Hydrogen bond controlled aggregation of guanidinium-carboxylate derivatives in the solid state

Zafar, Abdullah; Meléndez, Rosa E.; Geib, Steven J.; Hamilton, Andrew D.

doi:10.1016/s0040-4020(01)01106-1

Cited by 28 publications

(10 citation statements)

References 22 publications

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“…This observation could be attributed to overcharging of the polyplexes caused by an excess of polymer chains at high N/P ratios. , When the polplexes are overcharged with excess polymer chains, some cationic blocks may be more exposed on the polyplex surface and cause an increase in interactions between polyplexes and negatively charged species in reduced-serum media. In addition, guanidinium pendants can form bidentate hydrogen bonds with carboxylate polymer end groups according to previous literature. − Such interactions among polyplexes may further promote aggregation of P(MAGalNAc 41 - b -GPMA y ) polyplexes at high N/P ratios.…”

Section: Resultsmentioning

confidence: 96%

Cell Penetrating Polymers Containing Guanidinium Trigger Apoptosis in Human Hepatocellular Carcinoma Cells unless Conjugated to a Targeting N-Acetyl-Galactosamine Block

2017

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A series of 3-guanidinopropyl methacrylamide (GPMA)-based polymeric gene delivery vehicles were developed via aqueous reversible addition-fragmentation chain transfer (RAFT) polymerization. The polymers have been evaluated for their cellular internalization ability, transfection efficiency, and cytotoxicity. Two homopolymers: P(GPMA), P(GPMA), were synthesized to study the effect of guanidium polymer length on delivery efficiency and toxicity. In addition, an N-acetyl-d-galactosamine (GalNAc)-based hydrophilic block was incorporated to produce diblock polymers, which provides a neutral hydrophilic block that sterically protects plasmid-polymer complexes (polyplexes) from colloidal aggregation and aids polyplex targeting to hepatocytes via binding to asialoglycoprotein receptors (ASGPRs). Polyplexes formed with P(GPMA) (x = 20, 34) homopolymers were shown to be internalized via both energy-dependent and independent pathways, whereas polyplexes formed with block polymers were internalized through endocytosis. Notably, P(GPMA) polyplexes enter cells very efficiently but are also very toxic to human hepatocellular carcinoma (HepG2) cells and triggered cell apoptosis. In comparison, the presence of a carbohydrate block in the polymer structures reduced the cytotoxicity of the polyplex formulations and increased gene delivery efficiency with HepG2 cells. Transfection efficiency and toxicity studies were also carried out with HEK 293T (human embryonic kidney) cells for comparison. Results showed that polyplexes formed with the P(GPMA) homopolymers exhibit much higher transfection efficiency and lower toxicity with HEK 293T cells. The presence of the carbohydrate block did not further increase transfection efficiency in comparison to the homopolymers with HEK 293T cells, likely due to the lack of ASGPRs on the HEK 293T cell line. This study revealed that although guanidinium-based polymers have high membrane permeability, their application as plasmid delivery vehicles may be limited by their high cytotoxicity to certain cell types. Thus, the use of cell penetrating structures in polyplex formulations should be used with caution and carefully tailored toward individual cell/tissue types.

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Section: Resultsmentioning

confidence: 96%

Cell Penetrating Polymers Containing Guanidinium Trigger Apoptosis in Human Hepatocellular Carcinoma Cells unless Conjugated to a Targeting N-Acetyl-Galactosamine Block

2017

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“…Examples of synthetic procedures for selected key compounds are given in the following text. Synthetic details for other compounds can be found in the Supporting Information …”

Section: Methodsmentioning

confidence: 99%

“…Synthetic details for other compounds can be found in the Supporting Information. [26,[52][53][54][55][56][57] Generalp rocedure A-Steglich-typeesterification:Synthesis of P2 5-Diethylamino-2-iodobenzyl alcohol (10.0 g, 32.8 mmol, 1.0 equiv) was dissolved in CH 2 Cl 2 (100 mL). EDC-HCl (10.0 g, 52.3 mmol, 1.6 equiv), DIPEA (5.07 g, 39.3 mmol, 1.2 equiv), DMAP (0.4 g, 3.3 mmol, 0.1 equiv), and N-(tert-butoxycarbonyl)-l-glutamic acid 1tert-butyl ester (15.0 g, 49.5 mmol, 1.5 equiv) were added to the solution.…”

Section: Organic Synthesismentioning

confidence: 99%

A New Photocage Derived from Fluorene

Reinfelds

Cosel

Falahati

et al. 2018

Chemistry A European J

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Photolabile protecting groups (PPGs or photocages) are increasingly subject to molecular design to meet requirements such as absorbance in the visible spectral range, high molar absorption coefficients, and high quantum yields of leaving group release. Improvements in these properties for the promising 3-diethylaminobenzyl (DEAMb) photocage, the photoactivity of which is based on the Zimmerman meta effect, are reported. Expansion of the aromatic system with a second aromatic ring resulted in improved spectral properties. A systematic trend relating the electronic (π-donor or acceptor) properties of the new aryl substituent and its position in the DEAMb ring to changes in the spectral properties could be observed. Conclusions from the experimental results were supported by computations obtained by using time-dependent DFT. A second generation of DEAMb-based photocages was designed. A rigid linker was introduced to ensure more efficient conjugation of the aromatic ring π systems by limiting rotational freedom. The resulting fluorenol (9-hydroxyfluorene)-based photocages had superior spectral properties to those of simple biphenyl systems. The best uncaging cross section achieved was 5320 m cm (ϵΦ ).

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“…The general synthetic sequence toward the desired compounds is outlined in Scheme 1 12. Monoprotected diamines 1 were transformed into the respective thioureas 2 by methods described in the literature 13. The reaction of 2 with N , N ‐dimethylformamide dimethylacetal in DMF furnished the thioureido derivatives 3 , which were subsequently treated with α‐bromoketones (in this case with o ‐tolylphenacyl bromide, for example) to yield thiazoles 4 .…”

Section: Correlation Analysis Of Affinity (Pic50) Membrane Permeabilmentioning

confidence: 99%

Aminothiazole Derivatives as Neuropeptide Y5 Receptor Ligands: Finding the Balance between Affinity and Physicochemical Properties

et al. 2006

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Potential appetite control: A straightforward parallel solution‐phase synthesis of novel thiazole derivatives with varying linker moieties gave access to a set of compounds 1. Assessments of artificial membrane permeability and solubility show that some members of this compound class may be suitable antagonists for the neuropeptide Y5 receptor, which is involved in the stimulation of food intake.

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Hydrogen bond controlled aggregation of guanidinium-carboxylate derivatives in the solid state

Cited by 28 publications

References 22 publications

Cell Penetrating Polymers Containing Guanidinium Trigger Apoptosis in Human Hepatocellular Carcinoma Cells unless Conjugated to a Targeting N-Acetyl-Galactosamine Block

Cell Penetrating Polymers Containing Guanidinium Trigger Apoptosis in Human Hepatocellular Carcinoma Cells unless Conjugated to a Targeting N-Acetyl-Galactosamine Block

A New Photocage Derived from Fluorene

Aminothiazole Derivatives as Neuropeptide Y5 Receptor Ligands: Finding the Balance between Affinity and Physicochemical Properties

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