Role of 13-(di)phenylalkyl berberine derivatives in the modulation of the activity of human topoisomerase IB

Vieira, Sara; Castelli, Silvia; Falconi, Mattia; Takarada, Jéssica; Fiorillo, Gaetano; Buzzetti, Franco; Lombardi, Paolo; Desideri, Alessandro

doi:10.1016/j.ijbiomac.2015.02.051

Cited by 27 publications

(14 citation statements)

References 38 publications

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“…It has been shown that berberine (1a) and its derivatives act, for example, as anti-inflammatory [25], antibacterial [26,27], and anticancer reagents [28,29]. The latter property is mainly based on the binding interaction of berberine with nucleic acids and the resulting inhibition of topoisomerase and telomerase [2,30]. Most notably, berberine (1a) induces a strong growth inhibition in several human cancer cells, but has only a relatively low cytotoxicity in healthy cells [31,32].…”

Section: Introductionmentioning

confidence: 99%

Synthesis and investigation of quadruplex-DNA-binding, 9-O-substituted berberine derivatives

Becher¹,

Berdnikova²,

Ihmels³

et al. 2020

Beilstein J. Org. Chem.

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A small series of five novel berberine derivatives was synthesized by the Cu-catalyzed click reaction of 9-propargyladenine with 9-O-(azidoalkyl)berberine derivatives. The association of the resulting berberine–adenine conjugates with representative quadruplex-forming oligonucleotides 22AG dA(G3TTA)3G3 and a2 d(ACAG4TGTG4)2 was examined with photometric and fluorimetric titrations, thermal DNA denaturation analysis, and CD spectroscopy. The results from the spectrometric titrations indicated the formation of 2:1 or 1:1 complexes (ligand:G4-DNA) with log K b values of 10–11 (2:1) and 5–6 (1:1), which are typical for berberine derivatives. Notably, a clear relationship between the binding affinity of the ligands with the length of the alkyl linker chain, n, was not observed. However, depending on the structure, the ligands exhibited different effects when bound to the G4-DNA, such as fluorescent light-up effects and formation of ICD bands, which are mostly pronounced with a linker length of n = 4 (with a2) and n = 5 (with 22AG), thus indicating that each ligand–G4-DNA complex has a specific structure with respect to relative alignment and conformational flexibility of the ligand in the binding site. It was shown exemplarily with one representative ligand from the series that such berberine–adenine conjugates exhibit a selective binding, specifically a selectivity to quadruplex DNA in competition with duplex DNA, and a preferential thermal stabilization of the G4-DNA forms 22AG and KRAS. Notably, the experimental data do not provide evidence for a significant effect of the adenine unit on the binding affinity of the ligands, for example, by additional association with the loops, presumably because the adenine residue is sterically shielded by the neighboring triazole unit.

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Section: Introductionmentioning

confidence: 99%

Synthesis and investigation of quadruplex-DNA-binding, 9-O-substituted berberine derivatives

Becher¹,

Berdnikova²,

Ihmels³

et al. 2020

Beilstein J. Org. Chem.

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“…The ability of compounds 16 and 25 to cause DNA fragmentation was then evaluated, known antibacterial berberine’s derivatives obtained by modification at position 13 with alkyl and diphenyl alkyl possessing such activity [ 11 ]. Results showed that incubation of bacterial DNA extracted from B. subtilis or V. alginolyticus for 6 h at 37 °C with compounds 16 and 25 at 4-times their MIC did not caused DNA fragmentation ( Figure S2 ).…”

Section: Resultsmentioning

confidence: 99%

“…Berberine is a natural molecule present in some medicinal plants, mainly of the Berberidaceae family ( Berberis aquifolium , B. aristata , B. asiatica , B. chitria , B. lyceum , B. vulgaris ) but also in other species such as Argemone mexicana , Coptis japonica , Hydrastis canadensis , Papaver dubium , Thalictrum flavum [ 3 ]. Berberine and its derivatives [ 4 ] are known for having various biological activities such as antimalarial [ 5 ], antileishmanial [ 6 ], antiviral [ 7 , 8 ], hypolipidemic [ 9 ], anticancer [ 10 , 11 ] and antimicrobial effects [ 12 , 13 , 14 ]. Most of the active derivatives of berberine were obtained by substitution of various group at the position 9 and/or 13 resulting in higher activities compared to the parent molecule.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Evaluation of the Antibacterial Activities of 13-Substituted Berberine Derivatives

et al. 2020

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The biological activities of berberine, a natural plant molecule, are known to be affected by structural modifications, mostly at position 9 and/or 13. A series of new 13-substituted berberine derivatives were synthesized and evaluated in term of antimicrobial activity using various microorganisms associated to human diseases. Contrarily to the original molecule berberine, several derivatives were found strongly active in microbial sensitivity tests against Mycobacterium, Candida albicans and Gram-positive bacteria, including naïve or resistant Bacillus cereus, Staphylococcus aureus and Streptococcus pyogenes with minimal inhibitory concentration (MIC) of 3.12 to 6.25 µM. Among the various Gram-negative strains tested, berberine’s derivatives were only found active on Helicobacter pylori and Vibrio alginolyticus (MIC values of 1.5–3.12 µM). Cytotoxicity assays performed on human cells showed that the antimicrobial berberine derivatives caused low toxicity resulting in good therapeutic index values. In addition, a mechanistic approach demonstrated that, contrarily to already known berberine derivatives causing either membrane permeabilization, DNA fragmentation or interacting with FtsZ protein, active derivatives described in this study act through inhibition of the synthesis of peptidoglycan or RNA. Overall, this study shows that these new berberine derivatives can be considered as potent and safe anti-bacterial agents active on human pathogenic microorganisms, including ones resistant to conventional antibiotics.

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“…The most active compound in this assay appear to be NAX038 (67) and NAX014 (64). The 13-(di)phenylalkyl berberine derivatives (NAX035 (68), NAX045 (70) and NAX050 (71)) as topoisomerases IB inhibitors with therapeutic potential as anticancer and antimicrobial agents has also been outlined [148].…”

Section: C-13 Berberine Derivativesmentioning

confidence: 99%

“…While their IC50 value in Wnt/β-catenin suppression could lower below one µ M, their cytotoxicity IC50 values remain higher ranging from 7 to over 40 µ M. The most active compound in this assay appear to be NAX038 (67) and NAX014 (64). The 13-(di)phenylalkyl berberine derivatives (NAX035 (68), NAX045 (70) and NAX050 (71)) as topoisomerases IB inhibitors with therapeutic potential as anticancer and antimicrobial agents has also been outlined [148]. As discussed in the previous section, Bhowmik et al [136] prepared the 9-O-derrvative derivative (43, Figure 5) that target G-quadruplex.…”

Section: C-13 Berberine Derivativesmentioning

confidence: 99%

Recent Advances in Berberine Inspired Anticancer Approaches: From Drug Combination to Novel Formulation Technology and Derivatization

Habtemariam

2020

Molecules

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Berberine is multifunctional natural product with potential to treat diverse pathological conditions. Its broad-spectrum anticancer effect through direct effect on cancer cell growth and metastasis have been established both in vitro and in vivo. The cellular targets that account to the anticancer effect of berberine are incredibly large and range from kinases (protein kinase B (Akt), mitogen activated protein kinases (MAPKs), cell cycle checkpoint kinases, etc.) and transcription factors to genes and protein regulators of cell survival, motility and death. The direct effect of berberine in cancer cells is however relatively weak and occur at moderate concentration range (10–100 µM) in most cancer cells. The poor pharmacokinetics profile resulting from poor absorption, efflux by permeability-glycoprotein (P-gc) and extensive metabolism in intestinal and hepatic cells are other dimensions of berberine’s limitation as anticancer agent. This communication addresses the research efforts during the last two decades that were devoted to enhancing the anticancer potential of berberine. Strategies highlighted include using berberine in combination with other chemotherapeutic agents either to reduce toxic side effects or enhance their anticancer effects; the various novel formulation approaches which by order of magnitude improved the pharmacokinetics of berberine; and semisynthetic approaches that enhanced potency by up to 100-fold.

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Role of 13-(di)phenylalkyl berberine derivatives in the modulation of the activity of human topoisomerase IB

Cited by 27 publications

References 38 publications

Synthesis and investigation of quadruplex-DNA-binding, 9-O-substituted berberine derivatives

Synthesis and investigation of quadruplex-DNA-binding, 9-O-substituted berberine derivatives

Synthesis and Evaluation of the Antibacterial Activities of 13-Substituted Berberine Derivatives

Recent Advances in Berberine Inspired Anticancer Approaches: From Drug Combination to Novel Formulation Technology and Derivatization

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