Mass spectrometric characterization of organosulfates related to secondary organic aerosol from isoprene.

RATIONALE: A considerable fraction of atmospheric particulate fine matter consists of organosulfates, with some of the most polar ones originating from the oxidation of isoprene. Their structural characterization provides insights into the nature of gas-phase precursors as well as into formation pathways. METHODS: The structures of unknown polar organosulfates present in ambient particulate fine matter were characterized using liquid chromatography/(-)electrospray ionization mass spectrometry (LC/(-)ESI-MS), including ion trap MS(n) and accurate mass measurements, derivatization of the carbonyl group into 2,4-dinitrophenylhydrazones, detailed interpretation of the MS data, and in a selected case comparison of their LC and MS behavior with that of synthesized reference compounds. RESULTS: Polar organosulfates with molecular weights (MWs) of 156, 170, 184 and 200 were attributed to/or confirmed as derivatives of glycolic acid (156), lactic acid (170), 1,2-dihydroxy-3-butanone (184), glycolic acid glycolate (200), 2-methylglyceric acid (200), and 2,3-dihydroxybutanoic acid (200). In the case of the MW 184 compound an unambiguous assignment was obtained through synthesis of reference compounds. CONCLUSIONS: A more complete structural characterization of polar organosulfates that originate from isoprene secondary organic aerosol was achieved. An important atmospheric finding is the presence of an organosulfate that is related to methyl vinyl ketone, a major gas-phase oxidation product of isoprene. In addition, minor polar organosulfates related to crotonaldehyde were identified.

Formation of secondary organic aerosol marker compounds from the photooxidation of isoprene and isoprene-derived alkene diols under low-NO(x) conditions.

In the present work, we have evaluated whether isomeric C5-alkene diols (1,2-dihydroxy-2-methyl-3-butene, 1,2-dihydroxy-3-methyl-3-butene, and 1,4-dihydroxy-2-methyl-2-butene (cis + trans)), which have first been detected upon photooxidation of isoprene in the absence of NO and are known to be formed in the ambient atmosphere, can serve as precursors for the 2-methyltetrols, C5-alkene triols, and 2-methylglyceric acid under low-NO(x) conditions. The C5-alkene diols were prepared following published synthesis procedures. It is shown that under the applied chamber conditions the isomeric C5-alkene diols give rise to 2-methyltetrols with different threo/erythro abundance ratios and that certain diols produce 2-methylglyceric acid, but that they do not form C5-alkene triols. Furthermore, it is shown that the photooxidation of isoprene under the applied chamber conditions employing photolysis of H2O2 under dry conditions yields relatively small amounts of C5-alkene triols compared to those of the 2-methyltetrols, unlike under ambient conditions. It is argued that the chamber conditions are not optimal for the formation of C5-epoxydiols, which serve as gas-phase precursors for the C5-alkene triols, and likely as in some previous studies favor the formation of C5-alkene diols as a result of RO2 + RO2 reactions.

Selective Inhibitors of Fibroblast Activation Protein (FAP) with a (4-Quinolinoyl)-glycyl-2-cyanopyrrolidine Scaffold.

Fibroblast activation protein (FAP) is a serine protease that is generally accepted to play an important role in tumor growth and other diseases involving tissue remodeling. Currently there are no FAP inhibitors with reported selectivity toward both the closely related dipeptidyl peptidases (DPPs) and prolyl oligopeptidase (PREP). We present the discovery of a new class of FAP inhibitors with a N-(4-quinolinoyl)-Gly-(2-cyanopyrrolidine) scaffold. We have explored the effects of substituting the quinoline ring and varying the position of its sp(2) hybridized nitrogen atom. The most promising inhibitors combined low nanomolar FAP inhibition and high selectivity indices (>10(3)) with respect to both the DPPs and PREP. Preliminary experiments on a representative inhibitor demonstrate that plasma stability, kinetic solubility, and log D of this class of compounds can be expected to be satisfactory.

Acylated Gly-(2-cyano)pyrrolidines as inhibitors of fibroblast activation protein (FAP) and the issue of FAP/prolyl oligopeptidase (PREP)-selectivity.

A series of N-acylated glycyl-(2-cyano)pyrrolidines were synthesized with the aim of generating structure-activity relationship (SAR) data for this class of compounds as inhibitors of fibroblast activation protein (FAP). Specifically, the influence of (1) the choice of the N-acyl group and (2) structural modification of the 2-cyanopyrrolidine residue were investigated. The inhibitors displayed inhibitory potency in the micromolar to nanomolar range and showed good to excellent selectivity with respect to the proline selective dipeptidyl peptidases (DPPs) DPP IV, DPP9 and DPP II. Additionally, selectivity for FAP with respect to prolyl oligopeptidase (PREP) is reported. Not unexpectedly, the latter data suggest significant overlap in the pharmacophoric features that define FAP or PREP-inhibitory activity and underscore the importance of systematically evaluating the FAP/PREP-selectivity index for inhibitors of either of these two enzymes. Finally, this study forwards several compounds that can serve as leads or prototypic structures for future FAP-selective-inhibitor discovery.

Naphthalene proton sponges as hydride donors: diverse appearances of the tert-amino-effect.

It has been shown that the 1-NMe(2) group in the 2-substituted 1,8-bis(dimethylamino)naphthalenes (proton sponges) can intramolecularly donate a hydride ion to an appropriate electron-accepting ortho-substituent such as diarylcarbenium ion, ß,ß'-dicyanovinyl or methyleneiminium group. This produces the 1-N(+)(Me)=CH(2) functionality and triggers a number of further transformations (tert-amino effect) including peri-cyclization, ortho-cyclization or hydrolytic demethylation. In each particular case, the course of the reaction is determined by the nature of the ortho-substituent and the most potent nucleophile presenting in the reaction mixture. For 2,7-disubstituted 1,8-bis(dimethylamino)naphthalenes, two types of tandem tert-amino effect with the involvement of both peri-NMe(2) groups have been registered. The conclusion was made that proton sponges are generally more active in the tert-amino reactions than the corresponding monodimethylaminoarenes. This is ascribed both to higher electron donor ability of proton sponges and markedly shortened distance between electrophilic C(α)-atom in the ortho-substituent and hydrogen atoms of the nearest NMe(2) group. Most conversions observed proceed in good to high yields and are useful for the preparation of derivatives of benzo[h]quinoline, quino[7,8:7',8']quinoline, 2,3-dihydroperimidine, N,N,N'-trimethyl-1,8-diaminonaphthalene and proton sponge itself.

Synthesis of functionalized pyridazin-3(2H)-ones via nucleophilic substitution of hydrogen (SNH).

Reaction of 2-benzyl-5-halopyridazin-3(2H)-ones (3) with Grignard reagents followed by quenching with electrophiles unexpectedly yielded 4,5-disubstituted pyridazin-3(2H)-ones instead of 5-substituted pyridazin-3(2H)-ones. These reactions represent the first examples of cine substitution in which the anionic σ(H)-adduct is quenched by electrophiles (other than a proton) before elimination takes place. Insight into the reaction mechanism led to the direct transformation of 2-benzylpyridazin-3(2H)-one (7) and 2-benzyl-6-chloropyridazin-3(2H)-one (9) into the corresponding C-4 alkyl and aryl derivatives (when Br(2) was used as the electrophile).

Synthesis of functionalized pyridazin-3(2H)-ones via bromine-magnesium exchange on bromopyridazin-3(2H)-ones.

The potential of halogen-magnesium exchange reactions, followed by quenching with electrophiles, for the functionalization of the pyridazin-3(2H)-one core was investigated. 2-Benzyl-4-bromo-5-methoxy- (1), 2-benzyl-5-bromo-4-methoxy- (4), and 2-benzyl-4,5-dibromopyridazin-3(2H)-one (10) were selected as readily available model substrates. While 1 and 10 gave exclusively C-4 metalation, a tandem reaction involving nucleophilic substitution via addition elimination and bromine-magnesium exchange was observed with 4.