Monoterpene indole alkaloid azine derivatives as MDR reversal agents

Paterna, Angela; Khonkarn, Ruttiros; Mulhovo, Silva; Moréno, Alexis; Gírio, Patrícia; Baubichon‐Cortay, Hélène; Falson, Pierre; Ferreira, Maria‐José U.

doi:10.1016/j.bmc.2017.11.052

Cited by 26 publications

(19 citation statements)

References 28 publications

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“…Thus, the ability of NPs to hit several targets, generally allied with a reduced toxicity, render these compounds attractive templates for the development of multifunctional MDR reversers [ 31 ]. A rising number of papers has been reporting the ability of NPs to act synergistically with anticancer drugs and reverse MDR in cancer cells by modulation of the three main efflux pumps P-gp, MRP1 and BCRP, being referred by some authors as the “fourth-generation inhibitors” [ 64 , 65 , 66 ]. Among NPs, flavonoids and terpenoids along with alkaloids, cardiotonic steroids and coumarins are the most extensively studied classes for their ability to inhibit these efflux proteins [ 63 , 64 ].…”

Section: Introductionmentioning

confidence: 99%

Overcoming Multidrug Resistance: Flavonoid and Terpenoid Nitrogen-Containing Derivatives as ABC Transporter Modulators

2020

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Multidrug resistance (MDR) in cancer is one of the main limitations for chemotherapy success. Numerous mechanisms are behind the MDR phenomenon wherein the overexpression of the ATP-binding cassette (ABC) transporter proteins P-glycoprotein (P-gp), breast cancer resistance protein (BCRP) and multidrug resistance protein 1 (MRP1) is highlighted as a prime factor. Natural product-derived compounds are being addressed as promising ABC transporter modulators to tackle MDR. Flavonoids and terpenoids have been extensively explored in this field as mono or dual modulators of these efflux pumps. Nitrogen-bearing moieties on these scaffolds were proved to influence the modulation of ABC transporters efflux function. This review highlights the potential of semisynthetic nitrogen-containing flavonoid and terpenoid derivatives as candidates for the design of effective MDR reversers. A brief introduction concerning the major role of efflux pumps in multidrug resistance, the potential of natural product-derived compounds in MDR reversal, namely natural flavonoid and terpenoids, and the effect of the introduction of nitrogen-containing groups are provided. The main modifications that have been performed during last few years to generate flavonoid and terpenoid derivatives, bearing nitrogen moieties, such as aliphatic, aromatic and heterocycle amine, amide, and related functional groups, as well as their P-gp, MRP1 and BCRP inhibitory activities are reviewed and discussed.

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Section: Introductionmentioning

confidence: 99%

Overcoming Multidrug Resistance: Flavonoid and Terpenoid Nitrogen-Containing Derivatives as ABC Transporter Modulators

2020

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“…The monoterpene indole alkaloid of the corynanthe-type [18], dregamine (1), was previously isolated, in a large amount, from the alkaloid fraction of the methanol extract of Tabernaemontana elegans roots [13]. As mentioned above, dregamine (1) derivatives were reported as promising MDR reversers [13][14][15], prompting us to carry out new chemical modifications to obtain 19 azines (3-21) and 11 semicarbazone (22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32) derivatives.…”

Section: Chemistrymentioning

confidence: 99%

“…After stirring the mixture for 2 h at room temperature, the reaction product was sequentially purified by column chromatography (silica gel, CH 2 Cl 2 /MeOH, 1:0 to 97:3) and preparative TLC (CH 2 Cl 2 /MeOH, 97:3) to afford 6 mg (0.013 mmol, yield 16%) of an amorphous yellow powder. (14). Obtained from reaction of compound 2 (25 mg, 0.068 mmol, 1 equiv.)…”

Section: -[(4 -(Dimethylamino)benzylidenementioning

confidence: 99%

Exploring the Monoterpene Indole Alkaloid Scaffold for Reversing P-Glycoprotein-Mediated Multidrug Resistance in Cancer

et al. 2021

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Dregamine (1), a major monoterpene indole alkaloid isolated from Tabernaemontana elegans, was submitted to chemical transformation of the ketone function, yielding 19 azines (3–21) and 11 semicarbazones (22–32) bearing aliphatic or aromatic substituents. Their structures were assigned mainly by 1D and 2D NMR (COSY, HMQC, and HMBC) experiments. Compounds 3–32 were evaluated as multidrug resistance (MDR) reversers through functional and chemosensitivity assays in a human ABCB1-transfected mouse T-lymphoma cell model, overexpressing P-glycoprotein. A significant increase of P-gp inhibitory activity was observed for most derivatives, mainly those containing azine moieties with aromatic substituents. Compounds with trimethoxyphenyl (17) or naphthyl motifs (18, 19) were among the most active, exhibiting strong inhibition at 0.2 µM. Moreover, most of the derivatives showed selective antiproliferative effects toward resistant cells, having a collateral sensitivity effect. In drug combination assays, all compounds showed to interact synergistically with doxorubicin. Selected compounds (12, 17, 18, 20, and 29) were evaluated in the ATPase activity assay, in which all compounds but 12 behaved as inhibitors. To gather further insights on drug–receptor interactions, in silico studies were also addressed. A QSAR model allowed us to deduce that compounds bearing bulky and lipophilic substituents were stronger P-gp inhibitors.

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“…It is well known that they possess antibacterial (Veena et al, 2011;Chourasiya et al, 2015), antifungal (Kurteva et al, 2011), anticonvulsant (Gul et al, 2004), antineuroinflammatory (Subedi et al, 2017), anticancer (Krezel et al, 1999;Qian et al, 2010;Liang et al, 2014) and antioxidant (Li et al, 2011) activities. Also, they behave as aldose reductase inhibitors (Meanwell et al, 1991) and MDR reversal agents (Paterna et al, 2018). Due to their ability to donate the lone electron pairs, azines have found great application as chemical sensors for many metal ions (Wei et al, 2017;Tiwari et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Synthesis, complete assignment of 1H- and 13C-NMR spectra and antioxidant activity of new azine derivative bearing coumarin moiety

Ristić¹,

Dekić²,

Radulović³

et al. 2021

Bull Nat Sci Research

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In this research, the synthesis of a new azine derivative with coumarin moiety was performed in three reaction steps, starting from 4-hydroxycoumarin. The first step in synthesis was the acetylation of 4-hydroxycoumarin to yield 3-acetyl-4-hydroxycoumarin and then the obtained 3-acetyl-4-hydroxycoumarin was reacted with hydrazine hydrate and give a corresponding hydrazone. Condensation of the hydrazone with 4-ethoxy-3-methoxybenzaldehyde afforded the target compound 1-[1-(4-hydroxy-2-oxo-2H-chromen-3-yl)-ethylidene]-2-(4-etoxy-3-methoxybenzylidene)-hydrazine in a good yield. The resulting azine derivative is fully spectrally characterized, including complete assignment of 1H- and 13C-NMR spectra, as well as 2D NMR (1H-1H COSY, NOESY, HSQC and HMBC) spectra. The antioxidant activity of corresponding hydrazone and target compound was evaluated by DPPH method where hydrazone derivative displayed a significant and target azine good antioxidant activity, with IC50 (μM) values 11.69 and 216.60, respectively.

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Monoterpene indole alkaloid azine derivatives as MDR reversal agents

Cited by 26 publications

References 28 publications

Overcoming Multidrug Resistance: Flavonoid and Terpenoid Nitrogen-Containing Derivatives as ABC Transporter Modulators

Overcoming Multidrug Resistance: Flavonoid and Terpenoid Nitrogen-Containing Derivatives as ABC Transporter Modulators

Exploring the Monoterpene Indole Alkaloid Scaffold for Reversing P-Glycoprotein-Mediated Multidrug Resistance in Cancer

Synthesis, complete assignment of 1H- and 13C-NMR spectra and antioxidant activity of new azine derivative bearing coumarin moiety

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