicted for ambuic acid using a novel solid-state NMR approach. This NMR technique entails a comparison of measured shift tensor principal values with computed values for all diastereomers, allowing the selection of a best-fit structure. The proposed method extends previous solution NMR structural data by simultaneously modeling with high statistical probability hydrogen-bonding arrangements and molecular conformation at two positions. A dimeric structure is proposed for ambuic acid based on the initial poor fit of the carboxyl carbon tensors to a monomeric model. The dimer model, consisting of hydrogen bonding between pairs of neighboring carboxyl groups, reduces the root mean square error at the carboxy tensor by a factor of 2.7. Lattice details are thus also described by the proposed approach. The structural characterization method presented is of general applicability and may be especially useful for characterizing difficult to crystallize or hydrogen-poor materials.

Carbon Isotopes↗
PubMed2003

Nitrosation of 2-acetylcyclohexanone. 2. Reaction in water in the absence and presence of cyclodextrins.

The kinetic study of the nitrosation of the enol of 2-acetylcyclohexanone (ACHE) has been performed in aqueous acid media in the absence and presence of alpha- and beta-cyclodextrin. The reaction is first-order with respect to both reactants concentration: [nitrite] and [ACHE]; but, unexpectly, the dependence of both [H(+)] or [X(-)] (X(-) = Cl(-), Br(-), or SCN(-)) is not simple first-order. The experimental findings have been explained on the basis of a reaction mechanism that considers the formation of a chelate-nitrosyl complex intermediate in steady-state. Addition of both alpha-cyclodextrin (alpha-CD) or beta-cyclodextrin (beta-CD) diminishs strongly the observed rate constant, k(o), measured either for enol-nitrosation or for enol-ketonization reactions. In the case of beta-CD, the inhibition effect is explained through the formation of nonproductive inclusion complexes between the enol (EH) and beta-CD of 1:1 stoichiometry. Nevertheless, the quantitative interpretation of k(o)-[alpha-CD] profiles requires the assumption that the inclusion complexes formation of both 1:1 (EH/alpha-CD) and 1:2 (EH/alpha-CD(2)) stoichiometries. In the case of enol-ketonization, the EH/alpha-CD complex is nearly as reactive as the uncomplexed enol.

Algorithms↗