Mutagenicity of some substituted 1-phenyl-3,3-dimethyltriazenes. II. Chromosomal aberrations in human peripheral lymphocytes in vitro

The chromosome-breaking activity of four 1-(phenyl)-3,3-dimethyltriazenes was tested in vitro on human peripheral blood lymphocytes using S9 mix as a metabolic activation system. 1-(4-Nitrophenyl)-3,3-dimethyltriazene was the most active compound. The difference in the frequency of chromosomal aberrations in a test with and without metabolic activation was significant at the 1% level of significance. The lowest frequency of chromosomal aberrations was induced by 1-(4-methylphenyl)-3,3-dimethyltriazene which, under the conditions of this experiment, is the least stable and probably rapidly degraded to non-active compounds. The chromosomal aberrations were also induced by 1-(4-chlorophenyl)-3,3-dimethyltriazene and 1-(4-bromophenyl)-3,3-dimethyltriazene, this activity was unrelated to metabolic activation.     

Mutagenicity of some substituted 1-phenyl-3,3-dimethyltriazenes: II. Chromosomal aberrations in human peripheral lymphocytes in vitro

The chromosome-breaking activity of four 1-(phenyl)-3,3-dimethyltriazenes was tested in vitro on human peripheral blood lymphocytes using S9 mix as a metabolic activation system. 1-(4-Nitrophenyl)-3,3-dimethyltriazene was the most active compound. The difference in the frequency of chromosomal aberrations in a test with and without metabolic activation was significant at the 1% level of significance. The lowest frequency of chromosomal aberrations was induced by 1-(4-methylphenyl)-3,3-dimethyltriazene which, under the conditions of this experiment, is the least stable and probably rapidly degraded to non-active compounds. The chromosomal aberrations were also induced by 1-(4-chlorophenyl)-3,3-dimethyltriazene and 1-(4-bromophenyl)-3,3-dimethyltriazene, this activity was unrelated to metabolic activation.     

Induction of mitotic gene conversion by 3,3-dimethyl-I-phenyltriazene, I-(3-hydroxyphenyl-)-3,3-dimethyltriazene and by I-(4-hydroxyphenyl)-3,3-dimethyltriazene in Saccharomyces cerevisiae

The induction of mitotic gene conversion by 3,3-dimethyl-1-phenyltriazene (DMPT), 1-(3-hydroxyphenyl)-3,3-dimethyltriazene (3-HO-PDMT) and by 1-(4-hydroxyphenyl)-3,3-dimethyltriazene (4-HO-PDMT) in the diploid strain D4 of Saccharomyces cerevisiae was investigated. The frequencies of the non-reciprocal intragenic recombinations at two unlinked loci ade2 (adenine) and trp5 (tryptophan) were determined. Although all three triazenes showed marked convertogenic activities, significant differences in their genetic effectiveness have been observed. Thus both phenolic triazenes were found to be much stronger convertogens than the unhydroxylated parent compound, DMPT. An attempt is made to account for the established differences in convertogenicity by chemical reactivity that could be expected from the structural features of the tested alkaryltriazenes.     

Induction of 8-azaguanine- and ouabain-resistant mutants by cyclophosphamide and 1-(pyridyl-3)-3,3-dimethyltriazene in Chinese hamster cells cultured in diffusion chambers in mice.

A host-mediated assay is described for induction of 8-azaguanine-resistant (azgr) and ouabain-resistant (ouar) mutants in Chinese hamster V79 cells cultured in diffusion chambers (DC) in C3H mice. Injection of the hosts with the indirect mutagen/carcinogen cyclophosphamide (CPP) or 1-(pyridyl-3)-3,3-dimethyltriazene (PyDT) caused a dose-dependent increase in mutation frequency at the loci of azgr and ouar in the V79 target cells. Plating efficiency of V79 cells in DC in mice was decreased depending upon the dose of CPP or PyDT given to the hosts. In addition, the relationship between expression time and mutation frequency was examined and discussed. The data support the use of this system as an effective screening procedure for suspected environmental mutagens or carcinogens, especially those that need to be metabolically activated in vivo.     

Mutagenicity of some substituted 1-phenyl-3,3-dimethyltriazenes. I. The salmonella/mammalian microsome assay and repair test

The mutagenic activity and related biological properties of Br-, Cl-, NO2- and CH3-derivatives of 1-(phenyl)-3,3-dimethyltriazene were investigated in Salmonella/microsome assays with standard and preincubation metabolic activation and in the repair test using Salmonella and E. coli B/r. In the repair test, the CH3-derivative was slightly positive in the E. coli recA and uvrA repair system, the NO2-derivative had a killing effect on Salmonella typhimurium uvrB-deficient strains. In Salmonella mutagenicity assays, all tested triazene derivatives reverted frameshift tester strains, especially TA1537. The highest number of frameshift mutations was induced by the CH3-derivative in the presence of a standard metabolic activation system; direct mutagenicity of this derivative was weak, reaching about the same level of activity as seen after preincubation. The only test compound that induced mutations of the base-substitution type was the NO2-derivative; this derivative showed the highest mutagenicity when activated by preincubation.     

Influence of inhibition of the metabolic activation on the mutagenicity of some nitrosamines, triazenes, hydrazines and seniciphylline in Drosophila melanogaster

It is determined to what extent certain inhibitors of the xenobiotic metabolizing enzyme systems have an influence on the mutagenicity of various pro-mutagens in Drosophila. 1-Phenylimidazole (PhI) is used as an inhibitor of the cytochrome P-450 (P-450) mediated monooxygenase activities. Iproniazid (Ipr) is a typical monoamine oxidase (MAO) inhibitor which as well seems capable of inhibiting to a certain extent P-450 mediated metabolism. N, N-Dimethyl benzylamine (N, N-DMB) is used as a competitive substrate for the N-oxidizing flavin-containing dimethylaniline monooxygenase (FDMAM). The enzyme-inhibiting activities of PhI and Ipr were determined in vitro using microsomes obtained from Drosophila larvae and adults. Both compounds were capable of inhibiting benzo[a]pyrene (BP) hydroxylation and p-nitroanisole (p-NA) demethylation, although for Ipr 100-fold higher concentrations were required compared to PhI. As model-mutagens were used: the nitrosamines dimethylnitrosamine (DMN) and diethylnitrosamine (DEN), the triazenes 1-(2,4,6-trichlorophenyl)-3,3-dimethyltriazene (Cl3PDMT), 1-(3-pyridyl)-3,3-dimethyltriazene (PyDMT) and dacarbazine (DTIC), the hydrazines procarbazine (PCZ), 1,1-dimethylhydrazine (1,1-DMH) and 1,2-dimethylhydrazine (1,2-DMH) as well as the pyrrolizidine alkaloid seniciphylline (SPh). Simultaneous or pretreatment with Ipr results in a clear decrease of the mutagenicity of Cl3PDMT, while PhI pretreatment leads to an increased mutagenicity. This indicates that these two inhibitors do not inhibit the same enzyme or isozyme. For SPh too, Ipr pretreatment results in some decrease of the mutagenicity. This is in contrast to DEN, where the activation is clearly inhibited by PhI while Ipr has only a minor effect. For DMN, DTIC and PCZ both Ipr and PhI pretreatment caused considerable decreases of the mutagenicity. Inhibition of the FDMAM catalyzed activity by N,N-DMB resulted in an increase of mutagenicity with Cl3PDMT, in a moderate decrease of mutagenicity with DTIC, and a marked decrease with DMN, which was strongly inhibited. In contrast to the clear-cut mutagenicity of PCZ, 1,1-DMH and 1,2-DMH are not mutagenic in Drosophila. No change was observed upon inhibition of the various metabolizing activities. Apart from using strain differences in metabolizing activities and enzyme induction, enzyme inhibition can also be used to determine the influence of metabolism on the in vivo mutagenicity of promutagens in Drosophila.     

Structure/activity investigations in eight arylalkyltriazenes comparison of chemical stability,mode of decomposition,and SCE induction in Chinese hamster V79-E cells

A series of seven 1-aryl-3.3-dialkyltriazenes, including 1-phenyl-3.3-dimethyltriazene (DMPT), 1-phenyl-3.3-di-(trideuteromethyl)-triazene (DMPT-ds), 1-p-methylphenyl-3.3-dimethyltriazene (DMpMPT), 1-p-nitrophenyl-3.3-dimethyltriazene (DMpNPT), 1-phenyl-3.3-diethyltriazene (DEPT), 1-phenyl-3.3-di-n-propyltriazene (DnPrPT) and 1-phenyl-3.3-diisopropyltriazene (DiPrPT) and 1.3-diphenyl-3-methyltriazene (DPMT), was synthesized and characterized by UV/VIS, IR and ¹H-NMR spectroscopy. Chemical half-life was determined in phosphate buffer at 37° using UV/VIS spectroscopy. With the exception of DMpNPT, which was stable, the triazenes underwent pH-dependent hydrolytic decomposition (acid catalysis). By means of UV/VIS spectra, TLC and HPLC, phenol, aniline and secondary azocoupling products were identified after complete hydrolytic cleavage of the parent compounds. Pathways of spontaneous hydrolysis are proposed and discussed. Genotoxic activity of the triazenes was assayed by measurement of sister chromatid exchanges (SCE) in V79-E cells without and with rat liver S9 mix as an exogenous metabolizing system. In the direct SCE assay (without S9 mix), all triazenes except DMpNPT exerted a toxic action (cell cycle delay) in a narrow concentration range between no effect and overt cytotoxicity. This non-specific toxicity depended on the pH of the incubation system and was inversely proportional to chemical half-life. The toxicity of these agents is most likely due to the arenediazonium cation which is a relatively stable intermediate. In a sublethal concentration range most triazeness induced significant increases of SCE rates. These are interpreted as an indirect consequences of cytotoxicity. Upon metabolic activation, the compounds were genotoxic in a dose-dependent fashion. Their SCE-inducing capacity depended on the nature of the alkylating species generated, i.e., the alkyldiazonium cation, and on chemical stability. Surprisingly, no deuterium isotope effect was observed in DMPT-d₆. The order of genotoxic activity among the aryldialkyltriazenes was DMpNPT DMPT = DMPT- ds > DMpMPT DEPT > DnPrPT DiPrPT. DMPT was a marginal SCE inducer but very toxic upon metabolic activation. As monooxygenation of DPMT, like spontaneous hydrolysis, should generate a phenyldiazonium cation, the results suggest that arylation of DNA causes a very low SCE induction, if any.Abbreviations BUdR 5-bromodeoxyuridine - CP cyclophosphamide - DEPT 1-phenyl-3.3-diethyltriazene - DiPrPT 1-phenyl-3.3-diisopropyltriazene - DMPT 1-phenyl-3.3-dimethyltriazene - DMPT-d₆ 1-phenyl-3.3-di(trideuteromethyl)triazene - DMpMPT 1-p-methylphenyl-3.3-dimethyltriazene - DMpNPT 1-p-nitrophenyl-3.3-dimethyltriazene - DnPrPT 1-phenyl-3.3-di-n-propyltriazene - DPMT 1.3-diphenyl-3-methyltriazene - SCE sister chromatid exchange     

Chiral overcrowded alkenes; asymmetric synthesis of (3S,3'S)-(M, M)-(E)-(+)-1,1',2,2',3,3',4,4'-octahydro-3,3',7,7'-tetramethyl-4, 4'-biphenanthrylidenes

An asymmetric synthesis route towards (3S,3'S)-(M,M)-(E)-(+)-1,1',2, 2',3,3',4,4'-octahydro-3,3',7,7'-tetramethyl-4,4'-biphenanthrylidene was developed using the Evans procedure as a key step. The absolute configurations of the title compound and of its parent ketone were determined by CD spectroscopy and could be correlated with the stereochemical results of the asymmetric alkylation. Furthermore, a comparison was made with the known (3R,3'R)-(P,P)-(E)-(-)-1,1',2,2', 3,3',4,4'-octahydro-3,3',7,7'-dimethyl-4,4'-biphenanthrylidene. Finally, the X-ray crystallographic analysis of (3S,3'S)-(M, M)-(E)-(+)-1,1',2,2',3,3',4,4'-octahydro-3,3',7,7'-tetramethyl-4, 4'-biphenanthrylidene is presented.     

Synthesis and anticonvulsant activity of new 1-[2-oxo-2-(4-phenylpiperazin-1-yl)ethyl]pyrrolidine-2,5-diones

Twenty-two new 1-[2-oxo-2-(4-phenylpiperazin-1-yl)ethyl]pyrrolidine-2,5-diones were synthesized and tested for anticonvulsant activity. Initial anticonvulsant screening was performed using standard maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) screens in mice. Several compounds were tested additionally in the 6-Hz psychomotor seizure model. The neurotoxicity was determined applying the rotarod test. Excluding one compound, all other molecules were found to be effective in at least one seizure model. The most active were 1-(2-oxo-2-{4-[3-(trifluoromethyl)phenyl]piperazin-1-yl}ethyl)pyrrolidine-2,5-dione (14), 1-{2-[4-(4-chlorophenyl)piperazin-1-yl]-2-oxoethyl}-3-methylpyrrolidine-2,5-dione (17), 1-{2-[4-(4-chlorophenyl)piperazin-1-yl]-2-oxoethyl}-3,3-dimethylpyrrolidine-2,5-dione (23) and 3,3-dimethyl-1-(2-oxo-2-{4-[3-(trifluoromethyl)phenyl]piperazin-1-yl}ethyl)pyrrolidine-2,5-dione (26). These compounds showed high activity in the 6-Hz psychomotor seizure test as well as were active in the maximal electroshock and subcutaneous pentylenetetrazole (14 and 23) screens. Initial SAR studies for anticonvulsant activity have been discussed.     

Modulators of the human CCR5 receptor. Part 1: Discovery and initial SAR of 1-(3,3-diphenylpropyl)-piperidinyl amides and ureas

Investigation of weak screening hits led to the identification of N-alkyl-N-[1-(3,3-diphenylpropyl)piperidin-4-yl]-2-phenylacetamides and N-alkyl-N-[1-(3,3-diphenylpropyl)piperidin-4-yl]-N'-benzylureas as potent, selective ligands for the human CCR5 chemokine receptor.     

Lack of correlation between DNA-methylating activity and appearance of the immunogenic phenotype in clones of a murine lymphoma treated with mutagens

Summary The relationship between induction of novel immunogenicity by xenogenizing chemicals and DNA-methylating activity in murine tumors was investigated at the clonal level in L1210Ha cells treated with 5-azacytidine, N-methyl-N-nitro-N-nitrosoguanidine (MNNG) or 1-(p-chlorophenyl)-3,3-dimethyltriazene (DM-Cl). Cells were exposed to the drugs in vitro, cloned by limiting dilution, and assayed for transplantation immunogenicity and 5-methylcytosine content. The results showed that 0% (0/29, 5-azacytidine), 6.8% (2/29, MNNG) and 87.5% (28/32, DM-Cl) of the resulting clones were highly immunogenic, as judged by their tumorigenicity in intact compared to immunodepressed hosts. Frequency distribution analysis of the 5-methylcytosine content of drug-treated and parental clones showed that the methylation pattern was not significantly modified by tumor exposure to either 5-azacytidine or MNNG, and the two immunogenic clones induced by MNNG had methylcytosine levels very close to the 50th percentile value. In contrast, the extent of DNA methylation was increased in the cells treated with DM-Cl, but no obvious association was found between methylation status and immunogenicity of the drug-treated clones. In four 5-azacytidine-treated clones that displayed little or no immunogenicity, additional rounds of drug exposure led to progressive DNA demethylation, but failed, as a rule, to enhance tumor cell immunogenicity. Taken together, the present data indicate that, at least for the examined tumor, immunogenic variants are generated by mutagen treatment at high (MNNG) or very high (DM-Cl) frequencies under conditions in which hypomethylation-induced antigen amplification is unlikely.This work was supported by Progetto Finalizzato Oncologia, C. N. R, Rome-Italy, grant no. 87.01423.44 Abbreviations used: MNNG, N-methyl-N-nitro-N-nitrosoguanidine; DM-Cl, 1-(p-chlorophenyl)-3,3-dimethyltriazene; MST, difference (days) between median survival times of intact and irradiated mice injected with the same cells.     

Synthesis, cytotoxic effect and antiviral activity of 1-(beta-D-arabinofuranosyl)-5-bromo-N4-substituted cytosine and 1-(beta-D-arabinofuranosyl)-5-bromo-4-methoxypyrimidin-2(1H)-one derivatives

A convenient and mild synthesis of 5-bromo-N4-substituted-1-(beta-D-arabinofuranosyl)cytosine and 5-bromo-O4-methyl-1-(beta-D-arabinofuranosyl)pyrimidin-2(1H)-one derivatives by selective oxyfunctionalization of the corresponding 4-thionucleosides with 3,3-dimethyldioxirane is reported. The cytotoxicity and the antiviral activity against parainfluenza 1 (Sendai virus) of all new synthesized products are also reported.     

Isotope effects in O- and N-demethylations mediated by rat liver microsomes: an application of direct insertion electron impact mass spectrometry

Isotope effects of ～2 have been found for the O-demethylation of p-nitroanisole, p-methoxyacetanilide, and p-dimethoxybenzene and the respective trideuteromethyl derivatives, when mediated by rat liver microsomes.The direct insertion mode of electron impact mass spectrometry (the advantages and limitations of which are discussed) was used together with conventional methods (observation of formaldehyde release, product analysis by spectrophotometry) to determine the isotope effects. Only the mass spectrometry method was applicable for determining the isotope effect associated with the mono-O-demethylation of p-trideuteromethoxyanisole and an unusually large value (10) was found.An insignificant isotope effect (≯ 1.05) was found for the mono-N-demethylation of l-(o-carbamoylphenyl)-3,3-dimethyltriazene and its di-(trideuteromethyl) analogue. The protium and deuterium forms had closely similar growth-inhibitory activities for the TLX5 lymphoma in mice.     

Genetic characterization of ad-3 mutants induced by chemical carcinogens, I-phenyl-3-monomethyltriazene and I-phenyl-3,3-dimethyltriazene, in Neurospora crassa

180 ad-3 mutants of Neurospora crassa induced by 1-phenyl-3-monomethyl-triazene (PMMT) and 56 ad-3 mutants induced by 1-phenyl-3,3-dimethyltriazene (PDMT) were characterized by dikaryon, trikaryon and complementation tests. Results show that the spectrum of genetic alterations induced by PMMT is different from that of PDMT. This suggests that enzymatic dealkylation of PDMT to PMMT does not occur within Neuropsora crassa conidia, and that the mechanism of mutation induction of PDMT in N. crassa is different from that of PMMT. Hydrolytic breakdown products or its intact molecule or some other converted forms might be responsible for the mutagenic activity of PDMT.Mutation induction of PMMT in N. crassa appears to be via alkylation of DNA by carbonium ions produced by this compound, the same mechanism proposed for its carcinogenic activity. The frequencies of leakiness, allelic complementation and nonpolarized complementation patterns among PMMT-induced ad-3 mutants are similar to those of ad-3 mutants induced by other potent chemical carcinogens, such as MNNG and the aflatoxins.     

Photovoltaic properties of three new cyanine dyes for dye-sensitized solar cells.

Three carboxylated cyanine dyes, 2-[(1-butyl-3,3-dimethyl-5-carboxylindoline-2-ylidene)propenyl]-[1-butyl-3,3-dimethyl-7-(1-ethyl-1H-1,2,3-triazole-4-yl]-1H-benz[e]indolium iodide (), 2-[(1-butyl-3,3-dimethyl-5-carboxyl-indoline-2-ylidene)propenyl]-{1-butyl-3,3-dimethyl-7-[(4-piperidine-N-ethyl-1,8-naphthalimide)-1H-1,2,3-triazole-4-yl]}-1H-benz[e]indolium iodide (Cy2) and 2-[(1-butyl-3,3-dimethyl-5-carboxyl-indoline-2-ylidene)propenyl)-[1-butyl-3,3-dimethyl-7-{(4-piperidine-N-butyl-1,8-naphthalimide)-1H-1,2,3-triazole-4-yl}]-1H-benz[e]indolium iodide (Cy3), have been synthesized and characterized with regard to their structures and electrochemical properties. Upon adsorption onto a TiO(2) electrode, the absorption spectra of the three cyanine dyes are all broadened to both red and blue sides compared with their respective spectra in an acetonitrile and ethanol mixture. Cy2 and Cy3, containing a naphthalimide group, have stronger absorption intensities and broader absorption spectra than , which consequently leads to better light-to-electricity conversion properties. Among the three cyanine dyes, generated the highest photoelectric conversion yield of 4.80% (J(sc) = 14.5 mA cm(-2), V(oc) = 500 mV, FF = 0.49) under illumination with 75 mW cm(-2) white light from a Xe lamp.     

Synthesis of N-(1-methyl-1H-indol-3-yl)methyleneamines and 3,3-diaryl-4-(1-methyl-1H-indol-3-yl)azetidin-2-ones as potential antileishmanial agents

A series of N-(1-methyl-1H-indol-3-yl)methyleneamines and eight new 3,3-diaryl-4-(1-methyl-1H-indol-3-yl)azetidin-2-ones have been synthesized and screened for their antileishmanial activity against Leishmania major. 3,3-Diaryl-4-(1-methyl-1H-indol-3-yl)azetidin-2-ones have been synthesized by the Staudinger's ketene-imine cycloaddition employing two 2-diazo-1,2-diarylethanones as the precursors of diarylketenes. A marked improvement in anti-parasitic activity is observed by transformation of the methyleneamines to azetidin-2-ones in seven out of eight compounds. Two compounds displayed antileishmanial activity comparable to that of the clinically used antileshmanial drug, amphotericine B.     

Ferulic acid dehydrodimers from wheat bran: isolation,purification and antioxidant properties of 8-0-4-diferulic acid

Summary

Wheat bran contains several ester-linked dehydrodimers of ferulic acid, which were detected and quantified after sequential alkaline hydrolysis. The major dimers released were: trans-5-[(E)-2-carboxyvinyl]-2-(4-hydroxy-3-methoxy-phenyl)-7-methoxy-2,3-dihydrobenzofuran-3-carboxylic acid (5–8-BendiFA), (Z)-β-(4-[(E)-2-carboxyvinyl]-2-methoxy-phenoxy)-4-hydroxy-3-methoxycinnamic acid (8-O-4-diFA) and (E,E)-4,4′-dihydroxy-5,5′-dimethoxy-3,3′-bicinnamic acid (5–5-diFA). trans-7-hydroxy-1-(4-hydroxy-3methoxyphenyl)-6-methoxy-1,2-dihydro-naphthalene-2,3-dicarboxylic acid (8–8-diFA cyclic form) and 4,4′-dihydroxy-3,3′-dimethoxy-β,β'-bicinnamic acid (8–8-diFA non cyclic form) were not detected. One of the most abundant dimers, 8-O-4-diFA, was purified from de-starched wheat bran after alkaline hydrolysis and preparative HPLC. The resultant product was identical to the chemically synthesised 8-O-4-dimer by TLC and HPLC as confirmed by ¹H-NMR and mass spectrometry. The absorption maxima and absorption coefficients for the synthetic compound in ethanol were: λ_max: 323 nm, λ_min: 258 nm, ε_λmax (M^?1cm^?1): 24800 ± 2100 and ε₂₈₀ (M^?1cm^?1): 19700 ± 1100. The antioxidant properties of 8-O-4-diFA were assessed using: (a) inhibition of ascorbate/iron-induced peroxidation of phosphatidylcholine liposomes and; (b) scavenging of the radical cation of 2,2′-azinobis (3-ethyl-benzothiazoline-6-sulphonate) (ABTS) relative to the water-soluble vitamin E analogue, Trolox C. The 8-O-4-diFA was a better antioxidant than ferulic acid in both lipid and aqueous phases. This is the first report of the antioxidant activity of a natural diferulate obtained from a plant.     

Neolignan glycosides from Symplocos caudata

A phytochemical investigation of the roots of Symplocos caudata Wall (Symplocaceae) resulted in isolation and characterization of four optical isomers of a neolignan glycoside (1-4), a lignan lactone glycoside (5), a phenylpropanoid glycoside (6), as well as two known compounds (7, 8). Their structures were elucidated as (7S,8S)-threo-7,9,9'-trihydroxy-3,3'-dimethoxy-8-O-4'-neolignan-4-O-beta-d-glucopyranoside (1), (7R,8R)-threo-7,9,9'-trihydroxy-3,3'-dimethoxy-8-O-4'-neolignan-4-O-beta-d-glucopyranoside (2), (7R,8S)-erythro-7,9,9'-trihydroxy-3,3'-dimethoxy-8-O-4'-neolignan-4-O-beta-d-glucopyranoside (3), (7S,8R)-erythro-7,9,9'-trihydroxy-3,3'-dimethoxy-8-O-4'-neolignan-4-O-beta-d-glucopyranoside (4), 8R,8'R-matairesinol-4-O-beta-d-xylopyranosyl-(1-->2)-O-beta-d-glucopyranoside (5), 1-O-[beta-d-xylopyranosyl-(1-->6)-O-beta-d-glucopyranosyl]-2,6-dimethoxy-4-propenyl-phenol (6), matairesinoside (7), and (R)-1-O-(beta-d-glucopyranosyl)-2-[2-methoxy-4-(omega-hydroxypropyl)-phenoxyl]-propan-3-ol (8) on the basis of spectroscopic data (1D and 2D NMR, MS and CD) and chemical evidence.     

Modulators of the human CCR5 receptor. Part 2: SAR of substituted 1-(3,3-diphenylpropyl)-piperidinyl phenylacetamides

SAR and DMPK studies led to the identification of substituted N-alkyl-N-[1-(3,3-diphenylpropyl)piperidin-4-yl]-2-phenylacetamides as potent and orally bioavailable ligands for the human CCR5 chemokine receptor.     

(3,3-Difluoro-pyrrolidin-1-yl)-[(2S,4S)-(4-(4-pyrimidin-2-yl-piperazin-1-yl)-pyrrolidin-2-yl]-methanone: A potent,selective, orally active dipeptidyl peptidase IV inhibitor

A series of 4-substituted proline amides was synthesized and evaluated as inhibitors of dipeptidyl pepdidase IV for the treatment of type 2 diabetes. (3,3-Difluoro-pyrrolidin-1-yl)-[(2S,4S)-(4-(4-pyrimidin-2-yl-piperazin-1-yl)-pyrrolidin-2-yl]-methanone (5) emerged as a potent (IC₅₀ = 13 nM) and selective compound, with high oral bioavailability in preclinical species and low plasma protein binding. Compound 5, PF-00734200, was selected for development as a potential new treatment for type 2 diabetes.