Design and synthesis of sulfur based inhibitors of matrix metalloproteinase-1

Fibroblast collagenase (MMP-1), a member of the matrix metalloproteinases family, is believed to be a pathogenesis of arthritis, by cleaving triple-helical type II collagen in cartilage. From the similarity of the active site zinc binding mode with hydroxamate, we designed and synthesized alpha-mercaptocarbonyl possessing compounds (3-5), which incorporated various peptide sequences as enzyme recognition sites. The P4-P1 peptide incorporating compound (3) exhibited as potent inhibition as the hydroxamate (1) and the carboxylate (2) type inhibitors, with an IC50 of 10(-6) M order against MMP-1. But the inhibitor (3) related compounds (6-8) displayed decreased or no inhibitory potencies. These results suggest that the existence of both the carbonyl and thiol groups might be critical for the inhibition, and the distance between the two functional groups is important for inhibitory potency. For Pn' peptide incorporating compounds (4a-k), except for 4h and 4k, all compounds showed IC50 values under sub-nanomolar. Among them, for potent inhibition, Leu was better than Phe and Val as the P1' amino acid, and the P2' position amino acid was necessary, and preferentially Phe. Insertion of the Pn peptide into 4d or 4k, giving compounds 5a-c, did not increase the activities of 4d and 4k. Substitution of the mercapto group with other functional groups lost the activity of compound 4a. The stereochemical preference at the thiol-attached position was also determined by preparation of both isomers of 4a. It was found that the S configuration compound (36b) is approximately 100 times more potent than the corresponding R-isomer (36a).     

Assignment of UVB-responsive cis-element and protoplastization-(dilution-) and elicitor-responsive ones in the promoter region of a carrot phenylalanine ammonia-lyase gene (gDcPAL1)

Expression of a carrot phenylalanine ammonia-lyase (PAL) gene (gDcPAL1) in suspension-cultured carrot cells is induced by dilution of the culture or by application of a fungal elicitor, as well as by ultraviolet B (UVB) irradiation. We demonstrated that among its upstream cis-elements (Takeda et al. [1997] Photochem. Photobiol. 66, 464-470), L4 is UVB responsive, and L1 is protoplastization- (dilution-) and elicitor responsive, from studies with transiently transformed mutated or truncated g-DcPAL1 promoter-luc constructs. This conclusion is consistent with our observation that PAL activities induced by UVB and by protoplastization (dilution) or elicitor are additive.     

Preparation and Characterization of Phospha Sugar Analogues, 2,3-Dibromo-3-methyl-1- phenylphospholane 1-Oxide Derivatives,as Novel Anticancer Agents

The synthesis of new phospha sugar analogues or phosphorus heterocycles and their biological activities as novel anticancer agents are reported in this article. A 1,2-dibromo-1,2-dideoxy phospha sugar derivative, 2,3-dibromo-3-methyl-1-phenylphospholane 1-oxide (2), was prepared from 1-phenyl-3-methyl-2-phospholene 1-oxide (1), and the yield and ratio of diastereomers 2a to 2d were changed by a catalyst such as manganese(IV) oxide and manganese(II) bromide. The antitumor activities of the mixture of dibromides 2 and the separated diastereomeric components 2a to 2d of the dibromides were evaluated by MTT in vitro method against the human leukemia cell lines of K562 and U937. The results showed that all of the diastereomers 2a to 2d as well as the diastereomer mixture exert excellent anticancer activity, and moreover, among them, diastereomer 2d showed the highest antitumor activity.

Supplemental materials are available for this article. Go to the publisher's online edition of Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file.     

Invasion inhibitors of human fibrosarcoma HT 1080 cells from the rhizomes of Zingiber cassumunar: structures of phenylbutanoids, cassumunols

The methanolic extract and its EtOAc-soluble fraction from the rhizomes of Zingiber cassumunar inhibited invasion of human fibrosarcoma HT 1080 cells. From the EtOAc-soluble fraction, eight new phenylbutanoids, cassumunols A-H, were isolated together with 30 known constituents. The structures of new phenylbutanoids were elucidated on the basis of chemical and physicochemical evidence. Principal constituents were examined the inhibitory effects on the invasion of HT 1080 cells. Among them, phlain I and III, (E)-1-(3,4-dimethoxyphenyl)buta-1,3-diene, (E)-1-(2,4,5-trimethoxyphenyl)buta-1,3-diene, and (-)-β-sesquiphellandrene showed anti-invasion effects. Interestingly, (E)-1-(2,4,5-trimethoxyphenyl)buta-1,3-diene [inhibition (%) 46.8 ± 7.2 (p<0.05) at 30 μM] significantly inhibited the invasion, and only a weak cytotoxic effect was observed.     

Chiral Bis(oxazoline) Ruthenium Complexes with Bipyridyl‐Type N‐Heteroaromatics: Comparative Stereochemical and Photochemical Characterization of their Λ‐ and Δ‐Diastereomeric Geminate Isomers

Diastereomeric geminate pairs of chiral bis(2‐oxazoline) ruthenium complexes with bipyridyl‐type N‐heteroaromatics, Λ‐ and Δ‐[Ru(L‐ L)₂(iPr‐biox)]²⁺ (iPr‐biox=(4S,4′S)‐4,4′‐diisopropyl‐2,2′‐bis(2‐oxazoline); L‐ L=2,2′‐bipyridyl (bpy) for 1 Λ and 1 Δ, 4,4′‐dimethyl‐2,2′‐bipyridyl (dmbpy) for 2 Λ and 2 Δ, and 1,10‐phenanthroline (phen) for 3 Λ and 3 Δ), were separated as BF₄ and PF₆ salts and were subjected to the comparative studies of their stereochemical and photochemical characterization. DFT calculations of 1 Λ and 1 Δ electronic configurations for the lowest triplet excited state revealed that their MO‐149 (HOMO) and MO‐150 (lower SOMO) characters are interchanged between them and that the phosphorescence‐emissive states are an admixture of a Ru‐to‐biox charge‐transfer state and an intraligand excited state within the iPr‐biox. Furthermore, photoluminescence properties of the two Λ,Δ‐diastereomeric series are discussed with reference to [Ru(bpy)₃]²⁺.     

Genetic and expression analysis of all non‐synonymous single nucleotide polymorphisms in the human deoxyribonuclease I‐like 1 and 2 genes

Members of the human DNase I family, DNase I‐like 1 and 2 (DNases 1L1 and 1L2), with physiological role(s) other than those of DNase I, possess three and one non‐synonymous SNPs in the genes, respectively. However, only limited population data are available, and the effect of these SNPs on the catalytic activity of the enzyme remains unknown. Genotyping of all the non‐synonymous SNPs was performed in three ethnic groups including six different populations using the PCR‐RFLP method newly developed. Asian and African groups including Japanese, Koreans, Ghanaians and Ovambos were typed as a single genotype at each SNP, but polymorphism at only SNP V122I in DNase 1L1 was found in Caucasian groups including Germans and Turks; thus a Caucasian‐specific allele was identified. The DNase 1L1 and 1L2 genes show relatively low genetic diversity with regard to these non‐synonymous SNPs. The level of activity derived from the V122I, Q170H and D227A substituted DNase 1L1 corresponding to SNPs was similar to that of the wild‐type, whereas replacement of the Asp residue at position 197 in the DNase 1L2 protein with Ala, corresponding to SNP D197A, reduced its activity greatly. Thus, SNP V122I in DNase 1L1 exhibiting polymorphism exerts no effect on the catalytic activity, and furthermore SNP D197A in DNase 1L2, affecting its catalytic activity, shows no polymorphism. These findings permit us to postulate that the non‐synonymous SNPs identified in the DNase 1L1 and 1L2 genes may exert no influence on the activity levels of DNases 1L1 and 1L2 in human populations.     

HPLC retention behavior of poly-aromatic-hydrocarbons on aminopropyl silica gels modified with Cu(II)- and Ni(II)-phthalocyanine derivatives in non-polar eluent

A comparative study was conducted to elucidate the mechanism underlying the separation of poly-aromatic-hydrocarbons (PAHs) and related compounds thereof on a column packed with silica gels modified with Ni(II)- or Cu(II)-phthalocyanine derivatives (PCS) (Ni- or Cu-PCS(D) column) and commercially available PYE and NPE columns with a non-polar eluent, such as n-hexane. It has been revealed that the dominant interaction responsible to the separation of PAHs on the Cu-PCS(D) and the PYE columns with n-hexane is the pi-pi interaction; however, in the separation of PAHs having 4 rings such as pyrene on the Ni-PCS(D) column, participation of pi-d interaction was indicated. The predominant role of pi-pi interaction in the separation of PAHs of less than three rings on the Ni-PCS(D) column was demonstrated using anthracene. All the columns possessed planar recognition ability and were estimated to be potentially useful in the separation and the analysis of PAHs.     

Intercomparison of thermal conductivity and thermal diffusivity methods for plastics

An intercomparison of measurements of the thermal conductivity and thermal diffusivity of two poly(methyl methacrylates) is reported. A wide variety of methods were used: temperature wave analysis, laser flash, transient plane source (Hot Disk^®), transient line-source probe, and heat flux meter methods. Very good agreement of thermal conductivity results and, separately, of thermal diffusivity results was obtained. Similarly, good agreement between thermal conductivity and thermal diffusivity results, when converted using specific heat capacity and density values, was also obtained. Typically, the values were within a range of approximately ±10%. Considering the significant differences between the methods and the requirements on specimen dimensions, the level of agreement between results was considered to be good.     

Asymmetric 1,4-addition of organosiloxanes to alpha,beta-unsaturated carbonyl compounds catalyzed by a chiral rhodium complex

Highly enantioselective 1,4-addition of organosiloxanes to alpha,beta-unsaturated carbonyl compounds was found to be catalyzed by a chiral rhodium complex generated from [Rh(cod)(MeCN)(2)]BF(4) and (S)-BINAP. Both (E)- and (Z)-1-alkenyl groups as well as aryl groups can be introduced enantioselectively into the beta-position of a variety of ketones, esters, and amides. [reaction--see text]     

Exfoliated nanosheets as a new strong solid acid catalyst

Two-dimensional metal oxide sheets in HTiNbO(5) and HSr(2)Nb(3)O(10), cation-exchangeable layered metal oxides, were examined as solid acid catalysts. Exfoliation of HTiNbO(5) and HSr(2)Nb(3)O(10) in aqueous solutions formed colloidal single-crystal TiNbO(5)(-) and Sr(2)Nb(3)O(10)(-) nanosheets, which precipitated under an acidic condition to form aggregates of HTiNbO(5) nanosheets and HSr(2)Nb(3)O(10) nanosheets. Although esterification of acetic acid, cracking of cumene, and dehydration of 2-propanol were not catalyzed by original HTiNbO(5) because of the narrow interlayer distance, which prevents the insertion of organic molecules, HTiNbO(5) nanosheets functioned as a strong solid acid catalyst for the reactions. Nanosheets of HSr(2)Nb(3)O(10) exhibited no or slight catalytic activity for these reactions. NH(3) temperature-programmed desorption and (1)H magic-angle spinning nuclear magnetic resonance spectroscopy revealed that HTiNbO(5) nanosheets have strong Br?nsted acid sites, whereas HSr(2)Nb(3)O(10) nanosheets do not.