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Start Over Topic drug design Publication Type Academic Journals
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1. Design, synthesis and biological evaluation of novel aminopyrazole- and 7-azaindole-based Nek1 inhibitors and their effects on zebrafish kidney development.

Author

Pilakowski J, Baumann G, Shih YH, Meckel T, and Schmidt B

Subjects
Animals, Dose-Response Relationship, Drug, Indoles chemical synthesis, Indoles chemistry, Kidney growth & development, Kidney metabolism, Molecular Structure, NIMA-Related Kinase 1 metabolism, Protein Kinase Inhibitors chemical synthesis, Protein Kinase Inhibitors chemistry, Pyrazoles chemical synthesis, Pyrazoles chemistry, Structure-Activity Relationship, Zebrafish, Drug Design, Indoles pharmacology, Kidney drug effects, NIMA-Related Kinase 1 antagonists & inhibitors, Protein Kinase Inhibitors pharmacology, Pyrazoles pharmacology
Abstract

NIMA-related protein kinase Nek1 is crucially involved in cell cycle regulation, DNA repair and microtubule regulation and dysfunctions of Nek1 play key roles in amyotrophic lateral sclerosis (ALS), polycystic kidney disease (PKD) and several types of radiotherapy resistant cancer. Targeting of Nek1 could reveal a new class of radiosensitizing substances and provide useful tools to better understand the aforementioned diseases. In this report we explore substituted aminopyrazoles and 7-azaindoles as potent inhibitors for the Nek1 kinase domain and examine their effect on kidney organogenesis in Danio rerio., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Published
2021
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2. Design, synthesis, and evaluation of chitosan conjugated GGRGDSK peptides as a cancer cell-targeting molecular transporter.

Author

El-Sayed NS, Shirazi AN, El-Meligy MG, El-Ziaty AK, Nagieb ZA, Parang K, and Tiwari RK

Subjects
Amino Acid Sequence, Biological Transport, Cell Line, Tumor, Chemistry Techniques, Synthetic, Coloring Agents chemistry, Coloring Agents metabolism, Drug Carriers toxicity, Humans, Hydrophobic and Hydrophilic Interactions, Integrins metabolism, Nanoparticles chemistry, Oligopeptides toxicity, Particle Size, Permeability, Phosphopeptides chemistry, Phosphopeptides metabolism, Solubility, Water chemistry, Chitosan chemistry, Drug Carriers chemistry, Drug Design, Oligopeptides chemistry
Abstract

Targeting cancer cells using integrin receptor is one of the promising targeting strategies in drug delivery. In this study, we conjugated an integrin-binding ligand (GGRGDSK) peptide to chitosan oligosaccharide (COS) using sulfo-SMCC as a bifunctional linker to afford COS-SMCC-GGRGDSK. The conjugated polymer was characterized by FT-IR, (1)H NMR, (13)C NMR, and SEM. COS-SMCC-GGRGDSK did not show cytotoxicity up to a concentration of 1mg/mL in the human leukemia cell line (CCRF-CEM). The conjugate was evaluated for its ability to enhance the cellular uptake of a cell-impermeable cargo (e.g., F'-G(pY)EEI phosphopeptide) in CCRF-CEM, and human ovarian carcinoma (SK-OV-3) cancer cell lines. Additionally, RGD modified and unmodified COS polymers were used to prepare nanoparticles by ionic gelation and showed particle size ranging from 187 to 338nm, and zeta potential of 12.2-18.3mV using dynamic light scattering. The efficiency of COS-NPs and COS-SMCC-RGDSK NPs was assayed for translocation of two synthetic cytotoxic agents ((2-(2-aminoethylamino)-4-(4-chlorophenyl)-6-(1H-indol-3-yl) nicotinonitrile (ACIN), and 2-(2-aminoethylamino)-6-(1H-indol-3-yl)-4-(4-methoxyphenyl)-nicotinonitrile (AMIN)) into CCRF-CEM and human prostate (DU-145) cancer cell lines. The results showed a dramatic reduction in the cell viability on their treatment with RGD targeted COS NPs in comparison to paclitaxel (PTX), free drug, and drug-loaded COS NPs., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Published
2016
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