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2′-Hydroxy-4′,5′-dimethoxyacetophenone Exhibit Collagenase, Aldose Reductase Inhibition, and Anticancer Activity Against Human Leukemic Cells: An In Vitro, and In Silico Study

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Abstract

Diabetes is a serious growing concern that affects many parts of the body including the skin due to high sugar levels. Moreover, diabetic patients are at risk of developing cancer and are prone to a higher risk of hematological malignancies. In the present study, the inhibitory effect of 2′-Hydroxy-4′,5′-dimethoxyacetophenone was investigated on aldose reductase and collagenase enzymes, along with docking and ADMET analysis. MTT assay was also conducted to investigate the anti-leukemic effect of 2′-Hydroxy-4′,5′-dimethoxyacetophenone on human acute leukemia cells (32D-FLT3-ITD, Human HL-60/vcr, MOLT-3, and TALL-104 cell lines) and DPPH assay for establishing activity against oxidative stress. The 2′-Hydroxy-4′,5′-dimethoxyacetophenone showed potent inhibition of both the above tested enzymes with numerous strong interactions with the key catalytic residues in the active site of the enzymes. The MTT assay showed strong anti-cancer activity against entire tested human acute leukemia cells and was found non-toxic to normal (HUVEC) at the tested concentration. In DPPH free radical scavenging assay, 2′-Hydroxy-4′,5′-dimethoxyacetophenone showed strong inhibitory activity with IC50 of 157 µg/mL, which found comparable to the standard BHT. Our study demonstrated prominent pharmacological benefit of 2′-Hydroxy-4′,5′-dimethoxyacetophenone, against various leukemic cell lines, aldose reductase and collagenase enzymes, and free radical scavenging activity.

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Abbreviations

ADMET:

Absorption, distribution, metabolism, excretion, and toxicity

MTT:

(3-[4,5-Dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide)

HUVECs:

Human umbilical vein endothelial cells

DPPH:

Diphenylpicrylhydrazyl

BHT:

Butylated hydroxytoluene

ROS:

Reactive oxygen species

NADPH:

Nicotinamide adenine dinucleotide phosphate

CNS:

Central nervous system

DMSO:

Dimethyl sulfoxide

DMED:

Dulbecco’s Modified Eagle Medium

EDTA:

Ethylenediamine tetraacetic acid

ELISA:

Enzyme-linked immunosorbent assay

SASA:

Students Against Substance Abuse

FOSA:

Fiber Optic Sensing Association

FISA:

Foreign Intelligence Surveillance Act of 1978

NRU:

Neutral red uptake

References

  1. Priani, S. E., & Fakih, T. M. (2021). Insights into molecular interaction of flavonoid compounds in citrus peel bound to collagenase and elastase enzymes: A computational study. Pharmaceutical Sciences and Research, 8, 5.

    Google Scholar 

  2. Ghimeray, A. K., Jung, U. S., Lee, H. Y., Kim, Y. H., Ryu, E. K., & Chang, M. S. (2015). In vitro antioxidant, collagenase inhibition, and in vivo anti-wrinkle effects of combined formulation containing Punica granatum, Ginkgo biloba, Ficus carica, and Morus alba fruits extract. Clinical, Cosmetic and Investigational Dermatology, 8, 389–396.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Boran, R., Uğur, A., & Saraç, N. (2018). Investigation of hyaluronidase, collagenase and elastase inhibitory potentials and comparative evaluation of the antimicrobial, antioxidant and homeostatic activities of two natural polysaccharides. Süleyman Demirel Üniversitesi Fen Bilimleri Enstitüsü Dergisi, 22, 1182–1189.

    Article  CAS  Google Scholar 

  4. Abdul Wahab, N., Abdul Rahman, R., Ismail, A., Mustafa, S., & Hashim, P. (2014). Assessment of antioxidant capacity, anti-collagenase and anti-elastase assays of Malaysian unfermented cocoa bean for cosmetic application. Natural Products Chemistry & Research, 2(3), 1–6.

    Article  Google Scholar 

  5. Oshima, N., Narukawa, Y., Takeda, T., & Kiuchi, F. (2013). Collagenase inhibitors from Viola yedoensis. The Journal of Natural Medicines, 67, 240–245.

    Article  CAS  PubMed  Google Scholar 

  6. Hong, Y. H., Jung, E. Y., Noh, D. O., & Suh, H. J. (2014). Physiological effects of formulation containing tannase-converted green tea extract on skin care: Physical stability, collagenase, elastase, and tyrosinase activities. Integrative Medicine Research, 3, 25–33.

    Article  PubMed  Google Scholar 

  7. Wittenauer, J., Mäckle, S., Sußmann, D., Schweiggert-weisz, U., & Carle, R. (2015). Inhibitory effects of polyphenols from grape pomace extract on collagenase and elastase activity. Fitoterapia, 101, 179–187.

    Article  CAS  PubMed  Google Scholar 

  8. Han, X., Zhu, X., Hong, Z., Wei, L., Ren, Y., Wan, F., Zhu, S., Peng, H., Guo, L., Rao, L., & Feng, L. (2017). Structure-based rational design of novel inhibitors against fructose-1,6-bisphosphate aldolase from Candida albicans. Journal of Chemical Information and Modeling, 57(6), 1426–1438.

    Article  CAS  PubMed  Google Scholar 

  9. Jiang, T., Che, Q., Lin, Y., Li, H., & Zhang, N. (2006). Aldose reductase regulates TGF-beta1-induced production of fibronectin and type IV collagen in cultured rat mesangial cells. Nephrology, 11(2), 105–112.

    Article  CAS  PubMed  Google Scholar 

  10. Pal, P. B., Sonowal, H., Shukla, K., Srivastava, S. K., & Ramana, K. V. (2017). Aldose reductase mediates NLRP3 inflammasome-initiated innate immune response in hyperglycemia-induced Thp1 monocytes and male mice. Endocrinology, 158(10), 3661–3675.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Wei, J., Zhang, Y., Luo, Y., et al. (2014). Aldose reductase regulates miR-200a-3p/141-3p to coordinate Keap1–Nrf2, Tgfβ1/2, and Zeb1/2 signaling in renal mesangial cells and the renal cortex of diabetic mice. Free Radical Biology and Medicine, 67, 91–102.

    Article  CAS  PubMed  Google Scholar 

  12. Huang, Z., Hong, Q., Zhang, X., et al. (2017). Aldose reductase mediates endothelial cell dysfunction induced by high uric acid concentrations. Cell Communication and Signaling, 15(1), 3.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Dunlop, M. (2000). Aldose reductase and the role of the polyol pathway in diabetic nephropathy. Kidney International, 58, S3–S12.

    Article  Google Scholar 

  14. He, J., Gao, H.-X., Yang, N., Zhu, X. D., Sun, R. B., Xie, Y., Zeng, C. H., Zhang, J. W., Wang, J. K., Ding, F., & Aa, J. Y. (2019). The aldose reductase inhibitor epalrestat exerts nephritic protection on diabetic nephropathy in db/db mice through metabolic modulation. Acta Pharmacologica Sinica, 40(1), 86–97.

    Article  CAS  PubMed  Google Scholar 

  15. Quattrini, L., & La Motta, C. (2019). Aldose reductase inhibitors: 2013-present. Expert Opinion on Therapeutic Patents, 29, 199–213.

    Article  CAS  PubMed  Google Scholar 

  16. Prnova, M. S., Kovacikova, L., Svik, K., Bezek, S., Elmazoğlu, Z., Karasu, C., & Stefek, M. (2020). Triglyceride-lowering effect of the aldose reductase inhibitor cemtirestat-another factor that may contribute to attenuation of symptoms of peripheral neuropathy in STZ-diabetic rats. Naunyn-Schmiedeberg’s Archives of Pharmacology, 393, 651–661.

    Article  CAS  PubMed  Google Scholar 

  17. Kansal, R. (2016). Acute myeloid leukemia in the era of precision medicine: Recent advances in diagnostic classification and risk stratification. Cancer Biology & Medicine, 13, 41–54.

    Article  CAS  Google Scholar 

  18. De Kouchkovsky, I., & Abdul-Hay, M. (2016). Acute myeloid leukemia: A comprehensive review and 2016 update. Blood Cancer Journal, 6, e441. https://doi.org/10.1038/bcj.2016.50

    Article  PubMed  PubMed Central  Google Scholar 

  19. Redaelli, A., Laskin, B. L., Stephens, J. M., Botteman, M. F., & Pashos, C. L. (2005). A systematic literature review of the clinical and epidemiological burden of acute lymphoblastic leukaemia (ALL). European Journal of Cancer Care, 14(1), 53–62.

    Article  CAS  PubMed  Google Scholar 

  20. Paul, S., Kantarjian, H., & Jabbour, E. J. (2016). Adult acute lymphoblastic leukemia. Mayo Clinic Proceedings, 91(11), 1645–1666.

    Article  PubMed  Google Scholar 

  21. Timms, J. A., et al. (2016). DNA methylation as a potential mediator of environmental risks in the development of childhood acute lymphoblastic leukemia. Epigenomics, 8(4), 519–536.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Siegel, R. L., Miller, K. D., & Jemal, A. (2016). Cancer statistics, 2016. CA: A Cancer Journal for Clinicians, 66(1), 7–30.

    PubMed  Google Scholar 

  23. Grimwade, D., & Hills, R. K. (2009). Independent prognostic factors for AML outcome. Hematology, 2009, 385–395.

    Article  Google Scholar 

  24. Tüzün, B., & Saripinar, E. (2020). Molecular docking and 4D-QSAR model of methanone derivatives by electron conformational-genetic algorithm method. Journal of the Iranian Chemical Society, 17, 985–1000.

    Article  Google Scholar 

  25. Akkoç, S., Tüzün, B., İlhan, İÖ., & Akkurt, M. (2020). Investigation of structural, spectral, electronic, and biological properties of 1,3-disubstituted benzimidazole derivatives. Journal of Molecular Structure, 1219, 128582.

    Article  Google Scholar 

  26. Genç Bilgiçli, H., Bilgiçli, A. T., Günsel, A., Tüzün, B., Ergön, D., Yarasir, M. N., & Zengin, M. (2020). Turn-on fluorescent probe for Zn2+ ions based on thiazolidine derivative. Applied Organometallic Chemistry, 34(6), e5624.

    Article  Google Scholar 

  27. Douche, D., Elmsellem, H., Guo, L., Hafez, B., Tüzün, B., El Louzi, A., Bougrina, K., Karrouchi, K., & Himmi, B. (2020). Anti-corrosion performance of 8-hydroxyquinoline derivatives for mild steel in acidic medium: Gravimetric, electrochemical, DFT and molecular dynamics simulation investigations. Journal of Molecular Liquids, 308, 113042.

    Article  CAS  Google Scholar 

  28. Dilshad, R., Khan, K. R., Ahmad, S., Aati, H. Y., Al-qahtani, J. H., Sherif, A. E., Hussain, M., Ghalloo, B. A., Tahir, H., Basit, A., & Ahmed, M. (2022). Phytochemical profiling, in vitro biological activities, and in-silico molecular docking studies of Typha domingensis. Arabian Journal of Chemistry, 15(10), 104133.

    Article  CAS  Google Scholar 

  29. Wang, L., Lee, W., Oh, J. Y., Cui, Y. R., Ryu, B., & Jeon, Y. J. (2018). Protective effect of sulfated polysaccharides from Celluclast-assisted extract of Hizikia fusiforme against ultraviolet B-induced skin damage by regulating NF-κB, AP-1, and MAPKs signaling pathways in vitro in human dermal fibroblasts. Marine Drugs, 16(7), 239.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Barla, F., Higashijima, H., Funai, S., Sugimoto, K., Harada, N., Yamaji, R., Fujita, T., & Nakano, Y. H. (2009). Inui Inhibitive effects of alkyl gallates on hyaluronidase and collagenase. Bioscience, Biotechnology, and Biochemistry, 73, 2335–2337.

    Article  CAS  PubMed  Google Scholar 

  31. Zeng, Z. S., Cohen, A. M., & Guillem, J. G. (1999). Loss of basement membrane type IV collagen is associated with increased expression of metalloproteinases 2 and 9 (MMP-2 and MMP-9) during human colorectal tumorigenesis. Carcinogenesis, 20, 749–755.

    Article  CAS  PubMed  Google Scholar 

  32. Gamal, H., & Munusamy, S. (2016). Aldose reductase as a drug target for treatment of diabetic nephropathy: Promises and challenges. Protein & Peptide Letters, 24(1), 71–77.

    Article  Google Scholar 

  33. Iso, K., Tada, H., Kuboki, K., & Inokuchi, T. (2001). Long-term effect of epalrestat, an aldose reductase inhibitor, on the development of incipient diabetic nephropathy in type 2 diabetic patients. Journal of Diabetes and Its Complications, 15(5), 241–244.

    Article  CAS  PubMed  Google Scholar 

  34. Srivastava, S. K., Yadav, U. C. S., Reddy, A. B. M., et al. (2011). Aldose reductase inhibition suppresses oxidative stress-induced inflammatory disorders. Chemico-Biological Interactions, 191(1–3), 330–338.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Schrodinger, L. (2019). Small-molecule drug discovery suite 2019-4

  36. Schrödinger Release 2019-4: Protein preparation wizard; Epik, Schrödinger, LLC, New York, NY, 2016; Impact, Schrödinger, LLC, New York, NY, 2016; Prime, Schrödinger, LLC, New York, NY, 2019.

  37. Friesner, R. A., Murphy, R. B., Repasky, M. P., Frye, L. L., Greenwood, J. R., Halgren, T. A., Sanschagrin, P. C., & Mainz, D. T. (2006). Extra precision glide: Docking and scoring incorporating a model of hydrophobic enclosure for protein−ligand complexes. Journal of Medicinal Chemistry, 49, 6177–6196.

    Article  CAS  PubMed  Google Scholar 

  38. Sastry, G. M., Adzhigirey, M., Day, T., Annabhimoju, R., & Sherman, W. (2013). Protein and ligand preparation: Parameters, protocols, and influence on virtual screening enrichments. Journal of Computer-Aided Molecular Design, 27(3), 221–234.

    Article  PubMed  Google Scholar 

  39. Schrödinger, LLC. (2019). Schrödinger release 2019-4: LigPrep. Schrödinger, LLC.

  40. Shaneza, A., Umesh Kumar, G., Deepa, S., & Tahseen, K. (2018). Herbal treatment for the ovarian cancer SGVU. Journal of Pharmaceutical Education and Research, 3(2), 325–329.

    Google Scholar 

  41. Li, Z.-L., Fan, C., Chen, S.-L., Song, Y.-F., Yang, Y.-J., & Wang, S.-J. (2014). Synthesis of darirestat as an aldose reductase inhibitor (in Chinese). Journal of Shenyang Pharmaceutical University, 31(7), 521–525.

    CAS  Google Scholar 

  42. Grewal, A. S., Bhardwaj, S., Pandita, D., Lather, V., & Sekhon, B. S. (2015). Updates on aldose reductase inhibitors for management of diabetic complications and non-diabetic diseases. Mini-Reviews in Medicinal Chemistry, 16(2), 120–162.

    Article  Google Scholar 

  43. Peter, J. (2010). Oates: Aldose reductase inhibitors and diabetic kidney disease. Current Opinion in Investigational Drugs, 11(4), 402–416.

    Google Scholar 

  44. Thring, T. S., Hili, P., & Naughton, D. P. (2009). Anti-collagenase, anti-elastase and anti-oxidant activities of extracts from 21 plants. BMC Complementary and Alternative Medicine, 9, 27.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Bauman, L. (2004). CosmoDerm/CosmoPlast (human bioengineered collagen) for the aging face. Facial Plastic Surgery, 20, 125–128.

    Article  PubMed  Google Scholar 

  46. Chatatikun, M., & Chiabchalard, A. (2017). Thai plants with high antioxidant levels, free radical scavenging activity, anti-tyrosinase and anti-collagenase activity. BMC Complementary and Alternative Medicine, 17, 487.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Du, Q., Qian, Y., Yao, X., & Xue, W. (2020). Elucidating the tight-binding mechanism of two oral anticoagulants to factor Xa by using induced-fit docking and molecular dynamics simulation. Journal of Biomolecular Structure and Dynamics, 38(2), 625–633.

    Article  CAS  PubMed  Google Scholar 

  48. Schrödinger, LLC. (2020). Schrödinger release 2020-1: QikProp. Schrödinger, LLC.

  49. Türkmenoğlu, B., & Güzel, Y. (2018). Molecular docking and 4D-QSAR studies of metastatic cancer inhibitor thiazoles. Computational Biology and Chemistry, 76, 327–337.

    Article  PubMed  Google Scholar 

  50. Zheng, X., Zhang, L., Chen, W., Chen, Y., Xie, W., & Hu, X. (2012). Partial inhibition of aldose reductase by nitazoxanide and its molecular basis. ChemMedChem, 7(11), 1921–1923.

    Article  CAS  PubMed  Google Scholar 

  51. Xu, Q., He, C., Xiao, C., & Chen, X. (2016). Reactive oxygen species (ROS) responsive polymers for biomedical applications. Macromolecular Bioscience, 16, 635–646.

    Article  CAS  PubMed  Google Scholar 

  52. Zhang, H., Xiong, H., Ahmed, W., Yao, Y., Wang, S., Fan, C., & Gao, C. (2021). Reactive oxygen species-responsive and scavenging polyurethane nanoparticles for treatment of osteoarthritis in vivo. Chemical Engineering Journal, 409, 128147.

    Article  CAS  Google Scholar 

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The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

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Authors and Affiliations

  1. Department of Endocrinology, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, 450007, Henan, China

    Yingna Chu

  2. Department of Endocrinology, Qingdao Municipal Hospital, Qingdao, 266011, Shandong, China

    Juan Xiao

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  1. Yingna Chu
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  2. Juan Xiao
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YC contributed to the study conception and design. Material preparation, data collection and analysis were performed by JX. All authors read and approved the final manuscript.

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Correspondence to Yingna Chu.

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Chu, Y., Xiao, J. 2′-Hydroxy-4′,5′-dimethoxyacetophenone Exhibit Collagenase, Aldose Reductase Inhibition, and Anticancer Activity Against Human Leukemic Cells: An In Vitro, and In Silico Study. Mol Biotechnol 65, 881–890 (2023). https://doi.org/10.1007/s12033-022-00588-9

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