Novel Trisubstituted Harmine Derivatives with Original in Vitro Anticancer Activity

Frédérick, Raphaël; Bruyère, Céline; Vancraeynest, Christelle; Reniers, Jérémy; Meinguet, Céline; Pochet, Lionel; Backlund, Anders; Masereel, Bernard; Kiss, Róbert; Wouters, Johan

doi:10.1021/jm300542e

Cited by 77 publications

(68 citation statements)

References 52 publications

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“…SAR studies confirmed that substituents in position 2 and 9 displayed an important role in modulation of antitumor activities [134]. Derivatives of 59 that possess in R1, R2, and, R3 (Figure 11) a benzyl and 3'-fluorobenzyl groups are more likely to act as protein synthesis inhibitors [137].…”

Section: Harmine and Derivativesmentioning

confidence: 81%

Marine Natural Products as Models to Circumvent Multidrug Resistance

et al. 2016

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Multidrug resistance (MDR) to anticancer drugs is a serious health problem that in many cases leads to cancer treatment failure. The ATP binding cassette (ABC) transporter P-glycoprotein (P-gp), which leads to premature efflux of drugs from cancer cells, is often responsible for MDR. On the other hand, a strategy to search for modulators from natural products to overcome MDR had been in place during the last decades. However, Nature limits the amount of some natural products, which has led to the development of synthetic strategies to increase their availability. This review summarizes the research findings on marine natural products and derivatives, mainly alkaloids, polyoxygenated sterols, polyketides, terpenoids, diketopiperazines, and peptides, with P-gp inhibitory activity highlighting the established structure-activity relationships. The synthetic pathways for the total synthesis of the most promising members and analogs are also presented. It is expected that the data gathered during the last decades concerning their synthesis and MDR-inhibiting activities will help medicinal chemists develop potential drug candidates using marine natural products as models which can deliver new ABC transporter inhibitor scaffolds.

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Section: Harmine and Derivativesmentioning

confidence: 81%

Marine Natural Products as Models to Circumvent Multidrug Resistance

et al. 2016

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“…H NMR spectrum of compound 5a, as an example, compared with that of the hydrazide 3 used as a starting material, allowed us to note in addition to the signals relative to protons introduced by the hydrazide 3, the presence of two multiplets at d H 1.61 (4H, m, 2CH 2 ) and 1.24 (4H, m, 2CH 2 ) corresponding to the four methylene groups introduced by the anhydride and the disappearance of the signal related to the NH 2 protons at d H 4.38 (of intermediate 3). This structure was also evidenced by the observation in the 13 C NMR spectrum of characteristic signal at d C 167.4 corresponding to the two carbonyls of the amide functions. The same spectrum revealed three signals at d C 37.6 (2CH), 23.1 (2CH 2 ) and 21.0 (2CH 2 ) easly attributable to the methine and the two methylene groups of the anhydride moiety.…”

Section: Ache Inhibitory Activity Assaymentioning

confidence: 62%

“…1 H (300 MHz) and 13 C (75 MHz) NMR spectra were recorded on a Bruker AM-300 spectrometer, using CDCl 3 , CD 3 OD and DMSO-d 6 as solvent and non-deuterated residual solvent as internal standard. Chemicals shifts (d) are given in parts per million (ppm) and coupling constants (J) in Hertz.…”

Section: Chemistrymentioning

confidence: 99%

“…It is known to be anti-acetylcholinesterase, antimicrobial, antifungal and cytotoxic 12 . The latest research showed that harmine can inhibit the breast cancer protein BCRP so it was used as resistance to anticancer drugs 13 . Harmine derivatives 14 have received attention of researchers owing to their anti-alzheimer 15 , anticancer 16 and antiproliferative 17 activities.…”

Section: Introductionmentioning

confidence: 99%

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Synthesis, cytotoxic, anti-lipoxygenase and anti-acetylcholinesterase capacities of novel derivatives from harmine

Filali

Belkacem

Nejma

et al. 2016

Journal of Enzyme Inhibition and Medicinal Chemistry

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We synthesized two series of new hydrazide harmine derivatives. The reaction of harmine 1 with ethyl acetate chloride afforded the corresponding ethyl ester 2. The treatment of 2 with hydrazine hydrate gave the hydrazide 3 which further converted into hydrazones 4a-j and dihydrazides 5a-c. A series of new triazoles 7a-f has also been prepared from the suitable propargyl harmine 6. The synthesized derivatives were characterized by 1 H-NMR, 13 C-NMR, and HRMS and evaluated for their activities against MCF7, HCT116 OVCAR-3, acetylcholinesterase and 5-lipoxygenase. The most hydrazones derivatives 4a-j have a good cytotoxic activity against all cell lines, when 4a, 4d, 4f and 4 g are more active than 1 (against OVCAR-3 IC 50 16.7-2.5 mM). The compound 6 was the most active (IC 50 ¼ 1.9 mM) against acetylcholinesterase. Some compounds exhibited significant activity against 5-lipoxygenase (IC 50 ¼ 30.9-63.1 mM).

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“…Time-lapse acquisition of phase contrast microscopy pictures was automatically recorded every 4 min over a 72 h period in triplicate. 30,46−48 Quantitative data have been obtained by the counting of the number of cells on the pictures over time as previously described 30,46,48 and detailed in the legends of the figures. MTT Colorimetric Assay.…”

Section: Journal Of Medicinal Chemistrymentioning

confidence: 99%

Discovery and Characterization of R/S-N-3-Cyanophenyl-N′-(6-tert-butoxycarbonylamino-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)urea, a New Histone Deacetylase Class III Inhibitor Exerting Antiproliferative Activity against Cancer Cell Lines

et al. 2017

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A new series of N-aryl-N′-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)ureas bearing an alkoxycarbonylamino group at the 6-position were synthesized and examined as putative anticancer agents targeting sirtuins in glioma cells. On the basis of computational docking combined to in vitro sirtuin 1/2 inhibition assays, we selected compound 18 [R/S-N-3-cyanophenyl-N′-(6-tert-butoxycarbonylamino-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)urea] which displays a potent antiproliferative activity on various glioma cell types, assessed by quantitative videomicroscopy, eventually triggering senescence. The impact on normal glial cells was lower with a selectivity index of >10. Furthermore, human U373 and Hs683 glioblastoma cell lines served to demonstrate the inhibitory activity of 18 against histone deacetylase (HDAC) class III sirtuins 1 and 2 (SIRT1/2) by quantifying acetylation levels of histone and non-histone proteins. The translational potential of 18 was validated by an NCI-60 cell line screen and validation of growth inhibition of drug resistant cancer cell models. Eventually, the anticancer potential of 18 was validated in 3D glioblastoma spheroids and in vivo by zebrafish xenografts. In summary, compound 18 is the first representative of a new class of SIRT inhibitors opening new perspectives in the medicinal chemistry of HDAC inhibitors.

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Novel Trisubstituted Harmine Derivatives with Original in Vitro Anticancer Activity

Cited by 77 publications

References 52 publications

Marine Natural Products as Models to Circumvent Multidrug Resistance

Marine Natural Products as Models to Circumvent Multidrug Resistance

Synthesis, cytotoxic, anti-lipoxygenase and anti-acetylcholinesterase capacities of novel derivatives from harmine

Discovery and Characterization of R/S-N-3-Cyanophenyl-N′-(6-tert-butoxycarbonylamino-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)urea, a New Histone Deacetylase Class III Inhibitor Exerting Antiproliferative Activity against Cancer Cell Lines

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