scholarly journals Novel Disulfiram Derivatives as ALDH1a1-Selective Inhibitors

Molecules ◽  
2022 ◽  
Vol 27 (2) ◽  
pp. 480
Author(s):  
Ziad Omran
Keyword(s):  
Retinoic Acid ◽  
Aldehyde Dehydrogenase ◽  
Inhibitory Activity ◽  
Therapeutic Target ◽  
Chronic Alcoholism ◽  
Alcohol Metabolism ◽  
Aromatic Rings ◽  
Selective Inhibitors ◽  
Second Stage ◽  
Physiological Processes

Aldehyde dehydrogenase-1a1 (ALDH1a1), the enzyme responsible for the oxidation of retinal into retinoic acid, represents a key therapeutic target for the treatment of debilitating disorders such as cancer, obesity, and inflammation. Drugs that can inhibit ALDH1a1 include disulfiram, an FDA-approved drug to treat chronic alcoholism. Disulfiram, by carbamylation of the catalytic cysteines, irreversibly inhibits ALDH1a1 and ALDH2. The latter is the isozyme responsible for important physiological processes such as the second stage of alcohol metabolism. Given the fact that ALDH1a1 has a larger substrate tunnel than that in ALDH2, replacing disulfiram ethyl groups with larger motifs will yield selective ALDH1a1 inhibitors. We report herein the synthesis of new inhibitors of ALDH1a1 where (hetero)aromatic rings were introduced into the structure of disulfiram. Most of the developed compounds retained the anti-ALDH1a1 activity of disulfiram; however, they were completely devoid of inhibitory activity against ALDH2.

scholarly journals Discovery and Optimization of Selective Inhibitors of Meprin α (Part I)

2021 ◽  
Vol 14 (3) ◽  
pp. 203 ◽  
Author(s):  
Shurong Hou ◽  
Juan Diez ◽  
Chao Wang ◽  
Christoph Becker-Pauly ◽  
Gregg B. Fields ◽  
...  
Keyword(s):  
Inhibitory Activity ◽  
De Novo ◽  
Selective Inhibitors ◽  
Preclinical Development ◽  
Starting Point ◽  
Good Starting Point ◽  
Parallel Screening ◽  
Low Cytotoxicity

Meprin α and β are zinc-dependent proteinases implicated in multiple diseases including cancers, fibrosis, and Alzheimer’s. However, until recently, only a few inhibitors of either meprin were reported and no inhibitors are in preclinical development. Moreover, inhibitors of other metzincins developed in previous years are not effective in inhibiting meprins suggesting the need for de novo discovery effort. To address the paucity of tractable meprin inhibitors we developed ultrahigh-throughput assays and conducted parallel screening of >650,000 compounds against each meprin. As a result of this effort, we identified five selective meprin α hits belonging to three different chemotypes (triazole-hydroxyacetamides, sulfonamide-hydroxypropanamides, and phenoxy-hydroxyacetamides). These hits demonstrated a nanomolar to micromolar inhibitory activity against meprin α with low cytotoxicity and >30-fold selectivity against meprin β and other related metzincincs. These selective inhibitors of meprin α provide a good starting point for further optimization.

scholarly journals Role of Chronic Alcoholism Causing Cancer in Omnivores and Vegetarians through Epigenetic Modifications

2020 ◽  
Vol 07 (03) ◽  
pp. 080-086
Author(s):  
Syed Aaquil Hasan Syed Javid Hasan ◽  
Raisa Arifanie O'Zelian Pawirotaroeno ◽  
Syed Abrar Hasan Syed Javid Hasan ◽  
Elene Abzianidze
Keyword(s):  
Folate Deficiency ◽  
Chronic Alcoholism ◽  
Epigenetic Modifications ◽  
Alcohol Metabolism ◽  
Dna Hypomethylation ◽  
Contributing Factors ◽  
Vitamin Deficiencies ◽  
Adenosyl Methionine ◽  
And Oxidative Stress

AbstractOne of the significant consequences of alcohol consumption is cancer formation via several contributing factors such as action of alcohol metabolites, vitamin deficiencies, and oxidative stress. All these factors have been shown to cause epigenetic modifications via DNA hypomethylation, thus forming a basis for cancer development. Several published reviews and studies were systematically reviewed. Omnivores and vegetarians differ in terms of nutritional intake and deficiencies. As folate deficiency was found to be common among the omnivores, chronic alcoholism could possibly cause damage and eventually cancer in an omnivorous individual via DNA hypomethylation due to folate deficiency. Furthermore, as niacin was found to be deficient among vegetarians, damage in vegetarian chronic alcoholics could be due to increased NADH/NAD+ ratio, thus slowing alcohol metabolism in liver leading to increased alcohol and acetaldehyde which inhibit methyltransferase enzymes, eventually leading to DNA hypomethylation. Hence correcting the concerned deficiency and supplementation with S-adenosyl methionine could prove to be protective in chronic alcohol use.

scholarly journals Levels of the retinoic acid synthesizing enzyme aldehyde dehydrogenase-1A2 are lower in testicular tissue from men with infertility

2014 ◽  
Vol 101 (4) ◽  
pp. 960-966 ◽  
Author(s):  
John K. Amory ◽  
Samuel Arnold ◽  
María C. Lardone ◽  
Antonio Piottante ◽  
Mauricio Ebensperger ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Aldehyde Dehydrogenase ◽  
Testicular Tissue

scholarly journals Inhibitory effect of plant metabolites of Nigella sativa on conditionally pathogenic microflora of productive animals

2021 ◽  
Vol 282 ◽  
pp. 04014
Author(s):  
Anna Krivonogova ◽  
Albina Isaeva ◽  
Antonina Poryvaeva ◽  
Anastasia Chentsova ◽  
Pavel Sharavyev
Keyword(s):  
Inhibitory Activity ◽  
Postpartum Period ◽  
Nigella Sativa ◽  
Dairy Farm ◽  
Inhibitory Effect ◽  
Active Metabolites ◽  
Plant Metabolites ◽  
Antibiotic Resistant ◽  
Second Stage ◽  
Mucous Membranes

Objective: The effectiveness of a phytobiotic based on active metabolites of Nigella sativa L. against typical microorganisms of opportunistic microbiocenosis of the mucous membranes of highly productive cows was studied. Initially, the inhibitory activity of the phytobiotic was studied on cultures of wild multi-antibiotic-resistant isolates of P. aeruginosa and S. aureus isolated on a commercial dairy farm. It was found that the phytobiotic had the ability to inhibit the growth of isolates on the nutrient medium, but the severity of the inhibitory effect varied notably. At the second stage, an experiment was conducted with the local application of phytobiotics on cows that had inflammatory complications of the postpartum period. The results of the experiment showed a pronounced inhibitory effect of the phytobiotic on S. aureus, Str. uberis, P. aeruginosa, E. cloacae, C. albicans, and P. mirabilis. There was an involution of inflammatory symptoms and normalization of the clinical and microbiological state of the mucous membrane after the use of a phytobiotic preparation.

scholarly journals Structure-Based Optimization of a Novel Class of Aldehyde Dehydrogenase 1A (ALDH1A) Subfamily-Selective Inhibitors as Potential Adjuncts to Ovarian Cancer Chemotherapy

2018 ◽  
Vol 61 (19) ◽  
pp. 8754-8773 ◽  
Author(s):  
Brandt C. Huddle ◽  
Edward Grimley ◽  
Cameron D. Buchman ◽  
Mikhail Chtcherbinine ◽  
Bikash Debnath ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Aldehyde Dehydrogenase ◽  
Cancer Chemotherapy ◽  
Selective Inhibitors

Developmental role of endogenous retinoids in the determination of morphallactic field in budding tunicates

Development ◽  
1993 ◽  
Vol 117 (3) ◽  
pp. 835-845 ◽  
Author(s):  
K. Kawamura ◽  
K. Hara ◽  
S. Fujiwara
Keyword(s):  
Retinoic Acid ◽  
Aldehyde Dehydrogenase ◽  
Ectopic Expression ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Proximal Extremity ◽  
Developmental Role

We have extracted retinoids from the budding tunicate Polyandrocarpa misakiensis and, using HPLC, identified some major peaks as cis-retinal, all-trans-retinal and all-trans-retinoic acid, of which cis-retinal was most abundant (~2 micromolar). In developing buds, the amount of cis-retinal was about one-fifth that of the adult animals. In those buds, aldehyde dehydrogenase, which could metabolize retinal in vitro, was expressed in epithelial cells and then in mesenchymal cells at the proximal extremity, that is, the future developmental field of the bud. Exogenous retinoic acid comparable to the endogenous level could induce an additional field at the distal end of the bud, resulting in a double monster. The induction always accompanied an ectopic expression of aldehyde dehydrogenase. The results of this work suggest that retinoic acid or related molecule(s) act as an endogenous trigger of morphallactic development of Polyandrocarpa buds.

scholarly journals Alternative Biotransformation of Retinal to Retinoic Acid or Retinol by an Aldehyde Dehydrogenase from Bacillus cereus

2016 ◽  
Vol 82 (13) ◽  
pp. 3940-3946 ◽  
Author(s):  
Seung-Hye Hong ◽  
Ho-Phuong-Thuy Ngo ◽  
Hyun-Koo Nam ◽  
Kyoung-Rok Kim ◽  
Lin-Woo Kang ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Bacillus Cereus ◽  
Aldehyde Dehydrogenase ◽  
Catalytic Efficiency ◽  
No Oxidation ◽  
Wild Type ◽  
Biotechnological Production ◽  
Oxidation Activity ◽  
Content Type ◽  
Bacterial Enzyme

ABSTRACTA novel bacterial aldehyde dehydrogenase (ALDH) that converts retinal to retinoic acid was first identified inBacillus cereus. The amino acid sequence of ALDH fromB. cereus(BcALDH) was more closely related to mammalian ALDHs than to bacterial ALDHs. This enzyme converted not only small aldehydes to carboxylic acids but also the large aldehyde all-trans-retinal to all-trans-retinoic acid with NAD(P)+. We newly found thatBcALDH and human ALDH (ALDH1A1) could reduce all-trans-retinal to all-trans-retinol with NADPH. The catalytic residues inBcALDH were Glu266 and Cys300, and the cofactor-binding residues were Glu194 and Glu457. The E266A and C300A variants showed no oxidation activity. The E194S and E457V variants showed 15- and 7.5-fold higher catalytic efficiency (kcat/Km) for the reduction of all-trans-retinal than the wild-type enzyme, respectively. The wild-type, E194S variant, and E457V variant enzymes with NAD+converted 400 μM all-trans-retinal to 210 μM all-trans-retinoic acid at the same amount for 240 min, while with NADPH, they converted 400 μM all-trans-retinal to 20, 90, and 40 μM all-trans-retinol, respectively. These results indicate thatBcALDH and its variants are efficient biocatalysts not only in the conversion of retinal to retinoic acid but also in its conversion to retinol with a cofactor switch and that retinol production can be increased by the variant enzymes. Therefore,BcALDH is a novel bacterial enzyme for the alternative production of retinoic acid and retinol.IMPORTANCEAlthough mammalian ALDHs have catalyzed the conversion of retinal to retinoic acid with NAD(P)+as a cofactor, a bacterial ALDH involved in the conversion is first characterized. The biotransformation of all-trans-retinal to all-trans-retinoic acid byBcALDH and human ALDH was altered to the biotransformation to all-trans-retinol by a cofactor switch using NADPH. Moreover, the production of all-trans-retinal to all-trans-retinol was changed by mutations at positions 194 and 457 inBcALDH. The alternative biotransformation of retinoids was first performed in the present study. These results will contribute to the biotechnological production of retinoids, including retinoic acid and retinol.

scholarly journals Activation of c-Jun N-Terminal Kinase, a Potential Therapeutic Target in Autoimmune Arthritis

Cells ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 2466
Author(s):  
Benjamin Lai ◽  
Chien-Hsiang Wu ◽  
Jenn-Haung Lai
Keyword(s):  
Immune Responses ◽  
Proinflammatory Cytokines ◽  
Therapeutic Target ◽  
Signaling Molecules ◽  
Autoimmune Disorders ◽  
Autoimmune Arthritis ◽  
Potential Therapeutic Target ◽  
Downstream Signaling ◽  
Physiological Processes ◽  
Complex Manner

The c-Jun-N-terminal kinase (JNK) is a critical mediator involved in various physiological processes, such as immune responses, and the pathogenesis of various diseases, including autoimmune disorders. JNK is one of the crucial downstream signaling molecules of various immune triggers, mainly proinflammatory cytokines, in autoimmune arthritic conditions, mainly including rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis. The activation of JNK is regulated in a complex manner by upstream kinases and phosphatases. Noticeably, different subtypes of JNKs behave differentially in immune responses. Furthermore, aside from biologics targeting proinflammatory cytokines, small-molecule inhibitors targeting signaling molecules such as Janus kinases can act as very powerful therapeutics in autoimmune arthritis patients unresponsiveness to conventional synthetic antirheumatic drugs. Nevertheless, despite these encouraging therapies, a population of patients with an inadequate therapeutic response to all currently available medications still remains. These findings identify the critical signaling molecule JNK as an attractive target for investigation of the immunopathogenesis of autoimmune disorders and for consideration as a potential therapeutic target for patients with autoimmune arthritis to achieve better disease control. This review provides a useful overview of the roles of JNK, how JNK is regulated in immunopathogenic responses, and the potential of therapeutically targeting JNK in patients with autoimmune arthritis.

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