Plant-Derived Purification, Chemical Synthesis, and In Vitro/In Vivo Evaluation of a Resveratrol Dimer, Viniferin, as an HCV Replication Inhibitor

Oligostilbenoid compounds, a group of resveratrol multimers, display several anti-microbial activities through the neutralization of cytotoxic oxidants, and by inhibiting essential host and viral enzymes. In our previous study, we identified a series of oligostilbenoid compounds as potent hepatitis C virus (HCV) replication inhibitors. In particular, vitisin B, a resveratrol tetramer, exhibited the most dramatic anti-HCV activity (EC50 = 6 nM and CC50 > 10 μM) via the disruption of the viral helicase NS3 (IC50 = 3 nM). However, its further development as an HCV drug candidate was halted due to its intrinsic drawbacks, such as poor stability, low water solubility, and restricted in vivo absorption. In order to overcome these limitations, we focused on (+)-ε-viniferin, a resveratrol dimer, as an alternative. We prepared three different versions of (+)-ε-viniferin, including one which was extracted from the grapevine root (EVF) and two which were chemically synthesized with either penta-acetylation (SVF-5Ac) or no acetylation (SVF) using a newly established synthesis method. We confirmed their anti-HCV replication activities and minimal cytotoxicity by using genotype 1b and 2a HCV replicon cells. Their anti-HCV replication action also translated into a significant reduction of viral protein expression. Anti-HCV NS3 helicase activity by EVF was also verified in vitro. Finally, we demonstrated that SVF has improved pharmacokinetic properties over vitisin B. Overall, the favorable antiviral and pharmacokinetic properties of these three versions of viniferin warrant their further study as members of a promising new class of anti-HCV therapeutics.

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Etamycin as a Novel Mycobacterium abscessus Inhibitor

International Journal of Molecular Sciences ◽

10.3390/ijms21186908 ◽

2020 ◽

Vol 21 (18) ◽

pp. 6908

Author(s):

Bui Thi Bich Hanh ◽

Tae Ho Kim ◽

June-Woo Park ◽

Da-Gyum Lee ◽

Jae-Sung Kim ◽

...

Keyword(s):

Wild Type Strain ◽

Standard Of Care ◽

Mycobacterium Abscessus ◽

Drug Candidate ◽

Infection Model ◽

Excellent Activity ◽

Further Development ◽

Clinical Drug

The increase in drug-resistant Mycobacterium abscessus, which has become resistant to existing standard-of-care agents, is a major concern, and new antibacterial agents are strongly needed. In this study, we introduced etamycin that showed an excellent activity against M. abscessus. We found that etamycin significantly inhibited the growth of M. abscessus wild-type strain, three subspecies, and clinical isolates in vitro and inhibited the growth of M. abscessus that resides in macrophages without cytotoxicity. Furthermore, the in vivo efficacy of etamycin in the zebrafish (Danio rerio) infection model was greater than that of clarithromycin, which is recommended as the core agent for treating M. abscessus infections. Thus, we concluded that etamycin is a potential anti-M. abscessus candidate for further development as a clinical drug candidate.

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Evaluation of Alkaloids Isolated from Ruta graveolens as Photosynthesis Inhibitors

Molecules ◽

10.3390/molecules23102693 ◽

2018 ◽

Vol 23 (10) ◽

pp. 2693 ◽

Cited By ~ 8

Author(s):

Olívia Sampaio ◽

Lucas Vieira ◽

Barbara Bellete ◽

Beatriz King-Diaz ◽

Blas Lotina-Hennsen ◽

...

Keyword(s):

Plant Growth ◽

Positive Control ◽

Ruta Graveolens ◽

New Class ◽

Energy Transfers ◽

Low Toxicity ◽

Further Development ◽

Interesting Alternative

Eight alkaloids (1–8) were isolated from Ruta graveolens, and their herbicide activities were evaluated through in vitro, semivivo, and in vivo assays. The most relevant results were observed for Compounds 5 and 6–8 at 150 μM, which decreased dry biomass by 20% and 23%, respectively. These are significant results since they presented similar values with the positive control, commercial herbicide 3-(3,4-dichlorophenyl)-1,1-dimethylurea (DCMU). Based on the performed assays, Compound 5 (graveoline) is classified as an electron-transport inhibitor during the light phase of photosynthesis, as well as a plant-growth regulator. On the other hand, Compounds 6–8 inhibited electron and energy transfers, and are also plant-growth inhibitors. These phytotoxic behaviors based on acridone and quinolone alkaloids may serve as a valuable tool in the further development of a new class of herbicides since natural products represent an interesting alternative to replace commercial herbicides, potentially due their low toxicity.

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In vitro and in vivo pharmacokinetic characterization of LMT-28 as a novel small molecular interleukin-6 inhibitor

Asian-Australasian Journal of Animal Sciences ◽

10.5713/ajas.19.0463 ◽

2020 ◽

Vol 33 (4) ◽

pp. 670-677

Author(s):

Sung-Hoon Ahn ◽

Tae-Hwe Heo ◽

Hyun-Sik Jun ◽

Yongseok Choi

Keyword(s):

Mdck Cell ◽

Interleukin 6 ◽

Cell Permeability ◽

Oral Drug ◽

Drug Candidate ◽

Pharmacokinetic Parameters ◽

Pharmacokinetic Studies ◽

Pharmacokinetic Properties

Objective: Interleukin-6 (IL-6) is a T cell-derived B cell stimulating factor which plays an important role in inflammatory diseases. In this study, the pharmacokinetic properties of LMT-28 including physicochemical property, in vitro liver microsomal stability and an in vivo pharmacokinetic study using BALB/c mice were characterized.Methods: LMT-28 has been synthesized and is being developed as a novel therapeutic IL-6 inhibitor. The physicochemical properties and in vitro pharmacokinetic profiles such as liver microsomal stability and Madin-Darby canine kidney (MDCK) cell permeability assay were examined. For in vivo pharmacokinetic studies, pharmacokinetic parameters using BALB/c mice were calculated.Results: The logarithm of the partition coefficient value (LogP; 3.65) and the apparent permeability coefficient values (Papp; 9.7×10–6 cm/s) showed that LMT-28 possesses a moderate-high cell permeability property across MDCK cell monolayers. The plasma protein binding rate of LMT-28 was 92.4% and mostly bound to serum albumin. The metabolic half-life (t1/2) values of LMT-28 were 15.3 min for rat and 21.9 min for human at the concentration 1 μM. The area under the plasma drug concentration-time curve and Cmax after oral administration (5 mg/kg) of LMT-28 were 302±209 h∙ng/mL and 137±100 ng/mL, respectively.Conclusion: These data suggest that LMT-28 may have good physicochemical and pharmacokinetic properties and may be a novel oral drug candidate as the first synthetic IL-6 inhibitor to ameliorate mammalian inflammation.

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Rational Drug Design of Targeted and Enzyme Cleavable Vitamin E Analogs as Neoadjuvant to Chemotherapy: In Vitro and In Vivo Evaluation on Reduction of Cardiotoxicity of Doxorubicin.

10.1101/2021.05.20.445072 ◽

2021 ◽

Author(s):

Raghu S Pandurangi ◽

Orsolya Cseh ◽

Artee Luchman ◽

siguang Xu ◽

Cynthia Ma ◽

...

Keyword(s):

Vitamin E ◽

Drug Design ◽

Cancer Cells ◽

Water Solubility ◽

Therapeutic Index ◽

Rational Drug Design ◽

In Vivo Evaluation ◽

Rational Drug

Traditional drug design focus on specific target (s) expressed by cancer cells. However, cancer cells outsmart the interventions by activating survival pathways and/or downregulating cell death pathways. As the research in molecular biology of cancer grows exponentially, new methods of drug designs are needed to target multiple pathways/targets which are involved in survival of cancer cells. Vitamin E analogues including a-tocopheryl succinate (TOS) is a well-known anti-tumoregenic agent which is well studied both in vitro and in vivo tumor models. However, lack of targeting cancer cells and unexpected toxicity along with the poor water solubility of TOS compelled a rational drug design using both targeting and cleavable technologies incorporated in the new drug design. A plethora of Vitamin E derivatives (AMP-001, 002 and 003) were synthesized, characterized and studied for the improved efficacy and lowered toxicity in various cancer cells in vitro. Preliminary studies revealed AAAPT leading candidates reduced the invasive potential of brain tumor stem cells, synergized with different drugs and different treatments. AAAPT leading drug AMP-001 enhanced the therapeutic index of front-line drug Doxorubicin in triple negative breast cancer (TNBC) tumor rat model preserving the ventricular function when used as a neoadjuvant to Doxorubicin. These results may pave the way for reducing the cardiotoxicity of chemotherapy in clinical settings.

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Preparation, in vitro Characterization and Pharmacokinetic Study of Coenzyme Q10 Long-Circulating Liposomes

Drug Research ◽

10.1055/s-0043-121876 ◽

2017 ◽

Vol 68 (05) ◽

pp. 270-279 ◽

Cited By ~ 3

Author(s):

Shuoye Yang

Keyword(s):

Coenzyme Q10 ◽

Influencing Factor ◽

In Vivo Evaluation ◽

Box Behnken Design ◽

Molar Ratios ◽

In Vitro Characterization ◽

Pharmacokinetic Properties ◽

Pegylated Lipids

AbstractLong-circulating liposomal delivery systems of encapsulated Coenzyme Q10 (CoQ10), a ubiquinone anti-cataract agent, were developed with different molar ratios of PEGylated lipids and/or cholesterol. The resulting samples were contrasted through observation of morphology, analysis of particle size and Zeta potential, and in vivo pharmacokinetics. A protamine aggregation method with high selectivity was developed to determine the encapsulation efficiency (EE), after which the liposome formulation was further optimized by applying a Box Behnken design (BBD) using EE as the evaluation index. The results showed that liposomes had a large, unilamellar structure, and that particle sizes of cholesterol-containing liposomes increased along with the increase of cholesterol molar percentage, while the size of PEGylated vesicles decreased slightly as PEG-lipid contents increasing. The optimum formulation and optimal values of each influencing factor were quantitatively obtained, and the measured value was highly consistent with the predicted results. In vivo evaluation performed by liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) demonstrated that liposomal encapsulation largely prolonged half-lives and improved bioavailability for vectors prepared with either lipid component, and the liposomes composed of both cholesterol and PEG-lipid possessed the best pharmacokinetic properties. The results suggest that incorporating high contents of cholesterol and PEG modification could be a potentially useful method for enhancing the length of circulation and the sustained release effect for liposome-encapsulated chemicals.

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A New Class of Highly Potent Matrix Metalloproteinase Inhibitors Based on Triazole-Substituted Hydroxamates: (Radio)Synthesis and in Vitro and First in Vivo Evaluation

Journal of Medicinal Chemistry ◽

10.1021/jm300199g ◽

2012 ◽

Vol 55 (10) ◽

pp. 4714-4727 ◽

Cited By ~ 30

Author(s):

Verena Hugenberg ◽

Hans-Jörg Breyholz ◽

Burkhard Riemann ◽

Sven Hermann ◽

Otmar Schober ◽

...

Keyword(s):

Matrix Metalloproteinase ◽

Matrix Metalloproteinase Inhibitors ◽

In Vivo Evaluation ◽

New Class ◽

Metalloproteinase Inhibitors

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Design and synthesis of novel phthalazinone derivatives as potent poly(ADP-ribose)polymerase 1 inhibitors

Future Medicinal Chemistry ◽

10.4155/fmc-2020-0009 ◽

2020 ◽

Vol 12 (19) ◽

pp. 1691-1707

Author(s):

Minhang Xin ◽

Jiajia Sun ◽

Wei Huang ◽

Feng Tang ◽

Zhaoyu Liu ◽

...

Keyword(s):

Oral Exposure ◽

Drug Candidate ◽

Lead Compound ◽

Design And Synthesis ◽

Pharmacokinetic Properties ◽

Inhibitory Activities ◽

Sensitizing Effect ◽

Parp 1

Aim: The development of effective PARP-1 inhibitors has received great enthusiasm in medicinal chemistry communities. Results: A new series of novel phthalazinone derivatives were designed and synthesized. Among these, B1 and B16 displayed more potent PARP-1 inhibitory activities than olaparib. B16 gave an IC50 value of 7.8 nM against PARP-1, and a PF50 value of 3.4 in the sensitizing effect assay. The in vivo pharmacokinetic properties evaluation showed B16 displayed insufficient oral exposure, and it was also not stable in rat blood. Conclusion: The results indicated that our design phthalazinone derivatives were potent PARP-1 inhibitors, and compound B16 was a valuable lead compound with significant in vitro efficacy, deserving further optimization to develop anticancer drug candidate.

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