Discovery of benzimidazole derivatives as potent and selective aldehyde dehydrogenase 1A1 (ALDH1A1) inhibitors with glucose consumption improving activity

Ma, Zonghui; Jiang, Ling; Li, Bingyan; Liang, Dailin; Feng, Yu; Liu, Li; Jiang, Cheng

doi:10.1016/j.bmc.2021.116352

Cited by 15 publications

(9 citation statements)

References 38 publications

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“…The initial berberine 1 was inferior to all derivatives in the potency of its action. Metformin was used as a positive control in higher concentrations (1–5 mM), which were chosen bases on the literature data [ 9 ]. Metformin increased glucose consumption comparably with berberine.…”

Section: Resultsmentioning

confidence: 99%

9-N-n-alkyl Berberine Derivatives: Hypoglycemic Activity Evaluation

et al. 2022

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Several novel 9-N-n-alkyl derivatives of berberine (C5, C7, C10, C12) were synthesized. They were analyzed in vitro and in vivo for their hypoglycemic activity. In vitro studies showed that the derivatives with shorter alkyl substitutes at concentrations ranging from 2.5 to 10 μM were able to stimulate glucose consumption by HepG2 cells more prominently than the derivatives with longer substitutes (C10 and C12). All compounds demonstrated a better effect compared to berberine. Their impact on cells’ viability also depended on the alkyl substitutes length, but in this case, C10 and C12 derivatives demonstrated the best results. A similar correlation was also found in the OGTT, where the C5 derivative demonstrated a pronounced hypoglycemic effect at a dose of 15 mg/kg and C12 was less effective. This compound was further investigated in C57BL/6Ay mice for four weeks and was administered at a dose of 15 mg/kg. Pronounced effect of C12 on carbohydrate metabolism in mice was discovered: there was a decrease in fasting glucose levels and an increase in glucose tolerance in OGTT on the 14th and 28th days of the experiment. However, at the end of the experiment, signs of hepatosis exacerbation and an increase in the content of hepatic aminotransferases in blood were found.

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Section: Resultsmentioning

confidence: 99%

9-N-n-alkyl Berberine Derivatives: Hypoglycemic Activity Evaluation

et al. 2022

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“…Silybin could efficiently inhibit the proliferation, invasion, and metastasis of prostate cancer cells, by reducing ALDH1A1 expression levels (81). In 2015, Kesharwani et al reported a new approach for overcoming drug resistance to breast chemotherapy via the targeting of synthetic curcumin analogs against ALDH1A (37) potent and selective ALDH1A1 inhibitors (8). It has been proven that N42 could also selectively bind to and inhibit ALDH1A1 (9).…”

Section: Aldh1a1 Can Be Seen As a Therapeutic Target For Cancersmentioning

confidence: 99%

“…Another group of researchers reported that the ALDH1A1 inhibitor disulfiram and chemotherapeutic agent gemcitabine cooperatively inhibited breast tumor growth and tumorigenesis by purging ALDH+ tumor-initiating cells and activating T-cell immunity ( 89 ). Recently, benzimidazole derivatives have been found to act as potent and selective ALDH1A1 inhibitors ( 8 ). It has been proven that N42 could also selectively bind to and inhibit ALDH1A1 ( 9 ).…”

Section: Aldh1a1 Can Be Seen As a Therapeutic Target For Cancersmentioning

confidence: 99%

“…In the past decade, researchers have found that ALDH1A1 had vital physiological and pathophysiological functions in many systems, such as the central nervous system, as well as inflammatory and metabolic disorders (5)(6)(7). ALDH1A1 overexpression has been found to play an important role in obesity, diabetes, and other diseases (8)(9)(10)(11)(12)(13). Because the retinoic acid (RA) signaling pathway is involved in the regulation of gene expression in cancer stem cells (CSCs), researchers have focused on the role of ALDH1A1 in cancers worldwide (14)(15)(16).…”

Section: Introductionmentioning

confidence: 99%

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ALDH1A1 in Cancers: Bidirectional Function, Drug Resistance, and Regulatory Mechanism

Yue

et al. 2022

Front. Oncol.

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Aldehyde dehydrogenases 1 family member A1(ALDH1A1) gene codes a cytoplasmic enzyme and shows vital physiological and pathophysiological functions in many areas. ALDH1A1 plays important roles in various diseases, especially in cancers. We reviewed and summarized representative correlative studies and found that ALDH1A1 could induce cancers via the maintenance of cancer stem cell properties, modification of metabolism, promotion of DNA repair. ALDH1A1 expression is regulated by several epigenetic processes. ALDH1A1 also acted as a tumor suppressor in certain cancers. The detoxification of ALDH1A1 often causes chemotherapy failure. Currently, ALDH1A1-targeted therapy is widely used in cancer treatment, but the mechanism by which ALDH1A1 regulates cancer development is not fully understood. This review will provide insight into the status of ALDH1A1 research and new viewpoint for cancer therapy.

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“…Due to the important roles of Aldh1a1 in maintaining NAD + homeostasis in PTCs, compounds that modulate Aldh1a1 activity must be identi ed. In the present study, nicardipine was identi ed as a selective Aldh1a1 antagonist based on virtual screening, in vitro enzymatic activity assays 31 and BIAcore imaging. Nicardipine is a dihydropyridine-type Ca 2+ channel blocker (CCB) that exhibits unusual cerebrovascular characteristics and high antihypertensive action 32 .…”

Section: Introductionmentioning

confidence: 99%

Insig1 deletion in proximal tubular deregulates Aldh1a1 to consume NAD+ and contributes to renal fibrosis

Quan

et al. 2023

Preprint

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Profibrotic proximal tubules (PTs) were identified as a unique phenotype of PTCs in renal fibrosis. Controlling the process of renal fibrosis requires understanding how to manage the S1 subset's branch to the S3 subset rather than to the profibrotic PT subset. Insig1 is one of the branch-dependent genes involved in controlling this process, although its role in renal fibrosis is unknown. Here, we discovered the pathogenic effect of PTC-specific Insig1 deficiency on renal fibrosis in vivo and in vitro. Overexpression of Insig1 profoundly inhibited renal fibrosis. Insig1 deletion boosted SREBP1 nuclear localization, increasing Aldh1a1 transcriptional activity, causing excessive NAD+ consumption and ER enlargement, and accelerating renal fibrosis. We identified nicardipine as a selective inhibitor of Aldh1a1-restored NAD+ and ER homeostasis, which attenuated renal fibrosis. Together, our findings support Insig1 as a new therapeutic target for CKD.

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Discovery of benzimidazole derivatives as potent and selective aldehyde dehydrogenase 1A1 (ALDH1A1) inhibitors with glucose consumption improving activity

Cited by 15 publications

References 38 publications

9-N-n-alkyl Berberine Derivatives: Hypoglycemic Activity Evaluation

9-N-n-alkyl Berberine Derivatives: Hypoglycemic Activity Evaluation

ALDH1A1 in Cancers: Bidirectional Function, Drug Resistance, and Regulatory Mechanism

Insig1 deletion in proximal tubular deregulates Aldh1a1 to consume NAD+ and contributes to renal fibrosis

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