N,N-diethylaminobenzaldehyde (DEAB) as a substrate and mechanism-based inhibitor for human ALDH isoenzymes

Morgan, Cynthia A.; Parajuli, Bibek; Buchman, Cameron D.; Dria, Karl J.; Hurley, Thomas D.

doi:10.1016/j.cbi.2014.12.008

Cited by 108 publications

(118 citation statements)

References 30 publications

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“…Aldefluor ® active reagent, BODIPYaminoacetaldehyde (BAAA), is a non-toxic Aldefluor ® substrate that freely diffuses into intact and viable cells 14 .…”

Section: ■ Discussionmentioning

confidence: 99%

“…Viable cells stained by Aldefluor ® can be isolated with a sorter. An ALDH inhibitor, diethylaminobenzaldehyde (DEAB), is used to control the emitted fluorescence 14 . DEAB functions as a competitive inhibitor ALDH1A1, ALDH1A3, ALDH1B1 and ALDH5A1, greatly reducing the reaction rate and leaving the cells less fluorescent, and as covalent inhibitor ALDH2 and ALDH1A2, preventing the reaction from occurring 13 .…”

Section: ■ Discussionmentioning

confidence: 99%

“…The enzyme ALDH3A1 present in keratinocyte stem cells is not significantly inhibited by DEAB. But DEAB functions as a competitive inhibition to ALDH1A1, ALDH1A3, ALDH1B1 and ALDH5A1; and as a covalent inhibitor to ALDH2 and ALDH1A2 14 .…”

Section: ■ Introductionmentioning

confidence: 99%

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Aldefluor protocol to sort keratinocytes stem cells from skin

et al. 2017

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Purpose: To investigate the use Aldefluor ® and N, N -Dimethylaminobenzaldehyde (DEAB) to design a protocol to sort keratinocyte stem cells from cultured keratinocytes from burned patients. Methods: Activated Aldefluor ® aliquots were prepared and maintained at temperature between 2 to 8°C, or stored at -20°C. Next, the cells were collected following the standard protocol of sample preparation. Results: Best results were obtained with Aldefluor ® 1.5µl and DEAB 15 µl for 1 x 10 6 cells, incubated at 37°C for 15 minutes. Flow cytometer range for keratinocyte stem cells separation was evaluated. There were 14.8% of stem cells separated in one sample of keratinocyte culture used to pattern the protocol. After being defined the ideal concentration, the same test pattern was performed in other keratinocyte samples. We observed a final mean of 10.8%. Conclusion: Aldefluor ® has been shown as a favorable marking of epidermal keratinocyte stem cells for subsequent separation on a flow cytometer, with detection of 10.8% of epidermal keratinocyte stem cells, in this protocol.

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“…Aldefluor ® active reagent, BODIPYaminoacetaldehyde (BAAA), is a non-toxic Aldefluor ® substrate that freely diffuses into intact and viable cells 14 .…”

Section: ■ Discussionmentioning

confidence: 99%

Section: ■ Discussionmentioning

confidence: 99%

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Aldefluor protocol to sort keratinocytes stem cells from skin

et al. 2017

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“…His-tagged ALDH1A3 was produced and purified as previously described for ALDH3A1, except only a single passage on a nickel-NTA column was used for purification. 39 The two ALDH1A3 constructs behaved similarly when used in kinetic experiments.…”

Section: Methodsmentioning

confidence: 96%

“…25, 39, 51, 52 Human ALDH1A3 was prepared by one of two protocols. The first was by using the previous described method which yielded very little protein for enzymatic study.…”

Section: Methodsmentioning

confidence: 99%

Inhibition of the Aldehyde Dehydrogenase 1/2 Family by Psoralen and Coumarin Derivatives

Buchman

Hurley

2017

J. Med. Chem.

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Aldehyde dehydrogenase 2 (ALDH2), one of 19 ALDH superfamily members, catalyzes the NAD+-dependent oxidation of aldehydes to their respective carboxylic acids. In this study, we further characterized the inhibition of four psoralen and coumarin derivatives towards ALDH2 and compared them to the ALDH2 inhibitor daidzin for selectivity against five ALDH1/2 isoenzymes. Compound 2 (Ki=19 nM) binds within the aldehyde-binding site of the free enzyme species of ALDH2. Thirty-three structural analogs were examined to develop a stronger SAR profile. Seven compounds maintained or improved upon the selectivity towards one of the five ALDH1/2 isoenzymes, including compound 36, a selective inhibitor for ALDH2 (Ki=2.4 μM) and compound 32, which was 10-fold selective for ALDH1A1 (Ki=1.2 μM) versus ALDH1A2. Further medicinal chemistry on the compounds’ basic scaffold could enhance the potency and selectivity for ALDH1A1 or ALDH2 and generate chemical probes to examine the unique and overlapping functions of the ALDH1/2 isoenzymes.

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3D‐QSAR and scaffold hopping based designing of benzo[d]ox‐azol‐2(3H)‐one and 2‐oxazolo[4,5‐b]pyridin‐2(3H)‐one derivatives as selective aldehyde dehydrogenase 1A1 inhibitors: Synthesis and biological evaluation

Verma

Narendra

Raju

et al. 2022

Archiv der Pharmazie

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Aldehyde dehydrogenase 1 (ALDH1A1), an oxidoreductase class of enzymes, is overexpressed in various types of cancer cell lines and is the major cause of resistance to the Food and Drug Administration (FDA)‐approved drug, cyclophosphamide (CP). In cancer conditions, CP undergoes a sequence of biotransformations to form an active metabolite, aldophosphamide, which further biotransforms to its putative cytotoxic metabolite, phosphoramide mustard. However, in resistant cancer conditions, aldophosphamide is converted into its inactive metabolite, carboxyphosphamide, via oxidation with ALDH1A1. Herein, to address the issue of ALDH1A1 mediated CP resistance, we report a series of benzo[d]oxazol‐2(3H)‐one and 2‐oxazolo[4,5‐b]pyridin‐2(3H)‐one derivatives as selective ALDH1A1 inhibitors. These inhibitors were designed using a validated 3D‐quantitative structure activity relationship (3D‐QSAR) model coupled with scaffold hopping. The 3D‐QSAR model was developed using reported indole‐2,3‐diones based ALDH1A1 inhibitors, which provided field points in terms of electrostatic, van der Waals and hydrophobic potentials required for selectively inhibiting ALDH1A1. The most selective indole‐2,3‐diones‐based compound, that is, cmp 3, was further considered for scaffold hopping. Two top‐ranked bioisosteres, that is, benzo[d]oxazol‐2(3H)‐one and 2‐oxazolo[4,5‐b]pyridin‐2(3H)‐one, were selected for designing new inhibitors by considering the field pattern of 3D‐QSAR. All designed molecules were mapped perfectly on the 3D‐QSAR model and found to be predictive with good inhibitory potency (pIC50 range: 7.5–6.8). Molecular docking was carried out for each designed molecule to identify key interactions that are required for ALDH1A1 inhibition and to authenticate the 3D‐QSAR result. The top five inhibitor‐ALDH1A1 complexes were also submitted for molecular dynamics simulations to access their stability. In vitro enzyme assays of 21 compounds suggested that these compounds are selective toward ALDH1A1 over the other two isoforms, that is, ALDH2 and ALDH3A1. All the compounds were found to be at least three and two times more selective toward ALDH1A1 over ALDH2 and ALDH3A1, respectively. All the compounds showed an IC50 value in the range of 0.02–0.80 μM, which indicates the potential for these to be developed as adjuvant therapy for CP resistance.

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N,N-diethylaminobenzaldehyde (DEAB) as a substrate and mechanism-based inhibitor for human ALDH isoenzymes

Cited by 108 publications

References 30 publications

Aldefluor protocol to sort keratinocytes stem cells from skin

Aldefluor protocol to sort keratinocytes stem cells from skin

Inhibition of the Aldehyde Dehydrogenase 1/2 Family by Psoralen and Coumarin Derivatives

3D‐QSAR and scaffold hopping based designing of benzo[d]ox‐azol‐2(3H)‐one and 2‐oxazolo[4,5‐b]pyridin‐2(3H)‐one derivatives as selective aldehyde dehydrogenase 1A1 inhibitors: Synthesis and biological evaluation

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