Discovery and evaluation of cytisine N-isoflavones as novel EGFR/HER2 dual inhibitors

Wang, Yanqing; Yin, Xiaoying; Chen, Lingyan; Yin, Zhixiang; Zuo, Zhicheng

doi:10.1016/j.bioorg.2022.105868

Cited by 13 publications

(12 citation statements)

References 46 publications

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“…In many cases, the structure of the products was not established but was based on the chemical shifts of the H‐6 or H‐8 protons, as well as on the position of the peaks of the C6 and C8 atoms of the chromone core [7,31,33] . In our opinion, such conclusions may be doubtful, since the signals of the H‐6 and H‐8 protons are very close, sometimes less than 0.10 ppm, and the disappearance of one of the peaks does not confirm the formation of a specific isomer.…”

Section: Resultsmentioning

confidence: 89%

“…[4,5] In 2008 Guo and co-workers reported the isolation of methylene linked maackiain-cytisine hybrids tonkinensines A and B (1 a and 1 b) from Sophora tonkinensis with moderate cytotoxic activity. [6] Related isoflavone-cytisine Mannich base 1 c was isolated from the fruit of Sophora alopecuroides [7] which demonstrated activity in the inhibition of breast cancer cell metabolism. Unique derivative 1 d was isolated from the roots of Sophora tonkinensis which possess significant anti-tobacco mosaic virus activity.…”

Section: Introductionmentioning

confidence: 99%

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Structure–Activity Relationship Prediction‐Based Synthesis and Cytotoxicity Evaluation against the HEp‐2 Laryngeal Carcinoma Cell of Isoflavone–Cytisine Mannich Bases

Mrug,

Hodyna,

Metelytsia

et al. 2023

Chemistry & Biodiversity

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QSAR analysis of previously synthesized and nature‐inspired virtual isoflavone‐cytisine hybrids against the HEp‐2 laryngeal carcinoma cell lines was performed using the OCHEM web platform. The validation of the models using an external test set proved that the models can be used to predict the activity of newly designed compounds such as 8‐cytisinylmethyl derivatives of 5,7‐ and 6,7‐dihydroxyisoflavones. The synthetic procedure for selective aminomethylation of 5,7‐dihydroxyisoflavones with cytisine was developed. In vitro testing identified compound 7 f with cisplatin‐level cytotoxicity against HEp‐2 cell lines and compound 10 which was twice active than cisplatin after 72 h of incubation.

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Section: Resultsmentioning

confidence: 89%

Section: Introductionmentioning

confidence: 99%

Structure–Activity Relationship Prediction‐Based Synthesis and Cytotoxicity Evaluation against the HEp‐2 Laryngeal Carcinoma Cell of Isoflavone–Cytisine Mannich Bases

Mrug,

Hodyna,

Metelytsia

et al. 2023

Chemistry & Biodiversity

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“…Identification of known compounds done on the basis of the spectroscopic data as well as a comparison with those found in the literature as argentine ( 15 ), [(3-hydroxy-6-pyridinyl)-methyl]-cytisine ( 16 ), N -acetonylcytisine ( 17 ), N -(3-oxobutyl)cytisine ( 18 ), (−)-rhombifoline ( 19 ), methyl ester of 3-( N -cytisinyl)propanoic acid ( 20 ), thermseedline P ( 21 ), methyl ester of N -cytisinylacetic acid ( 22 ), thermseedline P ( 23 ), cytisine ( 24 ), N -methylcytisine ( 25 ), N -formylcytisine ( 26 ), N -acylcytisine ( 27 ), (−)-12-hydroxycytisine ( 28 ), cytisine-12-carbamide ( 29 ), thermseedline K ( 30 ), thermopsine ( 31 ) (Figure ), 13β-hydroxylthermopsine ( 32 ), thermseedline O ( 33 ), anagyrine ( 34 ), epibaptifoline ( 35 ), baptifoline ( 36 ), 13β-acetoxyanagyrine ( 37 ), (−)-lupanine ( 38 ), (+)-5,6-dehydrolupanine ( 39 ), daidzein ( 40 ), isoformononetin ( 41 ), 3 ′ ,4 ′ ,7-trihydroxyisoflavone ( 42 ), 4 ′ ,7-dihydroxy-3 ′ -methoxyisoflavone ( 43 ), cabreuvin ( 44 ), orobol ( 45 ), genistein ( 46 ), formononetin ( 47 ), 4 ′ ,7-dimethoxy-5-hydroxyisoflavone ( 48 ), 3 ′ -hydroxyglycitein ( 49 ), glycitein ( 50 ), 7-hydroxy-3-(4-hydroxy-phenyl)-5-methoxy-chromen-4-one ( 51 ), erythrinin B ( 52 ), and ononin ( 53 ) …”

Section: Resultsmentioning

confidence: 99%

Quinolizidine Alkaloids and Isoflavones from the Herb of Thermopsis lupinoides and Their Antiviral, Antifungal, and Insecticidal Activities

Zhang,

Tian,

Zhang

et al. 2024

J. Agric. Food Chem.

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As part of our ongoing investigation of natural bioactive substances from the genus Thermopsis of the tribe Fabaceae for agricultural protection, the chemical constituents of the herb Thermopsis lupinoides were systematically investigated, which led to the isolation of 39 quinolizidine alkaloids (QAs) (1−39), including 14 new QAs (1−14) and 14 isoflavones (40−53). Their structures were elucidated through comprehensive spectroscopic data analysis (IR, UV, NMR, HRESIMS), ECD calculations, and Xray crystallography. The antitomato spotted wilt virus (TSWV) and antifungal (against Botrytis cinerea, Gibberella zeae, Phytophythora capsica, and Alternaria alternata) and insecticidal (against Aphis fabae and Tetranychus urticae) activities of the isolated compounds were screened using the lesion counting method, mycelial inhibition assay, and spray method, respectively. The bioassay results showed that 34 exhibited excellent protective activity against TSWV, with an EC 50 value of 36.04 μg/mL, which was better than that of the positive control, ningnanmycin (86.03 μg/mL). The preliminary mechanistic exploration illustrated that 34 induced systemic acquired resistance in the host plant by acting on the salicylic acid signaling pathway. Moreover, 1 showed significant antifungal activity against B. cinerea (EC 50 value of 20.83 μg/mL), while 2 exhibited good insecticidal activity against A. fabae (LC 50 value of 24.97 μg/mL). This research is promising for the invention of novel pesticides from QAs with high efficiency and satisfactory ecological compatibility.

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“…The small-molecule BRD0539 was also subjected to explicit solvent MD simulation to obtain diverse initial configurations for docking. The force field parameters of BRD0539 were derived following the similar protocol as reported in our previous studies. , The geometry of BRD0539 was optimized at the B3LYP/6-31G* level of theory, followed by HF/6-31G* calculations of the molecular electrostatic potential. Then the antechamber program of AmberTools22 was used to derive the restrained electrostatic potential (RESP) charges of BRD0539 based on the electrostatic potential data generated above.…”

Section: Methodsmentioning

confidence: 99%

Identification of a Cryptic Binding Site in CRISPR-Cas9 for Targeted Inhibition

Zhang

Zuo

2023

J. Chem. Inf. Model.

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The need for precision control of CRISPR-Cas9 genome editing has created a demand for anti-CRISPR molecules. Recently, the first class of small-molecule Cas9 inhibitors has been identified, verifying the feasibility of regulating CRISPR-Cas9 activity using direct-acting small molecules. However, it remains enigmatic as to the location of the ligand binding site(s) on CRISPR-Cas9 and how the ligand binding leads to Cas9 functional inhibition. Here, we established an integrative computational protocol, including massive binding site mapping, molecular docking, molecular dynamics simulations, and free energy calculations. Ultimately, a Cas9 ligand binding site was discovered from the dynamics trajectories that is hidden within its carboxylterminal domain (CTD), a domain recognizing the protospacer adjacent motif (PAM). Using the top inhibitor BRD0539 as a probe, we demonstrated that the ligand binding induces significant CTD structural rearrangements toward an incompetent conformation for PAM DNA engagement. The revealed molecular mechanism of BRD0539 inhibiting Cas9 is in well agreement with the experimental data. This study provides a structural and mechanistic basis for the potency improvement of existing ligands and the rational discovery of novel small-molecule brakes for developing safer CRISPR-Cas9 technologies.

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Discovery and evaluation of cytisine N-isoflavones as novel EGFR/HER2 dual inhibitors

Cited by 13 publications

References 46 publications

Structure–Activity Relationship Prediction‐Based Synthesis and Cytotoxicity Evaluation against the HEp‐2 Laryngeal Carcinoma Cell of Isoflavone–Cytisine Mannich Bases

Structure–Activity Relationship Prediction‐Based Synthesis and Cytotoxicity Evaluation against the HEp‐2 Laryngeal Carcinoma Cell of Isoflavone–Cytisine Mannich Bases

Quinolizidine Alkaloids and Isoflavones from the Herb of Thermopsis lupinoides and Their Antiviral, Antifungal, and Insecticidal Activities

Identification of a Cryptic Binding Site in CRISPR-Cas9 for Targeted Inhibition

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