Explore the vast range of titles available.

The present article describes the successful performance of crossed aldol reactions of the CF[sub.3]-containing pseudo-C[sub.2] symmetric cyclic imide with various aldehydes. The utilization of HMPA as an additive attained the preferential formation of the anti-products in good to excellent yields, which contrasts with our previous method without this additive, proceeding to furnish the corresponding syn-isomers. The effective participation of ketones and α,β-unsaturated carbonyl compounds in reactions with this imide was also demonstrated to expand the application of this imide.

A series of ionic liquids were synthesized and their synergetic effects on the Cu catalyzed one-pot A.sup.3 coupling reactions were investigated for the synthesis of propargylamines. The results showed that the combined catalytic system based on ionic liquid [MEA][H.sub.2PO.sub.4] and CuI had excellent catalytic activity and selectivity for the target propargylamines, a series aromatic aldehyde with electro-withdrawing and donating groups and heteroaromatic aldehyde could all reach good to excellent isolated yields. This catalytic system benefit from mild reaction conditions and simple operation procedures, no volatile organic solvents and other additives were involved, and no inert gas protection were needed. In addition, the ionic liquid utilized in this work was easy to be prepared and its utilization made the catalytic system recyclable. All of these superiorities made this catalytic system efficient and eco-friendly for the synthesis of propargylamines.

Rate coefficients for the reaction of NO.sub.3 radicals with a series of aromatic aldehydes were measured in a 7300 L simulation chamber at ambient temperature and pressure by relative and absolute methods. The rate coefficients for benzaldehyde (BA), ortho-tolualdehyde (O-TA), meta-tolualdehyde (M-TA), para-tolualdehyde (P-TA), 2,4-dimethyl benzaldehyde (2,4-DMBA), 2,5-dimethyl benzaldehyde (2,5-DMBA) and 3,5-dimethyl benzaldehyde (3,5-DMBA) were k.sub.1 = 2.6 ± 0.3, k.sub.2 = 8.7 ± 0.8, k.sub.3 = 4.9 ± 0.5, k.sub.4 = 4.9 ± 0.4, k.sub.5 = 15.1 ± 1.3, k.sub.6 = 12.8 ± 1.2 and k.sub.7 = 6.2 ± 0.6, respectively, in the units of 10.sup.-15 cm.sup.3 molec..sup.-1 s.sup.-1 at 298 ± 2 K. The rate coefficient k.sub.13 for the reaction of the NO.sub.3 radical with deuterated benzaldehyde (benzaldehyde-d.sub.1) was found to be half that of k.sub.1 . The end product of the reaction in an excess of NO.sub.2 was measured to be C.sub.6 H.sub.5 C(O)O.sub.2 NO.sub.2 . Theoretical calculations of aldehydic bond energies and reaction pathways indicate that the NO.sub.3 radical reacts primarily with aromatic aldehydes through the abstraction of an aldehydic hydrogen atom. The atmospheric implications of the measured rate coefficients are briefly discussed.

Aldehyde dehydrogenases (ALDHs) are multifunctional enzymes that oxidize diverse endogenous and exogenous aldehydes. We conducted a meta-analysis based on The Cancer Genome Atlas and Gene Expression Omnibus data and detected genetic alterations in ALDH1A1, ALDH1A3, or ALDH3A1, 86% of which were gene amplification or mRNA upregulation, in 31% of nonsmall cell lung cancers (NSCLCs). The expression of these isoenzymes impacted chemoresistance and shortened survival times in patients. We hypothesized that these enzymes provide an oxidative advantage for the persistence of NSCLC. To test this hypothesis, we used genetic and pharmacological approaches with DIMATE, an irreversible inhibitor of ALDH1/3. DIMATE showed cytotoxicity in 73% of NSCLC cell lines tested and demonstrated antitumor activity in orthotopic xenografts via hydroxynonenal-protein adduct accumulation, GSTO1-mediated depletion of glutathione and increased H2O2. Consistent with this result, ALDH1/3 disruption synergized with ROS-inducing agents or glutathione synthesis inhibitors to trigger cell death. In lung cancer xenografts with high to moderate cisplatin resistance, combination treatment with DIMATE promoted strong synergistic responses with tumor regression. These results indicate that NSCLCs with increased expression of ALDH1A1, ALDH1A3, or ALDH3A1 may be targeted by strategies involving inhibitors of these isoenzymes as monotherapy or in combination with chemotherapy to overcome patient-specific drug resistance.

Aldehyde dehydrogenases (ALDHs) are promising cancer drug targets, as certain isoforms are required for the survival of stem-like tumor cells. We have discovered selective inhibitors of ALDH1B1, a mitochondrial enzyme that promotes colorectal and pancreatic cancer. We describe bicyclic imidazoliums and guanidines that target the ALDH1B1 active site with comparable molecular interactions and potencies. Both pharmacophores abrogate ALDH1B1 function in cells; however, the guanidines circumvent an off-target mitochondrial toxicity exhibited by the imidazoliums. Our lead isoform-selective guanidinyl antagonists of ALDHs exhibit proteome-wide target specificity, and they selectively block the growth of colon cancer spheroids and organoids. Finally, we have used genetic and chemical perturbations to elucidate the ALDH1B1-dependent transcriptome, which includes genes that regulate mitochondrial metabolism and ribosomal function. Our findings support an essential role for ALDH1B1 in colorectal cancer, provide molecular probes for studying ALDH1B1 functions and yield leads for developing ALDH1B1-targeting therapies.Aldehyde dehydrogenase 1B1-specific small-molecule inhibitors are identified that block the growth of colon cancer spheroids and organoids and are shown to potentially regulate mitochondrial metabolism and ribosomal function.

Reactive aldehydes are common carcinogens. They are also by-products of several metabolic pathways and, without enzymatic catabolism, may accumulate and cause DNA damage. Ethanol, which is metabolised to acetaldehyde, is both carcinogenic and teratogenic in humans. Here we find that the Fanconi anaemia DNA repair pathway counteracts acetaldehyde-induced genotoxicity in mice. Our results show that the acetaldehyde-catabolising enzyme Aldh2 is essential for the development of Fancd2 −/− embryos. Nevertheless, acetaldehyde-catabolism-competent mothers ( Aldh2 +/− ) can support the development of double-mutant ( Aldh2 −/− Fancd2 −/− ) mice. However, these embryos are unusually sensitive to ethanol exposure in utero , and ethanol consumption by postnatal double-deficient mice rapidly precipitates bone marrow failure. Lastly, Aldh2 −/− Fancd2 −/− mice spontaneously develop acute leukaemia. Acetaldehyde-mediated DNA damage may critically contribute to the genesis of fetal alcohol syndrome in fetuses, as well as to abnormal development, haematopoietic failure and cancer predisposition in Fanconi anaemia patients. Aldehyde toxicity in Fanconi anaemia Individuals with Fanconi anaemia exhibit developmental defects, stem-cell failure and a strong predisposition to leukaemia. Cells derived from patients with Fanconi anaemia are susceptible to DNA damage caused by DNA crosslinking agents such as cisplatin and mitomycin C. These are cancer chemotherapeutics, so cells are not normally exposed to them, prompting the question: what is the natural source of DNA damage repaired by this pathway? Experiments with mice deficient in Fancd2 (one of several Fanconi anaemia genes) and Aldh2 (which encodes an enzyme that detoxifies aldehydes) suggest that acetaldehyde is an endogenous source of DNA damage in Fanconi anaemia, contributing to cancer predisposition and haematopoeitic failure. Intriguingly, these mouse models also suggest a possible mechanism for the damaging effects of fetal alcohol exposure during pregnancy.

We have reported one-pot, three-component Mannich type reaction of aldehyde, amines and ketone (acetone and acetophenones), catalyzed by deep eutectic solvent (choline chloride/zinc chloride) at room temperature to give [beta]-amino carbonyls in good yields. The catalyst could be recycled at least four times without remarkable decrease in its catalytic activity. The general method is easy, fast and environmental friendly.

The function of haematopoietic stem and progenitor cells is impaired by damaged DNA; here, endogenously generated aldehydes are found to be one source of such damage, which is repaired by the Fanconi anaemia pathway. Bone-marrow failure in Fanconi anaemia Haematopoietic stem cells handle DNA-damage stress through enzymatic detoxification and DNA repair. Dismantling both protective mechanisms predisposes mice to leukaemia and susceptibility to exogenous aldehyde. Ketan Patel and colleagues now show that even if these mice escape leukaemia, they spontaneously develop features of Fanconi anaemia, such as aplastic anaemia and bone-marrow failure. The authors find that Aldh2 is the key enzyme protecting haematopoietic stem and progenitor cells from endogenous aldehyde toxicity. This genomic protection mechanism is dispensable in the more mature blood cells. These findings suggest that bone-marrow failure in Fanconi anaemia results from aldehyde-mediated genotoxicity in the haematopoietic stem- and progenitor-cell pool. Haematopoietic stem cells (HSCs) regenerate blood cells throughout the lifespan of an organism. With age, the functional quality of HSCs declines, partly owing to the accumulation of damaged DNA 1 , 2 , 3 . However, the factors that damage DNA and the protective mechanisms that operate in these cells are poorly understood. We have recently shown that the Fanconi anaemia DNA-repair pathway counteracts the genotoxic effects of reactive aldehydes 4 , 5 . Mice with combined inactivation of aldehyde catabolism (through Aldh2 knockout) and the Fanconi anaemia DNA-repair pathway ( Fancd2 knockout) display developmental defects, a predisposition to leukaemia, and are susceptible to the toxic effects of ethanol—an exogenous source of acetaldehyde 4 . Here we report that aged Aldh2 −/− Fancd2 −/− mutant mice that do not develop leukaemia spontaneously develop aplastic anaemia, with the concomitant accumulation of damaged DNA within the haematopoietic stem and progenitor cell (HSPC) pool. Unexpectedly, we find that only HSPCs, and not more mature blood precursors, require Aldh2 for protection against acetaldehyde toxicity. Additionally, the aldehyde-oxidizing activity of HSPCs, as measured by Aldefluor stain, is due to Aldh2 and correlates with this protection. Finally, there is more than a 600-fold reduction in the HSC pool of mice deficient in both Fanconi anaemia pathway-mediated DNA repair and acetaldehyde detoxification. Therefore, the emergence of bone marrow failure in Fanconi anaemia is probably due to aldehyde-mediated genotoxicity restricted to the HSPC pool. These findings identify a new link between endogenous reactive metabolites and DNA damage in HSCs, and define the protective mechanisms that counteract this threat.

Mammalian aldehyde oxidases (AOXs) are molybdo-flavoenzymes which are present in many tissues in various mammalian species, including humans and rodents. Different species contain a different number of AOX isoforms. In particular, the reasons why mammals other than humans express a multiplicity of tissue-specific AOX enzymes is unknown. In mouse, the isoforms mAOX1, mAOX3, mAOX4 and mAOX2 are present. We previously established a codon-optimized heterologous expression systems for the mAOX1-4 isoforms in Escherichia coli that gives yield to sufficient amounts of active protein for kinetic characterizations and sets the basis in this study for site-directed mutagenesis and structure-function studies. A direct and simultaneous comparison of the enzymatic properties and characteristics of the four enzymes on a larger number of substrates has never been performed. Here, thirty different structurally related aromatic, aliphatic and N-heterocyclic compounds were used as substrates, and the kinetic parameters of all four mAOX enzymes were directly compared. The results show that especially mAOX4 displays a higher substrate selectivity, while no major differences between mAOX1, mAOX2 and mAOX3 were identified. Generally, mAOX1 was the enzyme with the highest catalytic turnover for most substrates. To understand the factors that contribute to the substrate specificity of mAOX4, site-directed mutagenesis was applied to substitute amino acids in the substrate-binding funnel by the ones present in mAOX1, mAOX3, and mAOX2. An increase in activity was obtained by the amino acid exchange M1088V in the active site identified to be specific for mAOX4, to the amino acid identified in mAOX3.

Drug metabolism in humans is typically discussed in terms of P450 reactions, but growing evidence indicates aldehyde oxidase plays a central role as well. The first crystal structures of the human enzyme reveal a flexible tunnel to the active site and a new inhibitory site. Aldehyde oxidase (AOX) is a xanthine oxidase (XO)-related enzyme with emerging importance due to its role in the metabolism of drugs and xenobiotics. We report the first crystal structures of human AOX1, substrate free (2.6-Å resolution) and in complex with the substrate phthalazine and the inhibitor thioridazine (2.7-Å resolution). Analysis of the protein active site combined with steady-state kinetic studies highlight the unique features, including binding and substrate orientation at the active site, that characterize human AOX1 as an important drug-metabolizing enzyme. Structural analysis of the complex with the noncompetitive inhibitor thioridazine revealed a new, unexpected and fully occupied inhibitor-binding site that is structurally conserved among mammalian AOXs and XO. The new structural insights into the catalytic and inhibition mechanisms of human AOX that we now report will be of great value for the rational analysis of clinical drug interactions involving inhibition of AOX1 and for the prediction and design of AOX-stable putative drugs.