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

Buchman, Cameron D.; Hurley, Thomas D.

doi:10.1021/acs.jmedchem.6b01825

Cited by 42 publications

(18 citation statements)

References 62 publications

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“…However, few comprehensive structure-activity relationship (SAR) studies on psoralen exist to assess such claims. The pertinent studies report only a few compounds at a time, making it difficult to establish any generalizable principles (16,(22)(23)(24)(25). Moreover, applying modern medicinal chemistry approaches to screen a library of psoralens could identify derivatives with unprecedented potencies and minimal undesired offtarget effects.…”

Section: Introductionmentioning

confidence: 99%

Psoralen Derivatives with Enhanced Potency

Buhimschi

Gooden

Jing

et al. 2020

Photochem & Photobiology

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Psoralen is a furocoumarin natural product that intercalates within DNA and forms covalent adducts when activated by ultraviolet radiation. It is well known that this property contributes to psoralen’s clinical efficacy in several disease contexts, which include vitiligo, psoriasis, graft‐versus‐host disease and cutaneous T‐cell lymphoma. Given the therapeutic relevance of psoralen and its derivatives, we attempted to synthesize psoralens with even greater potency. In this study, we report a library of 73 novel psoralens, the largest collection of its kind. When screened for the ability to reduce cell proliferation, we identified two derivatives even more cytotoxic than 4′‐aminomethyl‐4,5′,8‐trimethylpsoralen (AMT), one of the most potent psoralens identified to date. Using MALDI‐TOF MS, we studied the DNA adduct formation for a subset of novel psoralens and found that in most cases enhanced DNA binding correlated well with cytotoxicity. Generally, our most potent derivatives contain positively charged substituents, which we believe increase DNA affinity and enhance psoralen intercalation. Thus, we provide a rational approach to guide efforts toward further optimizing psoralens to fully capitalize on this drug class’ therapeutic potential. Finally, the structure–activity insights we have gained shed light on several opportunities to study currently underappreciated aspects of psoralen’s mechanism.

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Section: Introductionmentioning

confidence: 99%

Psoralen Derivatives with Enhanced Potency

Buhimschi

Gooden

Jing

et al. 2020

Photochem & Photobiology

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“…Small molecule inhibitors of ALDH2 include daidzin, 19 Aldi compounds, 20 and 2P3. 21 Disulfiram, 22 cyanamide, 23 nitroglycerin, 24 pargyline, 25 molinate, 26 and Aldi-3 20 are irreversible inhibitors of ALDH2 by covalently modifying the catalytic Cys302 residue. Less is known about enzymes of the ALDH1A subfamily and inhibitors thereof, in part because these enzymes can utilize several different substrates.…”

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confidence: 99%

“…However, several crystal structures of ALDH1A1-inhibitor complexes have been reported recently. 21,27,28 Indole-2.3-dinones and diethylaminobenzaldehyde (DEAB) are pan-ALDH1A inhibitors reported to covalently attack the catalytic cysteines of ALDH3A1 and ALDH7A1. 29–31 Analogues of duocarmycin form covalent bonds with catalytic and noncatalytic cysteine residues in ALDH1A1.…”

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confidence: 99%

Structural Basis of ALDH1A2 Inhibition by Irreversible and Reversible Small Molecule Inhibitors

et al. 2017

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Enzymes of the ALDH1A subfamily of aldehyde dehydrogenases are crucial in regulating retinoic acid (RA) signaling and have received attention as potential drug targets. ALDH1A2 is the primary RA-synthesizing enzyme in mammalian spermatogenesis and is therefore considered a viable drug target for male contraceptive development. However, only a small number of ALDH1A2 inhibitors have been reported, and information on the structure of ALDH1A2 was limited to the NAD-liganded enzyme void of substrate or inhibitors. Herein, we describe the mechanism of action of structurally unrelated reversible and irreversible inhibitors of human ALDH1A2 using direct binding studies and X-ray crystallography. All inhibitors bind to the active sites of tetrameric ALDH1A2. Compound WIN18,446 covalently reacts with the side chain of the catalytic residue Cys320, resulting in a chiral adduct in (R) configuration. The covalent adduct directly affects the neighboring NAD molecule, which assumes a contracted conformation suboptimal for the dehydrogenase reaction. The reversible inhibitors interact predominantly through direct hydrogen bonding interactions with residues in the vicinity of Cys320 without affecting NAD. Upon interaction with inhibitors, a large flexible loop assumes regular structure, thereby shielding the active site from solvent. The precise knowledge of the binding modes provides a new framework for the rational design of novel inhibitors of ALDH1A2 with improved potency and selectivity profiles.

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“…The first tertiary structures of class 2 and 3 ALDH were published in 1996-1997 [20,21] and as of today crystal structures of several human ALDH are described in literature, e.g., ALDH1A1 [22], ALDH1A3 [23], ALDH2 [24], ALDH3A1 [24], 3A2 [25], ALDH4A1 [26]. Among ALDHs both, dimers and tetramers can be found.…”

Section: Bioinformatic Analysismentioning

confidence: 99%

Detection of ALDH3B2 in Human Placenta

Michorowska

Giebułtowicz

Wolinowska

et al. 2019

IJMS

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Aldehyde dehydrogenase 3B2 (ALDH3B2) gene contains a premature termination codon, which can be skipped or suppressed resulting in full-length protein expression. Alternatively, the longest putative open reading frame starting with the second in-frame start codon would encode short isoform. No unequivocal evidence of ALDH3B2 expression in healthy human tissues is available. The aim of this study was to confirm its expression in human placenta characterized by the highest ALDH3B2 mRNA abundance. ALDH3B2 DNA and mRNA were sequenced. The expression was investigated using western blot. The identity of the protein was confirmed using mass spectrometry (MS). The predicted tertiary and quaternary structures, subcellular localization, and phosphorylation sites were assessed using bioinformatic analyses. All DNA and mRNA isolates contained the premature stop codon. In western blot analyses, bands corresponding to the mass of full-length protein were detected. MS analysis led to the identification of two unique peptides, one of which is encoded by the nucleotide sequence located upstream the second start codon. Bioinformatic analyses suggest cytoplasmic localization and several phosphorylation sites. Despite premature stop codon in DNA and mRNA sequences, full-length ALDH3B2 was found. It can be formed as a result of premature stop codon readthrough, complex phenomenon enabling stop codon circumvention.

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

Cited by 42 publications

References 62 publications

Psoralen Derivatives with Enhanced Potency

Psoralen Derivatives with Enhanced Potency

Structural Basis of ALDH1A2 Inhibition by Irreversible and Reversible Small Molecule Inhibitors

Detection of ALDH3B2 in Human Placenta

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