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A series of 2-(N-cyclicamino)chromone derivatives (1a-4c) and 3-(N-cyclicamino)chromone derivatives (5a-8c) were synthesized, and their monoamine oxidase (MAO) A and B inhibitory activities were studied as part of a structure-activity relationship investigation. Compounds 1a-4c showed no remarkable inhibition for MAO-A or MAO-B, whereas compounds 5a-8c (with a few exceptions) showed significant and selective inhibition of MAO-B. Of these compounds, 7c, 7-methoxy-3-(4-phenyl-1-piperazinyl)-4H-1-benzopyran-4-one inhibited MAO-B the most potently and selectively, having IC50 of 15 nM and an MAO-B selectivity index of more than 6700; c.f, 50 nM and 2000, respectively, for safinamide. The mode of inhibition of 7c to MAO-B was competitive and reversible. Considering the IC50 values and selectivity indices of the other synthetic compounds, the presence of the methoxy group on the chromone ring (R2) of 7c seemed to increase MAO-B inhibition. Molecular docking analysis also supports this hypothesis. Our results suggest that 3-(N-cyclicamino)chromones are useful lead compounds for the development of MAO-B inhibitors.

A novel p-coumaroyl dimethyl malate (1) was isolated from the Pandanus amaryllifolius leaf in addition to three known analogs of p-coumaroyl dimethyl malate (2-4), and their structures were elucidated by analysis of the spectroscopic data. The p-coumaroyl malate derivatives were isolated as a mixture of E and Z isomers. To determine the cause of isomerization, the p-coumaroyl malate isolated in this study was synthesized. We concluded that the Z isomer might be an artifact generated from the E isomer through purification steps.

A series of piperic acid amides (4?24, 29, 30) were synthesized and their 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical scavenging and α-glucosidase inhibitory activities were evaluated. Among the synthesized compounds, the amides 11, 13 and 15, which contain o-methoxyphenol, catechol or 5-hydroxyindole moieties, showed potent DPPH free radical scavenging activity (11: EC50 140??M; 13: EC50 28??M; 15: EC50 20??M). The amides 10, 18 and 23 showed higher inhibitory activity of α-glucosidase (10: IC50 21??M; 18: IC50 21??M; 23: IC50 12??M). These data suggest that the hydrophobicity of the conjugated amines is an important determinant of α-glucosidase inhibitory activity. In addition, the amides 13 and 15 showed both potent DPPH free radical scavenging activity and α-glucosidase inhibitory activity (13: IC50 46??M; 15: IC50 46??M). This is the first report identifying the DPPH free radical scavenging and α-glucosidase inhibitory activities of piperic acid amides and suggests that these amides may serve as lead compounds for the development of novel α-glucosidase inhibitors with antioxidant activity.

A series of fatty acid amides were synthesized and their peroxisome proliferator-activated receptor α (PPAR-α) agonistic activities were evaluated in a normal rat liver cell line, clone 9. The mRNAs of the PPAR-α downstream genes, carnitine-palmitoyltransferase-1 and mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase, were determined by real-time reverse transcription-polymerase chain reaction (RT-PCR) as PPAR-α agonistic activities. We prepared nine oleic acid amides. Their PPAR-α agonistic activities were, in decreasing order, N-oleoylhistamine (OLHA), N-oleoylglycine, Oleamide, N-oleoyltyramine, N-oleoylsertonin, and Olvanil. The highest activity was found with OLHA. We prepared and evaluated nine N-acylhistamines (N-acyl-HAs). Of these, OLHA, C16:0-HA, and C18:1Δ(9)-trans-HA showed similar activity. Activity due to the different chain length of the saturated fatty acid peaked at C16:0-HA. The PPAR-α antagonist, GW6471, inhibited the induction of the PPAR-α downstream genes by OLHA and N-oleoylethanolamide (OEA). These data suggest that N-acyl-HAs could be considered new PPAR-α agonists.

Three functional groups (2-propenyl, 2-propynyl, and 2,3-butadienyl) were introduced onto one of the terminal amino groups of spermidine. Of the six compounds synthesized, N-(3-aminopropyl)-N'-2,3-butadienyl-1,4-butanediamine (N(8)-butadienyl Spd) and N-[3-(2,3-butadienylamino)propyl]-1,4-butanediamine (N(1)-butadienyl Spd) irreversibly inactivated human spermine oxidase (SMO) and N(1)-acetylpolyamine oxidase (APAO). Interestingly, N(8)-butadienyl Spd inactivated SMO far more potently than N,N'-di-2,3-butadienyl-1,4-butanediamine (MDL 72527).

An assay method to measure N(1)-acetylpolyamine oxidase (PAO) activity with N(1),N(11)-didansylnorspermine (DiDNS333) as the substrate by high performance liquid chromatography (HPLC) was developed. Dansylpolyamines were synthesized, and their activity as a substrate for partially purified PAO from rat liver was evaluated. Among the dansylpolyamines, DiDNS333 was a useful substrate for the development of the PAO assay method. DiDNS333 was degraded by PAO to 1-dansylamido-3-propanal (DNS3al) and N(1)-dansylnorspermidine (DNS33). As DNS3al was separated into two peaks by HPLC of the assay mixture containing aminoguanidine, determination of DNS33 was used for the development of the assay method. When the assay method was applied to inhibition studies, the DNS33 peak on the chromatogram was consistently produced, and weak interference was found in the incubation with higher concentrations of natural polyamines. This result suggested that contaminating polyamines in biological samples do not interfere with this method. When the assay method was applied to cell extract from Chinese hamster ovary cell samples, the PAO activity, even at the low level in the cells, could easily be detected with as little as 10 microg of protein, which corresponds to 1x10(5) cells. This HPLC method is a rapid, sensitive and useful assay for the measurement of PAO activity.

We recently reported that C-terminal polyamine modification occurs when proteins are digested with trypsin in the presence of polyamine [Biochem. Biophys. Res. Commun., 356, 159-162 (2007)]. In the present study, the characteristics of this C-terminal modification in the presence of protease and amine were investigated. When hemoglobin (HB) was digested with trypsin in the presence of N-(2-pyridyl)-1,4-diaminobutane (Py4), formation of the modified peptide was dependent on time and on HB or Py4 concentration. When synthetic peptide was treated with trypsin in the presence of Py4, ca. 0.1% of the peptide was modified with Py4. When HB or cytochrome C was treated with a range of serine proteases in the presence of various amines (Py4, N-(2-pyridyl)-1,3-diaminopropane, tranexamic acid, isonicotinic acid hydrazide and ampicillin), the modified peptide was detected in all cases tested, thus suggesting that amine modification widely accompanies digestion by proteases.

Prodrugs that can readily release polyamine into cells without the problem of generating cytotoxic compound by serum amine oxidase would be extremely useful for elucidation of polyamine function. As linear polyamines with acetamide groups on both sides are thought to be stable in the presence of serum amine oxidase and produce polyamines by the catalytic reaction of acetylpolyamine oxidase (PAO), a series of diacetyltetraamines, diacetylpentaamines and diacetylhexaamines was prepared as prodrugs and tested for substrate activity against PAO, partially purified from rat liver. Of the compounds, N(1),N(15)-diacetyl-1,15-diamino-4,8,12-triazapentadecane (DA3333) and N(1),N(16)-diacetyl-1,16-diamino-4,8,13-triazahexadecane (DA3343) were found to be stable in culture medium containing newborn bovine serum, and to produce reasonable amounts of norspermidine and spermidine, respectively. DA3333 and DA3343 were then applied to 1-aminooxy-3-aminopropane (AOAP)-treated HTC cells with depleted putrescine and spermidine, and arrested growth. Cell growth recovered with DA3333 and DA3343, but growth rate was reduced in cells with added DA3333 compared with growth rates in cells with added DA3343 and control cells untreated with AOAP. Significant amounts of norspermidine and spermidine were found in cells with added DA3333 and DA3343, respectively. These results show the potential use of diacetylpolyamines in introducing polyamines into cells.

A close relationship between rat liver regeneration and the concentration ratio of spermidine to spermine (spd : spm) was demonstrated by the oral administration of trans-4-methylcyclohexylamine (MCHA), a specific inhibitor of putrescine aminopropyltransferase. A decrease in recovery rate of remnant liver with MCHA, as a percentage index of remnant liver weight to body weight, correlated well with a decrease of the spd : spm value, with a correlation coefficient of 0.952 for the remnant livers on day 3 after partial hepatectomy. The decrease in recovery rate could be explained by a prolonged cell cycle based on the data of the proliferating cell nuclear antigen labelling index and mitotic cell index in both livers of day 2 and day 3 after partial hepatectomy. The results presented here will give a new aspect in the field of polyamine regulation to control cell growth in vivo.

A novel enantioselective synthesis of 1, 3-dioxin-4-ones having a 2-hydroxylated alkyl group at the 6-position has been accomplished by chiral tartaric acid-derived acylborane-mediated aldol condensation of the silyl enol ether derived from 6-methyl-derivatives of 1, 3-dioxin-4-one with achiral aldehydes.

Utilizing an enaminoketone (1) as starting material, 3-substituted chromones were synthesized by the reactions of acid anhydrides derivatives under mild conditions.

We describe a convenient preparation of isoflavones by the cross-coupling reactions of 3-iodo-chromone (1) with arylboronic acids (2) catalyzed by tetrakis(triphenylphosphine)palladium(0).