Diamine and PEGylated-diamine conjugates of triterpenic acids as potential anticancer agents

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A set of 18 amide derivatives of oleanolic or maslinic acid has been semi-synthesised. Twelve were diamine conjugates at C-28 of these triterpenic acids and the other six were PEGylated-diamine derivatives. The cytotoxic effects of these 18 triterpenic derivatives in three cancer-cell lines (B16-F10, HT29, and Hep G2) have been assayed, and have been compared to three non-tumour cell lines of the same or a similar tissue (HPF, IEC-18, and WRL68). The cell viability percentages for the non-tumour HPF line for almost all diamine conjugates of the tested triterpenic acids ranged from 81% to 94%. The best cytotoxic results were achieved with the diamine conjugates of oleanolic or maslinic acid with the shortest and the longest diamine chain (IC50 values from 0.76 μM to 1.76 μM), on the B16-F10 cell line, being between 140- and 20-fold more effective than their corresponding precursors. Four diamine conjugates of these triterpenic acids showed apoptotic effects on treated cells of the B16-F10 line, with total apoptosis rates, relative to control, of between 73% and 90%. The DNA-histogram analysis revealed that all compounds tested produced cell-cycle arrest in B16-F10 cells, increasing the number of these cells in the S phase. All the compounds analysed, except one, did not cause changes in mitochondrial-membrane potential during apoptosis of the B16-F10 cancer cells, suggesting an activation of the extrinsic apoptotic pathway for these compounds. (Eur J Med Chem. 2018 Mar 25;148:325-336.)

An intranasally delivered peptide drug ameliorates cognitive decline in Alzheimer transgenic mice

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Alzheimer’s disease (AD) is the most common neurodegenerative disease. Imbalance between the production and clearance of amyloid β (Aβ) peptides is considered to be the primary mechanism of AD pathogenesis. This amyloid hypothesis is supported by the recent success of the human anti‐amyloid antibody aducanumab, in clearing plaque and slowing clinical impairment in prodromal or mild patients in a phase Ib trial. Here, a peptide combining polyarginines (polyR) (for charge repulsion) and a segment derived from the core region of Aβ amyloid (for sequence recognition) was designed. The efficacy of the designed peptide, R8‐Aβ(25–35), on amyloid reduction and the improvement of cognitive functions were evaluated using APP/PS1 double transgenic mice. Daily intranasal administration of PEI‐conjugated R8‐Aβ(25–35) peptide significantly reduced Aβ amyloid accumulation and ameliorated the memory deficits of the transgenic mice. Intranasal administration is a feasible route for peptide delivery. The modular design combining polyR and aggregate‐forming segments produced a desirable therapeutic effect and could be easily adopted to design therapeutic peptides for other proteinaceous aggregate‐associated diseases.
Alzheimer’s disease (AD) is the most common neurodegenerative disease that causes dementia across multiple cognitive domains. Its incidence increases significantly with age and doubles every 5 years among the geriatric population ≧ 65 years of age. Despite remarkable scientific advancement and the vast resources invested in drug development, no effective therapy is currently available for AD. Thus, it is listed as one of the major unmet medical needs worldwide. Peptide drugs have been used with consistent benefits for many years and have advantages over small molecules, such as higher potency and fewer off‐target side effects (Craik et al, 2013). In addition, the properties of easy customization and synthesis under a well‐controlled environment make peptides excellent candidates for AD drug development. Neurodegenerative diseases encompass a heterogeneous group of neurological diseases characterized by synoptic and neuronal losses caused by multiple factors. Misfolded proteinaceous aggregates which exist in a variety of these diseases besides AD, including Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, are considered one of them, and may cause or contribute to these diseases through their prionlike property (Kim & Holtzman, 2010; de Calignon et al, 2012; Luk et al, 2012; Smethurst et al, 2016). In spite of the difference in the constituent proteins and complexity of assembly mechanism, the proteinaceous aggregates across these diseases share common structural conformations such as a β‐sheet conformation in the backbone (Funke & Willbold, 2012). This provides the basis for a rational design of therapeutic peptides for these misfolded aggregate‐associated diseases by applying a universal principle to reverse the process of formation. (EMBO Mol Med. 2017 May; 9(5): 703–715.)

A calorimetric evaluation of the interaction of amphiphilic prodrugs of idebenone with a biomembrane model

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Lipoamino acids (LAA) are useful promoieties to modify physicochemical properties of drugs, namely lipophilicity and amphiphilicity. The resulting membrane-like character of drug–LAA conjugates can increase the absorption profile of drugs through cell membranes and biological barriers. To show the role of amphiphilicity with respect to lipophilicity in the interaction of drugs with biomembranes, in the present study we evaluated the mode of such an interaction of lipophilic conjugates of LAA with the antioxidant drug idebenone (IDE). DSC analysis and transfer kinetic studies were carried out using dimyristoylphosphatidylcholine (DMPC) multilamellar liposomes (MLVs) as a model. For comparison, two esters of IDE with alkanoic acids were synthesized and included in the analysis. The experimental results indicate that based on their different structure, IDE–LAA conjugates interacted at different levels with respect to pure IDE with DMPC bilayers. In particular, a progressive penetration inside the vesicles was observed upon incubation of IDE–LAA compounds with empty liposomes. The enhanced amphiphilicity of the drug due to the LAA moieties caused more complex interactions with DMPC bilayers, compared to those registered with the native drug or IDE alkanoate esters.(J Colloid Interface Sci. 2006 Jul 15;299(2):626-35.)

Novel derivatives of abietic and dehydroabietic acid

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Abietic and dehydroabietic acid are interesting diterpenes with a highly diverse repertoire of associated bioactivities. They have, among others, shown antibacterial and antifungal activity, potentially valuable in the struggle against the increasing antimicrobial resistance and imminent antibiotic shortage. In this paper, we describe the synthesis of a set of 9 abietic and dehydroabietic acid derivatives containing amino acid side chains and their in vitro antimicrobial profiling against a panel of human pathogenic microbial strains. Furthermore, their in vitro cytotoxicity against mammalian cells was evaluated. The experimental results showed that the most promising compound was 10 [methyl N-(abiet-8,11,13-trien-18-yl)-d-serinate], with an MIC90 of 60 μg/mL against Staphylococcus aureus ATCC 25923, and 8 μg/mL against methicillin-resistant S. aureusStaphylococcus epidermidis and Streptococcus mitis. The IC50 value for compound 10 against Balb/c 3T3 cells was 45 μg/mL. ( 2017 Jan 1;25(1):132-137.)

Galloyl-RGD as a new cosmetic ingredient

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The cosmetics market has rapidly increased over the last years. For example, in 2011 it reached 242.8 billion US dollars, which was a 3.9% increase compared to 2010. There have been many recent trials aimed at finding the functional ingredients for new cosmetics. Gallic acid is a phytochemical derived from various herbs, and has anti-fungal, anti-viral, and antioxidant properties. Although phytochemicals are useful as cosmetic ingredients, they have a number of drawbacks, such as thermal stability, residence time in the skin, and permeability through the dermal layer. To overcome these problems, we considered conjugation of gallic acid with a peptide.


We synthesized galloyl-RGD, which represents a conjugate of gallic acid and the peptide RGD, purified it by HPLC and characterized by MALDI-TOF with the aim of using it as a new cosmetic ingredient. Thermal stability of galloyl-RGD was tested at alternating temperatures (consecutive 4°C, 20°C, or 40°C for 8 h each) on days 2, 21, 41, and 61. Galloyl-RGD was relatively safe to HaCaT keratinocytes, as their viability after 48 h incubation with 500 ppm galloyl-RGD was 93.53%. In the group treated with 50 ppm galloyl-RGD, 85.0% of free radicals were removed, whereas 1000 ppm galloyl-RGD suppressed not only L-DOPA formation (43.8%) but also L-DOPA oxidation (54.4%).


Galloyl-RGD is a promising candidate for a cosmetic ingredient. (. 2014; 15: 18.)

Novel 3-phenylcoumarin-lipoic acid conjugates as multi-functional agents for potential treatment of Alzheimer’s disease

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New series of triazole-containing 3-phenylcoumarin-lipoic acid conjugates were designed as multi-functional agents for treatment of Alzheimer’s disease. The target compounds 4a-o were synthesized via the azide-alkyne cycloaddition reaction and their biological activities were primarily evaluated in terms of neuroprotection against H2O2-induced cell death in PC12 cells and AChE/BuChE inhibition. The promising compounds 4j and 4i containing four carbons spacer were selected for further biological evaluations. Based on the obtained results, the benzocoumarin derivative 4j with IC50 value of 7.3 µM was the most potent AChE inhibitor and displayed good inhibition toward intracellular reactive oxygen species (ROS). This compound with antioxidant and metal chelating ability showed also protective effect on cell injury induced by Aβ1-42 in SH-SY5Y cells. Although the 8-methoxycoumarin analog 4i was slightly less active than 4j against AChE, but displayed higher protection ability against H2O2-induced cell death in PC12 and could significantly block Aβ-aggregation. The results suggested that the prototype compounds 4i and 4j might be promising multi-functional agents for the further development of the disease-modifying treatments of Alzheimer’s disease. ( 2018 Sep;79:223-234.)

Traversal of the Blood–Brain Barrier by Cleavable l-Lysine Conjugates of Apigenin

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Apigenin, a flavone abundant in parsley and celery, is known to act on several CNS receptors, but its very poor water solubility (<0.001 mg/mL) impedes its absorption in vivo and prevents clinical use. Herein, apigenin was directly conjugated with glycine, l-phenylalanine, and l-lysine to give the corresponding carbamate derivatives, all of which were much more soluble than apigenin itself (0.017, 0.018, and 0.13 mg/mL, respectively). The Lys-apigenin carbamate 10 had a temporary sedative effect on the mice within 5 min of intraperitoneal administration (single dose of 0.4 mg/g) and could be detected in the mice brain tissues at a concentration of 0.82 μg/g of intact Lys-apigenin carbamate 10 and 0.42 ug/g of apigenin at 1.5 h. This study accomplished the delivery of apigenin across the BBB in a manner that might be applicable to other congeners, which should inform the future development of BBB-crossing flavonoids.(J. Agric. Food Chem., 2018, 66 (30), pp 8124–8131)

Hyaluronic Acid Conjugates as Vectors for the Active Targeting of Drugs, Genes and Nanocomposites in Cancer Treatment

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Hyaluronic acid is a high molecular weight (106 –107 Da) glycosaminoglycan polymer composed of repeating disaccharides: ?1,3 N-acetyl glucosaminyl-? 1,4 glucuronide. HA is ubiquitous, being the main component of extracellular matrix, and is essential for proper cell growth, structural stability of organs, and tissue organization. From the pharmaceutical standpoint, HA is a promising component, because it is biodegradable, biocompatible, nontoxic, hydrophilic, and nonimmunogenic. HA contains several chemical groups to which other components can be conjugated. The carboxylate on the glucuronic acid, the N-acetylglucosamine hydroxyl, and the reducing termination, have all been successfully utilized in conjugation reactions with drugs. The acetyl group may be enzymatically removed from the N-acetylglucosamine, and is thus also a potential site for drug conjugation. Low levels of the hyaluronic acid receptor CD44 are found on the surface of epithelial, hematopoietic, and neuronal cells; it is overexpressed in many cancer cells, and in particular in tumor-initiating cells. HA has recently attracted considerable interest in the field of developing drug delivery systems, having been used, as such or encapsulated in different types of nanoassembly, as ligand to prepare nano-platforms for actively targeting drugs, genes, and diagnostic agents. This review describes recent progress made with the several chemical strategies adopted to synthesize conjugates and prepare novel delivery systems with improved behaviors.
Cancer is a leading cause of death worldwide, accounting for 7.6 million deaths (around 13% of all deaths) in 2008. Deaths from cancer worldwide are projected to continue rising, with an estimated 13.1 million deaths in 2030. Lung, stomach, liver, colon and breast cancers cause the most cancer deaths each year.Conjugation of cytotoxic drugs with macromolecules improves their pharmacokinetic profile, prolonging the distribution and elimination phases. Furthermore, the slow release of active drug from the carrier may result in sustained high intratumoral drug levels and lower plasma concentrations of the active drug. In order to achieve this combined effect, a macromolecule-drug conjugate should preferentially release the active drug within the tumor tissue. The following components are essential to reach this goal: a biodegradable linkage, a suitable spacer, and a potent bioactive anticancer agent. Among the most widely studied macromolecules are N-(2-hydroxypropyl) methacrylamide (HPMA), polyglutamate, human serum albumin, dextrans, heparin, chitosan, dendrimers, multi-arm polyethylene glycol (PEG), and hyaluronic acid.The molecular weight of native HA has a wide range. In water, high molecular weight HA self-aggregates to form a viscous solution in which each molecule forms a sponge-like matrix with a radius of about 100 nanometers; this makes it a suitable candidate for passive tumor accumulation. In addition, HA plays an important physiological role in the tumorigenesis process, and consequently HA receptors are overexpressed on many types of tumor cells. This feature could be exploited in drug delivery, by using the receptor as an anchor to attach prodrugs or nanomedicine-based delivery systems, through a ligand, so as to increase the efficiency of anticancer drugs. (Molecules 2014, 19(3), 3193-3230.)