scholarly journals Design, Synthesis, and In Vitro/In Vivo Anti-Cancer Activities of Novel (20S)-10,11-Methylenedioxy-Camptothecin Heterocyclic Derivatives

2020 ◽  
Vol 21 (22) ◽  
pp. 8495
Author(s):  
Xiufen Dai ◽  
Guanzhao Wu ◽  
Yixuan Zhang ◽  
Xiaomin Zhang ◽  
Ruijuan Yin ◽  
...  
Keyword(s):  
Water Solubility ◽  
A549 Cells ◽  
Antitumor Efficacy ◽  
Cytotoxic Activities ◽  
Design Synthesis ◽  
Cycle Arrest ◽  
Heterocyclic Derivatives ◽  
Ic50 Values

A novel camptothecin analogue, (20S)-10,11-methylenedioxy-camptothecin (FL118), has been proven to show significant antitumor efficacy for a wide variety of solid tumors. However, the further development of FL118 is severely hindered due to its extremely poor water solubility and adverse side effects. Here, two series of novel 20-substituted (20S)-10,11-methylenedioxy-camptothecin coupled with 5-substituted uracils and other heterocyclic rings through glycine were synthesized. All the derivatives showed superior cytotoxic activities in vitro with IC50 values in the nanomolar range. Among them, 12e displayed higher cytotoxic activities in several cancer cell lines with better water solubility than FL118. Our results further showed that, like FL118, 12e inhibited cell proliferation resulting from cell cycle arrest and apoptosis by blocking the anti-apoptotic gene transcription of survivin, Mcl-1, Bcl-2, and XIAP in both A549 cells and NCI-H446 cells. Furthermore, 12e did not show any inhibitory activity on Topo I, which is involved in hematopoietic toxicity. In vivo, 12e showed similar antitumor efficacy to FL118 but lower toxicity. Our findings indicate that 12e is a promising therapeutic agent for cancer treatment, and the core structure of FL118 represents a promising platform to generate novel FL118-based antitumor drugs.

scholarly journals Considerable Improvement of Ursolic Acid Water Solubility by Its Encapsulation in Dendrimer Nanoparticles: Design, Synthesis and Physicochemical Characterization

Nanomaterials ◽  
2021 ◽  
Vol 11 (9) ◽  
pp. 2196 ◽  
Author(s):  
Silvana Alfei ◽  
Anna Maria Schito ◽  
Guendalina Zuccari
Keyword(s):  
Ursolic Acid ◽  
Water Solubility ◽  
Drug Loading ◽  
Physicochemical Characterization ◽  
Systemic Toxicity ◽  
Water Soluble ◽  
Design Synthesis ◽  
Pentacyclic Triterpenoid

Ursolic acid (UA) is a pentacyclic triterpenoid found in many medicinal plants and aromas endowed with numerous in vitro pharmacological activities, including antibacterial effects. Unfortunately, UA is poorly administered in vivo, due to its water insolubility, low bioavailability, and residual systemic toxicity, thus making urgent the development of water-soluble UA formulations. Dendrimers are nonpareil macromolecules possessing highly controlled size, shape, and architecture. In dendrimers with cationic surface, the contemporary presence of inner cavities and of hydrophilic peripheral functions, allows to encapsulate hydrophobic non-water-soluble drugs as UA, to enhance their water-solubility and stability, and to promote their protracted release, thus decreasing their systemic toxicity. In this paper, aiming at developing a new UA-based antibacterial agent administrable in vivo, we reported the physical entrapment of UA in a biodegradable not cytotoxic cationic dendrimer (G4K). UA-loaded dendrimer nanoparticles (UA-G4K) were obtained, which showed a drug loading (DL%) much higher than those previously reported, a protracted release profile governed by diffusion mechanisms, and no cytotoxicity. Also, UA-G4K was characterized by principal components analysis (PCA)-processed FTIR spectroscopy, by NMR and elemental analyses, and by dynamic light scattering experiments (DLS). The water solubility of UA-G4K was found to be 1868-fold times higher than that of pristine UA, thus making its clinical application feasible.

scholarly journals Design, synthesis and pharmacological evaluation of novel 2-chloro-3-(1H-benzo[d]imidazol-2-yl)quinoline derivatives as antitumor agents: in vitro and in vivo antitumor activity, cell cycle arrest and apoptotic response

RSC Advances ◽  
2018 ◽  
Vol 8 (43) ◽  
pp. 24376-24385 ◽  
Author(s):  
Wen-Bin Kuang ◽  
Ri-Zhen Huang ◽  
Yi-Lin Fang ◽  
Gui-Bin Liang ◽  
Chen-Hui Yang ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Antitumor Agents ◽  
Quinoline Derivatives ◽  
Apoptotic Response ◽  
Design Synthesis ◽  
Cycle Arrest ◽  
In Vivo Antitumor Activity ◽  
Combination Principle

A series of novel 2-chloro-3-(1H-benzo[d]imidazol-2-yl)quinoline derivatives were designed and synthesized as antitumor agents under the combination principle. The antitumor activity and mechanisms were then evaluated.

scholarly journals Effect of Quarum Sensing Molecules on Aspergillus fumigatus

2019 ◽  
Vol 17 (4) ◽  
pp. 348-358
Author(s):  
Thanwa WONGSUK ◽  
Passanesh SUKPHOPETCH
Keyword(s):  
Aspergillus Fumigatus ◽  
Biofilm Formation ◽  
Cell Damage ◽  
A549 Cells ◽  
Alveolar Epithelial Cells ◽  
Cytotoxic Activities ◽  
Solid Media ◽  
Opportunistic Fungal Pathogen

Aspergillus fumigatus is an opportunistic fungal pathogen to which immunocompromised patients are especially susceptible. A. fumigatus can form biofilms both in vitro and in vivo. Quorum sensing molecules (QSMs) have activity against some fungi. This study aimed to determine the activity of the QSMs farnesol, tyrosol, phenylethanol and tryptophol against the growth A. fumigatus on solid media, and against its ability to form biofilms. The activity of each QSM against planktonic A. fumigatus growth was assessed using the CLSI M38-A2 broth microdilution assay, while QSM inhibition of A. fumigatus’s biofilm formation was measured in crystal violet, and 2, 3-bis (2-methoxy-4-nitro-5-sulfo-phenyl)-2H-tetrazolium-5-caboxanilide (XTT) assays. The QSMs reduced the colony diameter of the studied strains in a QSM-dependent pattern. Tryptophol showed the best effect and tyrosol showed the poorest effect. The minimum inhibitory concentrations (MICs) for farnesol, tyrosol, phenylethanol and tryptophol tested against A. fumigatus were > 32, > 32, 16 and 8 mM, respectively. The effective concentration each QSM required to inhibit A. fumigatus biofilm formation were higher than the planktonic MICs. In this study, the performance of QSMs against A. fumigatus ranked from best to worst as follows: tryptophol, phenylethanol, farnesol and tyrosol. Because of phenylethanol and tryptophol showed the strongest effect to the growth and biofilm formation of A. fumigatus. Therefore, the cytotoxic activities of phenylethanol and tryptophol in A549 cells (lung alveolar epithelial cells) were determined. However, phenylethanol and tryptophol induced A549 cell damage (at MIC level), as demonstrated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) and lactate dehydrogenase (LDH) assays.

scholarly journals Design, Synthesis, and Cytotoxic Analysis of Novel Hederagenin–Pyrazine Derivatives Based on Partial Least Squares Discriminant Analysis

2018 ◽  
Vol 19 (10) ◽  
pp. 2994 ◽  
Author(s):  
Kang Fang ◽  
Xiao-Hua Zhang ◽  
Yao-Tian Han ◽  
Gao-Rong Wu ◽  
De-Sheng Cai ◽  
...  
Keyword(s):  
Discriminant Analysis ◽  
Least Squares ◽  
Partial Least Squares ◽  
Cell Lines ◽  
Antitumor Agents ◽  
A549 Cells ◽  
In Vitro Cytotoxicity ◽  
Design Synthesis ◽  
Cycle Arrest

Hederagenin (He) is a novel triterpene template for the development of new antitumor compounds. In this study, 26 new He–pyrazine derivatives were synthetized in an attempt to develop potent antitumor agents; they were screened for in vitro cytotoxicity against tumor and non-tumor cell lines. The majority of these derivatives showed much stronger cytotoxic activity than He. Remarkably, the most potent was compound 9 (half maximal inhibitory concentration (IC50) was 3.45 ± 0.59 μM), which exhibited similar antitumor activities against A549 (human non-small-cell lung cancer) as the positive drug cisplatin (DDP; IC50 was 3.85 ± 0.63 μM), while it showed lower cytotoxicity on H9c2 (murine heart myoblast; IC50 was 16.69 ± 0.12 μM) cell lines. Compound 9 could induce the early apoptosis and evoke cell-cycle arrest at the synthesis (S) phase of A549 cells. Impressively, we innovatively introduced the method of cluster analysis modeled as partial least squares discriminant analysis (PLS-DA) into the structure–activity relationship (SAR) evaluation, and SAR confirmed that pyrazine had a profound effect on the antitumor activity of He. The present studies highlight the importance of pyrazine derivatives of He in the discovery and development of novel antitumor agents.

scholarly journals Design, Synthesis, Anticancer Evaluation and Molecular Modeling of Novel Estrogen Derivatives

Molecules ◽  
2019 ◽  
Vol 24 (3) ◽  
pp. 416 ◽  
Author(s):  
Abd Amr ◽  
Elsayed Elsayed ◽  
Mohamed Al-Omar ◽  
Hanan Badr Eldin ◽  
Eman Nossier ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Anticancer Agents ◽  
Docking Study ◽  
Breast Cancer Cell Lines ◽  
Cytotoxic Activities ◽  
Molecular Docking Study ◽  
Design Synthesis ◽  
Elemental Analyses

A series of estrone derivatives 3–8 was designed and synthesized using estrone arylmethylenes 2a,b as starting materials and their structures were confirmed by different spectral data and elemental analyses. All the newly synthesized compounds exhibited potent in vitro and in vivo cytotoxic activities against breast cancer cell lines. In addition, all compounds were subjected to in vitro and in vivo inhibition assays for EGFR and VEGFR-2 kinases as well as p53 ubiquitination activity to obtain more details about their mechanism of action. Based on the promising results, a molecular docking study was investigated for the most representative compound 5a against the two targets, EGFR and VEGFR-2 kinases, to assess its binding affinity, hoping to rationalize and obtain potent anticancer agents in the future.

scholarly journals Design, Synthesis, and Anticancer Effect Studies of Iridium(III) Polypyridyl Complexes against SGC-7901 Cells

Molecules ◽  
2019 ◽  
Vol 24 (17) ◽  
pp. 3129 ◽  
Author(s):  
Li-Xia Zhang ◽  
Yi-Ying Gu ◽  
Yang-Jie Wang ◽  
Lan Bai ◽  
Fan Du ◽  
...  
Keyword(s):  
Dna Damage ◽  
Atp Depletion ◽  
Design Synthesis ◽  
Cycle Arrest ◽  
Mtt Method ◽  
Mitochondrial Membrane Depolarization ◽  
Cell Proliferation Activity ◽  
Ic50 Values ◽  
Nih 3T3

Three iridium(III) complexes ([Ir(Hppy)2(L)](PF6) (Hppy = 2-phenylpyridine, L = 5-nitrophenanthroline, NP), 1; 5-nitro-6-amino-phenanthroline (NAP), 2; and 5,6-diamino-phenanthroline (DAP) 3 were synthesized and characterized. The cytotoxicities of Ir(III) complexes 1–3 against cancer cell lines SGC-7901, A549, HeLa, Eca-109, HepG2, BEL-7402, and normal NIH 3T3 cells were investigated using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazoliumbromide (MTT) method. The results showed that the three iridium(III) complexes had moderate in vitro anti-tumor activity toward SGC-7901 cells with IC50 values of 3.6 ± 0.1 µM for 1, 14.1 ± 0.5 µM for 2, and 11.1 ± 1.3 µM for 3. Further studies showed that 1–3 induce cell apoptosis/death through DNA damage, cell cycle arrest at the S or G0/G1 phase, ROS elevation, increased levels of Ca2+, high mitochondrial membrane depolarization, and cellular ATP depletion. Transwell and Colony-Forming assays revealed that complexes 1–3 can also effectively inhibit the metastasis and proliferation of tumor cells. These results demonstrate that 1–3 induce apoptosis in SGC-7901 cells through ROS-mediated mitochondrial damage and DNA damage pathways, as well as by inhibiting cell invasion, thereby exerting anti-tumor cell proliferation activity in vitro.

scholarly journals Inhibitory Effect of pH-Responsive Nanogel Encapsulating Ginsenoside CK against Lung Cancer

Polymers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 1784
Author(s):  
Ziyang Xue ◽  
Rongzhan Fu ◽  
Zhiguang Duan ◽  
Lei Chi ◽  
Chenhui Zhu ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Water Solubility ◽  
Drug Loading ◽  
Survival Rates ◽  
A549 Cells ◽  
Ph Responsive ◽  
Antitumor Effects ◽  
Hydrophobic Cavity

Ginsenoside CK is one of the intestinal bacterial metabolites of ginsenoside prototype saponins, such as ginsenoside Rb1, Rb2, Rc, and Rd. Poor water solubility and low bioavailability have limited its application. The nanogel carriers could specifically deliver hydrophobic drugs to cancer cells. Therefore, in this study, a nanogel was constructed by the formation of Schiff base bonds between hydrazide-modified carboxymethyl cellulose (CMC-NH2) and aldehyde-modified β-cyclodextrin (β-CD-CHO). A water-in-oil reverse microemulsion method was utilized to encapsulate ginsenoside CK via the hydrophobic cavity of β-CD. β-CD-CHO with a unique hydrophobic cavity carried out efficient encapsulation of CK, and the drug loading and encapsulation efficiency were 16.4% and 70.9%, respectively. The drug release of CK-loaded nanogels (CK-Ngs) in vitro was investigated in different pH environments, and the results showed that the cumulative release rate at pH 5.8 was 85.5% after 140 h. The methylthiazolyldiphenyl-tetrazolium bromide (MTT) toxicity analysis indicated that the survival rates of A549 cells in CK-Ngs at 96 h was 2.98% compared to that of CK (11.34%). In vivo animal experiments exhibited that the inhibitory rates of CK-Ngs against tumor volume was 73.8%, which was higher than that of CK (66.1%). Collectively, the pH-responsive nanogel prepared herein could be considered as a potential nanocarrier for CK to improve its antitumor effects against lung cancer.

scholarly journals 13-Methyl-palmatrubine induces apoptosis and cell cycle arrest in A549 cells in vitro and in vivo

2016 ◽  
Vol 36 (5) ◽  
pp. 2526-2534 ◽  
Author(s):  
Jingxian Chen ◽  
Xingang Lu ◽  
Chenghua Lu ◽  
Chunying Wang ◽  
Haizhu Xu ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
A549 Cells ◽  
Cycle Arrest
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