Structure‐Based Design and Synthesis of Harmine Derivatives with Different Selectivity Profiles in Kinase versus Monoamine Oxidase Inhibition

Balint, Balázs; Wéber, Csaba; Cruzalegui, Francisco; Burbridge, Mike F.; Kotschy, András

doi:10.1002/cmdc.201600539

Cited by 27 publications

(40 citation statements)

References 22 publications

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“…Simple replacement of the harmine 1-methyl group with a chlorine atom ( 1–5 ) significantly improved the DYRK1A inhibition by 3-fold compared to harmine with IC 50 of 8.81 nM (reported in the literature IC 50 56 nM). 60 We also investigated the effect of introducing polar groups such as hydroxyl, hydroxymethyl, and acetyl at the 1-position of harmine. Replacing 1-methyl with a hydroxyl substituent (or its pyridone tautomer) dramatically reduced the DYRK1A inhibition, rendering the compound inactive, unlike the Cl-subsitutent.…”

Section: Resultsmentioning

confidence: 99%

Development of Kinase-Selective, Harmine-Based DYRK1A Inhibitors that Induce Pancreatic Human β-Cell Proliferation

et al. 2018

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DYRK1A has been implicated as an important drug target in various therapeutic areas, including neurological disorders and oncology. DYRK1A has more recently been shown to be involved in pathways regulating human β-cell proliferation, thus making it a potential therapeutic target for both Type 1 and Type 2 diabetes. Our group, using a high-throughput phenotypic screen, identified harmine that is able to induce β-cell proliferation both in vitro and in vivo. Since harmine has suboptimal kinase selectivity, we sought to expand structure-activity relationships for harmine's DYRK1A activity, to enhance selectivity, while retaining human β-cell proliferation capability. We carried out the optimization of the 1-position of harmine and synthesized 15 harmine analogues. Six compounds showed excellent DYRK1A inhibition with IC in the range of 49.5-264 nM. Two compounds, 2-2 and 2-8, exhibited excellent human β-cell proliferation at doses of 3-30 μM, and compound 2-2 showed improved kinase selectivity as compared to harmine.

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Section: Resultsmentioning

confidence: 99%

Development of Kinase-Selective, Harmine-Based DYRK1A Inhibitors that Induce Pancreatic Human β-Cell Proliferation

et al. 2018

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“…As shown in Figure 2, harmine was N-alkylated with selective alkyl halides, namely, 1-bromo-3-phenylpropane, 1-bromopropane, 1-bromobutane and 1-bromo-2-methylpropane using sodium hydride as a base (Figure 2, Step I). These alkyl halides were selected on the basis of earlier reports of MOA, DYRK1A and anticancer activities of harmine analogs [21][22][23][24][25]. In 2017, Kotschy and his team outlined the modifications to harmine scaffold with different selectivity, inhibitory profiles for kinase and monoamine oxidases [21][22][23][24][25].…”

Section: Resultsmentioning

confidence: 99%

“…These alkyl halides were selected on the basis of earlier reports of MOA, DYRK1A and anticancer activities of harmine analogs [21][22][23][24][25]. In 2017, Kotschy and his team outlined the modifications to harmine scaffold with different selectivity, inhibitory profiles for kinase and monoamine oxidases [21][22][23][24][25]. The alkylated harmine was then subjected to selective O-demethylation by refluxing with HBr in AcOH (Figure 2, Step II) followed by O-propargylation with Cs 2 CO 3 as a base (Figure 2, Step III).…”

Section: Resultsmentioning

confidence: 99%

Isoform Selectivity of Harmine-Conjugated 1,2,3-Triazoles against Human Monoamine Oxidase

et al. 2018

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Compounds 3e and 4c exhibited an IC of 0.83 ± 0.03 and 0.43 ± 0.002 μM against MAO-A and an IC of 0.26 ± 0.04 and 0.36 ± 0.001 μM against MAO-B, respectively. Molecular docking studies revealed π-π interactions between the synthesized molecules and aromatic amino acid residues. Conclusion & future perspective: The current study delineates the structural requirements for MAO-A selectivity and such information may be helpful in designing selective analogs for kinase, DYRK1A and harmine-based cytotoxics without apparent MAO enzyme inhibition.

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“…Berdasarkan data penelitian dari Bálint dkk, modifikasi harmine melalui hidroksilasi gugus metil pada cincin piridine dapat menginhibisi DYRK1a. [27] Seperti yang sudah dijelaskan sebelumnya, harmine berikatan dengan DYRK1a hanya melalui Leu241 dan Lys188. Studi yang dilakukan oleh Kumar dkk berhasil menunjukkan adanya residu pada DYRK1a yang dapat menjadi tempat berikatan tambahan, seperti Glu203 dan Phe308.…”

Section: Harmine Melalui Hidroksilasi Gugus Metil Pada Cincin Piridineunclassified

1-hydroxymethyl Harmine-TGFβSF Inhibitor: Inovasi Terapi Diabetes Melitus Terbaru Melalui Inisiasi Proses Regenerasi Sel β Pankreas pada Penderita DM Tipe 1 dan 2

2021

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Background: Type 1 and 2 diabetes mellitus (DM) is a chronic metabolic disease most commonly affects millions of people worldwide. Despite the differences in pathogenesis, both share one thing in common - that is the drastic depletion in the number of pancreatic β cells. Unfortunately, physiological proliferation of β cells has come to a halt starting from the first year of neonatal. To overcome this problem, researchers have been searching for molecules with the ability to induce β cells proliferation. Upon extensive screening, only harmine was proven to be the most potent β cells proliferation inducer. Furthermore, combination of harmine with TGFβSF inhibitor was found to boost harmine’s effectivity even more. Another development was also made to improve harmine’s selectivity by incorporating 1-hydroxymethyl group. Objective: Evaluate the potency of 1-hydroxymethyl harmine-TGFβSF inhibitor as a novel therapy for DM. Method: A systematic literature study was conducted with the database from Pubmed, Google Scholar, ScienceDirect, and Proquest for articles published within 2015-2019. Discussion: This literature review yields result that harmine-TGFβSF inhibitor is proven to induce β cells proliferation up to 18%/day or equal to 18 times the normal cell proliferation rate during embryogenesis. Moreover, incorporating 1-hydroxymethyl group into harmine is proven not only to improve selectivity but also lessen the toxicity, making 1-hydroxymethyl harmine safe as a novel therapy for diabetes. Conclusion: 1-hydroxymethyl harmine-TGFβSF inhibitor display promising potential as a novel therapy for all type of diabetes patients. Keywords: diabetes mellitus, harmine, TGFβSF inhibitor, β cell proliferation Latar Belakang: Diabetes Melitus (DM) tipe 1 maupun tipe 2 merupakan penyakit metabolik kronis yang paling banyak ditemukan di seluruh dunia. Walaupun memiliki proses patogenesis yang berbeda, namun kedua tipe DM ini ternyata memiliki kesamaan, yaitu terjadinya penurunan kuantitas sel β pankreas. Sayangnya, kemampuan regenerasi sel β pankreas manusia telah terhenti semenjak tahun pertama masa neonatal. Untuk menangani permasalahan tersebut, para peneliti menemukan sebuah molekul bernama harmine yang terbukti efektif menginisiasi proses regenerasi sel β pankreas. Selanjutnya, untuk meningkatkan efektifitas dari harmine agar lebih baik lagi, peneliti kemudian mengkombinasikan harmine dengan TGFβSF inhibitor. Sedangkan, untuk meningkatkan selektivitas dari harmine, peneliti menambahkan gugus 1-hidroksimetil pada molekul tersebut. Tujuan: Evaluasi potensi 1-hydroxymethyl harmine-TGFβSF inhibitor sebagai terapi utama bagi semua penderita DM. Metode: Penelitian dilakukan dengan melakukan tinjauan pustaka dari beberapa database jurnal, yakni PubMed, Google Scholar, ScienceDirect dan ProQuest dengan kriteria literatur dipublikasikan dalam kurun waktu 2015-2019. Pembahasan: Studi literatur ini menunjukan bahwa harmine-TGFβSF inhibitor telah terbukti mampu meningkatkan proliferasi sel β pankreas manusia hingga mencapai 18%/hari atau setara dengan 18 kali kecepatan embriogenesis pada sel normal. Selain itu, penambahan gugus 1-hidroksimetil pada harmine juga telah terbukti tidak hanya mampu meningkatkan selektivitas dari molekul tersebut, tetapi juga mampu menurunkan efek toksisitasnya, sehingga aman digunakan sebagai terapi anti-diabetes terbaru. Kesimpulan: 1-hydroxymethyl harmine-TGFβSF inhibitor memiliki potensi yang menjanjikan untuk menjadi terapi baru bagi semua tipe penderita DM. Kata Kunci: diabetes mellitus, harmine, proliferasi sel β, TGFβSF inhibitor

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Structure‐Based Design and Synthesis of Harmine Derivatives with Different Selectivity Profiles in Kinase versus Monoamine Oxidase Inhibition

Cited by 27 publications

References 22 publications

Development of Kinase-Selective, Harmine-Based DYRK1A Inhibitors that Induce Pancreatic Human β-Cell Proliferation

Development of Kinase-Selective, Harmine-Based DYRK1A Inhibitors that Induce Pancreatic Human β-Cell Proliferation

Isoform Selectivity of Harmine-Conjugated 1,2,3-Triazoles against Human Monoamine Oxidase

1-hydroxymethyl Harmine-TGFβSF Inhibitor: Inovasi Terapi Diabetes Melitus Terbaru Melalui Inisiasi Proses Regenerasi Sel β Pankreas pada Penderita DM Tipe 1 dan 2

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