Covalent bonding of azoles to quaternary protoberberine alkaloids

Grycová, Lenka; Hulová, Dagmar; Maier, Lukáš; Standara, Stanislav; Nečas, Marek; Lemière, Filip; Kareš, Radovan; Dostál, Jiřı́; Marek, Radek

doi:10.1002/mrc.2325

Cited by 14 publications

(4 citation statements)

References 39 publications

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“…Some modifications of Ber have been carried out trying to improve its bioactivity and bioavailability in antimicrobial, antidiabetic, antihyperlipidemic, and antitumor effects. Modification at C8 and C13 greatly increased the antimicrobial activity of Ber , which is closely related to the substituent chain length. − Most of the Ber derivatives with halogen and heteroaromatics on C8 and C9 positions displayed stronger hypoglycemic ability than Ber . , Structure–activity studies on the antitumor effect of Ber mainly focused on the C8, C9, and C13 positions; for example, 13-alkyl derivatives of Ber showed higher antitumor activities than Ber , and a moderate alkyl chain length was beneficial for its antitumor activity. − However, almost all these modifications are randomly made and effect-oriented, lacking a structural basis for the mechanism of Ber ’s effects. Most of these derivatives, by inserting either a long aliphatic chain or a heterocyclic ring, may have significant effects but lose the biosafety of Ber because the structures were changed too much.…”

Section: Introductionmentioning

confidence: 99%

Structure–Activity Relationship Study Enables the Discovery of a Novel Berberine Analogue as the RXRα Activator to Inhibit Colon Cancer

Jiang

Xiong

et al. 2020

J. Med. Chem.

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We reported recently that berberine (Ber), a traditional oriental medicine to treat gastroenteritis, binds and activates retinoid X receptor α (RXRα) for suppressing the growth of colon cancer cells. Here, we extended our studies based on the binding mode of Ber with RXRα by design, synthesis, and biological evaluation of a focused library of 15 novel Ber analogues. Among them, 3,9-dimethoxy-5,6-dihydroisoquinolino[3,2-a]isoquinolin-7-ium chloride (B-12) was identified as the optimal RXRα activator. More efficiently than Ber, B-12 bound and altered the conformation of RXRα/LBD, thereby suppressing the Wnt/β-catenin pathway and colon cancer cell growth via RXRα mediation. In addition, B-12 not only preserved Ber's tumor selectivity but also greatly improved its bioavailability. Remarkably, in mice, B-12 did not show obvious side effects including hypertriglyceridemia as other RXRα agonists or induce hepatorenal toxicity. Together, our study describes an approach for the rational design of Ber-derived RXRα activators as novel effective antineoplastic agents for colon cancer.

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Section: Introductionmentioning

confidence: 99%

Structure–Activity Relationship Study Enables the Discovery of a Novel Berberine Analogue as the RXRα Activator to Inhibit Colon Cancer

Jiang

Xiong

et al. 2020

J. Med. Chem.

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“…IR spectra exhibited vibrations in the range 1653-1664 cm 1 that corresponded to the vibrational frequency of a tertiary amide. PMR and 13 C NMR spectra showed resonances for the berberine molecule that were similar to those of berberine chloride and indicated that this fragment was unchanged [11]. PMR spectra of 2 exhibited resonances for methylene protons of OCH 2 CON as singlet with chemical shifts G 4.99-5.26 ppm.…”

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confidence: 87%

Synthesis of berberine bromide analogs containing tertiary amides of acetic acid in the 9-O-position

et al. 2013

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547.978.1+547.833.8 V. G. Vasilcev, and N. F. Salakhutdinov 9-O-Acetamide analogs of berberine bromide were prepared in 20-87% yields via reaction of the isoquinoline alkaloid berberrubine with tertiary amides of bromoacetic acid. Aminolysis did not occur during reaction of methyl-2-(9-demethoxyberberine bromide-9-yl)hydroxyacetate with secondary amines. The corresponding acid or its ethyl ester was isolated.The leading cause of death (greater than 50% of all lethalities) in the majority of economically developed countries remains as before cardiovascular diseases (CVD) of atherosclerotic origin and their complications (acute myocardial infarct, sudden cardiac death). Hyperlipidemia and, in particular, hypercholesterolemia is the principal risk factor of atherosclerotic CVD. Drugs used in medical practice and developed to lower cholesterol can be divided into two classes that differ in principle according to their mechanism of action. The first class includes drugs that inhibit the synthesis of endogenous cholesterol. Such chemical compounds (e.g., statins) interrupt the synthetic pathway of cholesterol in vivo by blocking (mostly by a competing mechanism) the activity of the corresponding enzyme. The second class comprises compounds that regulate by one method or another the amounts of cholesterol already synthesized by the body or obtained in food and enable its amount to be maintained within acceptable limits.

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“…A restricted rotation around the newly formed C-N bond was studied experimentally by temperature-dependent NMR measurements. [19][20][21][22] In addition, the experimental NMR observations were complemented by the molecular modeling and quantum chemical calculations using density functional theory. This paper is arranged as follows: In preparation and characterization section, synthesis of 6-substituted azoles of dihydrobenzo[c]phenanthridine and their characterization by using 1 H and 13 C NMR spectroscopy is described.…”

Section: Introductionmentioning

confidence: 99%

“…The synthetized 5,6‐dihydrobenzo[ c ]phenanthridines were investigated by NMR spectroscopy and computational chemistry with the aim to determine their molecular structures. A restricted rotation around the newly formed C–N bond was studied experimentally by temperature‐dependent NMR measurements . In addition, the experimental NMR observations were complemented by the molecular modeling and quantum chemical calculations using density functional theory.…”

Section: Introductionmentioning

confidence: 99%

Structure and NMR properties of 6‐substituted‐5,6‐dihydrobenzo[c]phenanthridine alkaloids

Kadam

Maier

Šolomek

et al. 2013

J of Physical Organic Chem

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We report a preparation of new 6-substituted-5,6-dihydrobenzo[c]phenanthridines by the reaction of azoles with quaternary benzo[c]phenanthridine alkaloids sanguinarine and chelerythrine. The prepared compounds have been characterized by NMR spectroscopy, mass spectrometry, and single-crystal X-ray diffraction. Conformational behaviors of carbazole derivatives in solution have been investigated by low-temperature NMR experiments. Barriers to rotation around newly formed C6-N bonds were determined to be 12-13 kcal/mol. Quantum chemical calculations have been used to reproduce the experimental observations. Large structural effects on several 1 H NMR resonances were observed experimentally, analyzed by Density Functional Theory (DFT) calculations at B3LYP/6-311+G(d,p)/PCM level, and interpreted by ring-current effects of the benzo[c]phenanthridine and carbazole units.

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Covalent bonding of azoles to quaternary protoberberine alkaloids

Cited by 14 publications

References 39 publications

Structure–Activity Relationship Study Enables the Discovery of a Novel Berberine Analogue as the RXRα Activator to Inhibit Colon Cancer

Structure–Activity Relationship Study Enables the Discovery of a Novel Berberine Analogue as the RXRα Activator to Inhibit Colon Cancer

Synthesis of berberine bromide analogs containing tertiary amides of acetic acid in the 9-O-position

Structure and NMR properties of 6‐substituted‐5,6‐dihydrobenzo[c]phenanthridine alkaloids

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