Valorizing Constituents of Cashew Nut Shell Liquid toward the Sustainable Development of New Drugs against Chagas Disease.

Six new ether phospholipid analogues encompassing constituents from cashew nut shell liquid as the lipid portion were synthesized in an effort to valorize byproducts of the cashew industry toward the generation of potent compounds against Chagas disease. Anacardic acids, cardanols, and cardols were used as the lipid portions and choline as the polar headgroup. The compounds were evaluated for their in vitro antiparasitic activity against different developmental stages of Trypanosoma cruzi. Compounds 16 and 17 were found to be the most potent against T. cruzi epimastigotes, trypomastigotes, and intracellular amastigotes exhibiting selectivity indices against the latter 32-fold and 7-fold higher than current drug benznidazole, respectively. Hence, four out of six analogues can be considered as hit-compounds toward the sustainable development of new treatments for Chagas disease, based on inexpensive agro-waste material.

Design, synthesis and biological evaluation of antiparasitic dinitroaniline-ether phospholipid hybrids.

A series of nine novel ether phospholipid-dinitroaniline hybrids were synthesized in an effort to deliver more potent antiparasitic agents with improved safety profile compared to miltefosine. The compounds were evaluated for their in vitro antiparasitic activity against L. infantum, L.donovani, L. amazonensis, L. major and L. tropica promastigotes, L. infantum and L. donovani intracellular amastigotes, Trypanosoma brucei brucei and against different developmental stages of Trypanosoma cruzi. The nature of the oligomethylene spacer between the dinitroaniline moiety and the phosphate group, the length of the side chain substituent on the dinitroaniline and the choline or homocholine head group were found to affect both the activity and toxicity of the hybrids. The early ADMET profile of the derivatives did not reveal major liabilities. Hybrid 3, bearing an 11-carbon oligomethylene spacer, a butyl side chain and a choline head group, was the most potent analogue of the series. It exhibited a broad spectrum antiparasitic profile against the promastigotes of New and Old World Leishmania spp., against intracellular amastigotes of two L. infantum strains and L. donovani, against T. brucei and against T. cruzi Y strain epimastigotes, intracellular amastigotes and trypomastigotes. The early toxicity studies revealed that hybrid 3 showed a safe toxicological profile while its cytotoxicity concentration (CC50) against THP-1 macrophages being >100 µM. Computational analysis of binding sites and docking indicated that the interaction of hybrid 3 with trypanosomatid α-tubulin may contribute to its mechanism of action. Furthermore, compound 3 was found to interfere with the cell cycle in T. cruzi epimastigotes, while ultrastructural studies using SEM and TEM in T. cruzi showed that compound 3 affects cellular processes that result in changes in the Golgi complex, the mitochondria and the parasite's plasma membrane. The snapshot pharmacokinetic studies showed low levels of 3 after 24 h following oral administration of 100 mg/Kg, while, its homocholine congener compound 9 presented a better pharmacokinetic profile.

Convolutional Neural Networks-Based Framework for Early Identification of Dementia Using MRI of Brain Asymmetry.

Computer-aided diagnosis of health problems and pathological conditions has become a substantial part of medical, biomedical, and computer science research. This paper focuses on the diagnosis of early and progressive dementia, building on the potential of deep learning (DL) models. The proposed computational framework exploits a magnetic resonance imaging (MRI) brain asymmetry biomarker, which has been associated with early dementia, and employs DL architectures for MRI image classification. Identification of early dementia is accomplished by an eight-layered convolutional neural network (CNN) as well as transfer learning of pretrained CNNs from ImageNet. Different instantiations of the proposed CNN architecture are tested. These are equipped with Softmax, support vector machine (SVM), linear discriminant (LD), or [Formula: see text] -nearest neighbor (KNN) classification layers, assembled as a separate classification module, which are attached to the core CNN architecture. The initial imaging data were obtained from the MRI directory of the Alzheimer's disease neuroimaging initiative 3 (ADNI3) database. The independent testing dataset was created using image preprocessing and segmentation algorithms applied to unseen patients' imaging data. The proposed approach demonstrates a 90.12% accuracy in distinguishing patients who are cognitively normal subjects from those who have Alzheimer's disease (AD), and an 86.40% accuracy in detecting early mild cognitive impairment (EMCI).

Current Treatments to Control African Trypanosomiasis and One Health Perspective.

Human African Trypanosomiasis (HAT, sleeping sickness) and Animal African Trypanosomiasis (AAT) are neglected tropical diseases generally caused by the same etiological agent, Trypanosoma brucei. Despite important advances in the reduction or disappearance of HAT cases, AAT represents a risky reservoir of the infections. There is a strong need to control AAT, as is claimed by the European Commission in a recent document on the reservation of antimicrobials for human use. Control of AAT is considered part of the One Health approach established by the FAO program against African Trypanosomiasis. Under the umbrella of the One Health concepts, in this work, by analyzing the pharmacological properties of the therapeutic options against Trypanosoma brucei spp., we underline the need for clearer and more defined guidelines in the employment of drugs designed for HAT and AAT. Essential requirements are addressed to meet the challenge of drug use and drug resistance development. This approach shall avoid inter-species cross-resistance phenomena and retain drugs therapeutic activity.

Design, Synthesis and Antiparasitic Evaluation of Click Phospholipids.

A library of seventeen novel ether phospholipid analogues, containing 5-membered heterocyclic rings (1,2,3-triazolyl, isoxazolyl, 1,3,4-oxadiazolyl and 1,2,4-oxadiazolyl) in the lipid portion were designed and synthesized aiming to identify optimised miltefosine analogues. The compounds were evaluated for their in vitro antiparasitic activity against Leishmania infantum and Leishmania donovani intracellular amastigotes, against Trypanosoma brucei brucei and against different developmental stages of Trypanosoma cruzi. The nature of the substituents of the heterocyclic ring (tail) and the oligomethylene spacer between the head group and the heterocyclic ring was found to affect the activity and toxicity of these compounds leading to a significantly improved understanding of their structure-activity relationships. The early ADMET profile of the new derivatives did not reveal major liabilities for the potent compounds. The 1,2,3-triazole derivative 27 substituted by a decyl tail, an undecyl spacer and a choline head group exhibited broad spectrum antiparasitic activity. It possessed low micromolar activity against the intracellular amastigotes of two L. infantum strains and T. cruzi Y strain epimastigotes, intracellular amastigotes and trypomastigotes, while its cytotoxicity concentration (CC50) against THP-1 macrophages ranged between 50 and 100 µM. Altogether, our work paves the way for the development of improved ether phospholipid derivatives to control neglected tropical diseases.

Pharmacoepigenomics circuits induced by a novel retinoid-polyamine conjugate in human immortalized keratinocytes.

Retinoids are widely used in diseases spanning from dermatological lesions to cancer, but exhibit severe adverse effects. A novel all-trans-Retinoic Acid (atRA)-spermine conjugate (termed RASP) has shown previously optimal in vitro and in vivo anti-inflammatory and anticancer efficacy, with undetectable teratogenic and toxic side-effects. To get insights, we treated HaCaT cells which resemble human epidermis with IC50 concentration of RASP and analyzed their miRNA expression profile. Gene ontology analysis of their predicted targets indicated dynamic networks involved in cell proliferation, signal transduction and apoptosis. Furthermore, DNA microarrays analysis verified that RASP affects the expression of the same categories of genes. A protein-protein interaction map produced using the most significant common genes, revealed hub genes of nodal functions. We conclude that RASP is a synthetic retinoid derivative with improved properties, which possess the beneficial effects of retinoids without exhibiting side-effects and with potential beneficial effects against skin diseases including skin cancer.

Brain Asymmetry Detection and Machine Learning Classification for Diagnosis of Early Dementia.

Early identification of degenerative processes in the human brain is considered essential for providing proper care and treatment. This may involve detecting structural and functional cerebral changes such as changes in the degree of asymmetry between the left and right hemispheres. Changes can be detected by computational algorithms and used for the early diagnosis of dementia and its stages (amnestic early mild cognitive impairment (EMCI), Alzheimer's Disease (AD)), and can help to monitor the progress of the disease. In this vein, the paper proposes a data processing pipeline that can be implemented on commodity hardware. It uses features of brain asymmetries, extracted from MRI of the Alzheimer's Disease Neuroimaging Initiative (ADNI) database, for the analysis of structural changes, and machine learning classification of the pathology. The experiments provide promising results, distinguishing between subjects with normal cognition (NC) and patients with early or progressive dementia. Supervised machine learning algorithms and convolutional neural networks tested are reaching an accuracy of 92.5% and 75.0% for NC vs. EMCI, and 93.0% and 90.5% for NC vs. AD, respectively. The proposed pipeline offers a promising low-cost alternative for the classification of dementia and can be potentially useful to other brain degenerative disorders that are accompanied by changes in the brain asymmetries.

Phospholipid Analogues as Chemotherapeutic Agents Against Trypanosomatids.

BACKGROUND: Neglected tropical diseases (NTDs) represent a serious problem in a number of countries around the world and especially in Africa and South America, affecting mostly the poor population which has limited access to the healthcare system. The drugs currently used for the treatment of NTDs are dated many decades ago and consequently, present in some cases very low efficacy, high toxicity and development of drug resistance. In the search for more efficient chemotherapeutic agents for NTDs, a large number of different compound classes have been synthesized and tested. Among them, ether phospholipids, with their prominent member miltefosine, are considered one of the most promising. OBJECTIVE: This review summarizes the literature concerning the development of antiparasitic phospholipid derivatives, describing the efforts towards more efficient and less toxic analogues while providing an overview of the mechanism of action of this compound class against trypanosomatids. CONCLUSION: Phospholipid analogues are already known for their antiprotozoal activity. Several studies have been conducted in order to synthesize novel derivatives with the aim to improve current treatments such as miltefosine, with promising results. Photolabeling and fluorescent alkyl phospholipid analogues have contributed to the clarification of the mode of action of this drug family.

Synthesis, biological evaluation and QSAR studies of new thieno[2,3-d]pyrimidin-4(3H)-one derivatives as antimicrobial and antifungal agents.

A series of new thieno[2,3-d]pyrimidin-4(3H)-one derivatives were synthesized and evaluated for their activity against four gram-positive and four gram-negative bacterial and eight fungal species. The majority of the compounds exhibited excellent antimicrobial and antifungal activity, being more potent than the control compounds. Compound 22, bearing a m-methoxyphenyl group and an ethylenediamine side chain anchored at C-2 of the thienopyrimidinone core, is the most potent antibacterial compound with broad antimicrobial activity with MIC values in the range of 0.05-0.13 mM, being 6 to 15 fold more potent than the controls, streptomycin and ampicillin. Furthermore, compounds 14 and 15 which bear a p-chlorophenyl and m-methoxyphenyl group, respectively, and share a 2-(2-mercaptoethoxy)ethan-1-ol side chain showed the best antifungal activity, being 10-15 times more potent than ketoconazole or bifonazole with MIC values 0.013-0.026 and 0.027 mM, respectively. Especially in the case of compound 15 the low MIC values were accompanied by excellent MFC values ranging from 0.056 to 0.058 mM. Evaluation of toxicity in vitro on HFL-1 human embryonic primary cells and in vivo in the nematode C. elegans revealed no toxic effects for both compounds 15 and 22 tested at the MIC concentrations. Ligand-based similarity search and molecular docking predicted that the antibacterial activity of analogue 22 is related to inhibition of the topoisomerase II DNA gyrase enzyme and the antifungal activity of compound 15 to CYP51 lanosterol demethylase enzyme. R-Group analysis as a means of computational structure activity relationship tool, highlighted the compounds' crucial pharmacophore features and their impact on the antibacterial and antifungal activity. The presence of a N-methyl piperidine ring fused to the thienopyrimidinone core plays an important role in both activities.

Evolving Connectionist Models to Capture Population Variability across Language Development: Modeling Children's Past Tense Formation.

Children's acquisition of the English past tense has been widely studied as a testing ground for theories of language development, mostly because it comprises a set of quasi-regular mappings. English verbs are of two types: regular verbs, which form their past tense based on a productive rule, and irregular verbs, which form their past tenses through exceptions to that rule. Although many connectionist models exist for capturing language development, few consider individual differences. In this article, we explore the use of populations of artificial neural networks (ANNs) that evolve according to behavioral genetics principles in order to create computational models capable of capturing the population variability exhibited by children in acquiring English past tense verbs. Literature in the field of behavioral genetics views variability in children's learning in terms of genetic and environmental influences. In our model, the effects of genetic influences are simulated through variations in parameters controlling computational properties of ANNs, and the effects of environmental influences are simulated via a filter applied to the training set. This filter alters the quality of information available to the artificial learning system and creates a unique subsample of the training set for each simulated individual. Our approach uses a population of twins to disentangle genetic and environmental influences on past tense performance and to capture the wide range of variability exhibited by children as they learn English past tenses. We use a novel technique to create the population of ANN twins based on the biological processes of meiosis and fertilization. This approach allows modeling of both individual differences and development (within the lifespan of an individual) in a single framework. Finally, our approach permits the application of selection on developmental performance on the quasi-regular task across generations. Setting individual differences within an evolutionary framework is an important and novel contribution of our work. We present an experimental evaluation of this model, focusing on individual differences in performance. The experiments led to several novel findings, including: divergence of population attributes during selection to favor regular verbs, irregular verbs, or both; evidence of canalization, analogous to Waddington's developmental epigenetic landscape, once selection starts targeting a particular aspect of the task domain; and the limiting effect on the power of selection in the face of stochastic selection (roulette wheel), sexual reproduction, and a variable learning environment for each individual. Most notably, the heritability of traits showed an inverse relationship to optimization. Selected traits show lower heritability as the genetic variation of the population reduces. The simulations demonstrate the viability of linking concepts such as heritability of individual differences, cognitive development, and selection over generations within a single computational framework.

Synthesis of nοvel artemisinin dimers with polyamine linkers and evaluation of their potential as anticancer agents.

The natural product artemisinin and derivatives thereof are currently considered as the drugs of choice for the treatment of malaria. At the same time, a significant number of such drugs have also shown interesting anticancer activity. In the context of the present research work, artemisinin was structurally modified and anchored to naturally occurring polyamines to afford new artemisinin dimeric conjugates whose potential anticancer activity was evaluated. All artemisinin conjugates tested were more effective than artemisinin itself in decreasing the number of MCF7 breast cancer cells. The effect required conjugation and was not due to the artemisinin analogue or the polyamine, alone or in combination. To elucidate potential mechanism of action, we used the most effective conjugates 6, 7, 9 and 12 and found that they decreased expression and secretion of the angiogenic growth factor pleiotrophin by the cancer cells themselves, and inhibited angiogenesis in vivo and endothelial cell growth in vitro. These data suggest that the new artemisinin dimers are good candidates for the development of effective anticancer agents.

TAT Peptide-Conjugated Magnetic PLA-PEG Nanocapsules for the Targeted Delivery of Paclitaxel: In Vitro and Cell Studies.

Paclitaxel (PTX) and organophilic iron oxide nanocrystals of 7 nm average size were co-encapsulated in the oily core of poly(lactide)-poly(ethyleneglycol) (PLA-PEG) nanocapsules in order to develop magnetically responsive nanocarriers of PTX. The nanocapsules were prepared by a solvent displacement technique and exhibited satisfactory drug and iron oxide loading efficiency, high colloidal stability, and sustained drug release properties. Drug release also proved responsive to an alternating magnetic field. Magnetophoresis experiments showed that the magnetic responsiveness of the nanocapsules depended on their SPION content. The PTX-loaded nanocapsules exhibited comparable to free PTX cytotoxicity against the A549 lung cancer cell line at 24 h of incubation but higher cytotoxicity than free drug at 48 h of incubation. The conjugation of a cysteine-modified TAT peptide (HCys-Tyr-Gly-Arg-Lys-Lys-Arg-Arg-Gln-Arg-Arg-Arg-NH2) on the surface of the nanocapsules resulted to highly increased uptake of nanocapsules by cancer cells, as well as to profound improvement of their cytotoxicity against the cancer cells. The results obtained justify further investigation of the prospects of these multifunctional PLA-PEG nanocapsules as a targeted delivery system of paclitaxel.

Synthesis and antiproliferative activity of two diastereomeric lignan amides serving as dimeric caffeic acid-l-DOPA hybrids.

Two new diastereomeric lignan amides (4 and 5) serving as dimeric caffeic acid-l-DOPA hybrids were synthesized. The synthesis involved the FeCl3-mediated phenol oxidative coupling of methyl caffeate to afford trans-diester 1a as a mixture of enantiomers, protection of the catechol units, regioselective saponification, coupling with a suitably protected l-DOPA derivative, separation of the two diastereomers thus obtained by flash column chromatography and finally global chemoselective deprotection of the catechol units. The effect of hybrids 4 and 5 and related compounds on the proliferation of two breast cancer cell lines with different metastatic potential and estrogen receptor status (MDA-MB-231 and MCF-7) and of one epithelial lung cancer cell line, namely A-549, was evaluated for concentrations ranging from 1 to 256µM and periods of treatment of 24, 48 and 72h. Both hybrids showed interesting and almost equipotent antiproliferative activities (IC50 64-70µM) for the MDA-MB-231 cell line after 24-48h of treatment, but they were more selective and much more potent (IC50 4-16µM) for the MCF-7 cells after 48h of treatment. The highest activity for both hybrids and both breast cancer lines was observed after 72h of treatment (IC50 1-2µM), probably as the result of slow hydrolysis of their methyl ester functions.

Synthesis of minoxidil conjugates and their evaluation as HL-60 differentiation agents.

Activation of minoxidil (MNX) with N,N'-carbonyldiimidazole and coupling with natural polyamines (PAs) and commercially available aliphatic or aromatic amines provided a series of new conjugates which were evaluated for their ability to induce differentiation to HL-60 acute myeloid leukemia cancer cells, using a modified NBTZ reduction test. Although neither MNX nor 4,4'-methylenedianiline (MDA) or 2,7-diaminofluorene (DAF), alone or in combination, had any effect, the MNX-spermine (SPM) conjugate (11) and the conjugates 7 and 8 of MNX with MDA and DAF exhibited a differentiation-inducing effect at a concentration of 10 µM without being toxic on proliferating human peripheral blood mononuclear cells.

Investigation on Toxicity and Teratogenicity in Rats of a Retinoid-Polyamine Conjugate with Potent Anti-Inflammatory Properties.

Previous studies have shown that N(1),N(12)-bis(all-trans-retinoyl)spermine (RASP), a retinoid analog, inhibits RNase P activity and angiogenesis in the chicken embryo chorioallantoic membrane, demonstrates anti-tumor activity on prostate cancer cells, and acts as anti-inflammatory agent, being more effective and less toxic than all-trans retinoic acid. In an attempt to further characterize the biological profile of RASP, we tested its effects on organ toxicity and teratogenicity by daily oral gavage of RASP at a level of 50 mg/Kg of body weight in two generations of rats. We found that this compound does not induce changes to the body growth, the appearance of physical features, and the animal's reflexes. Additionally, no substantial histopathological lesions were found in brain, heart, lung, thymus, liver, thyroid gland, adrenal gland, pituitary gland, kidneys, spleen, skin, femora, prostate, testis, epididymis, vagina, uterus, and ovaries of RASP-treated animals. These results suggest RASP, as a promising lead compound for the treatment of several dermatological disorders and certain cancer types, has apparently minimal toxic side-effects as revealed in this two-generation reproduction study in rats.

Synthesis and biological evaluation of new C-10 substituted dithranol pleiotropic hybrids.

Selective alkylation of the antipsoriatic drug dithranol (DTR) at C-10 with tert-butyl bromoacetate, followed by acid-mediated deprotection, produced the corresponding carboxylic acid 4 which was coupled with selectively protected polyamines (PAs), such as putrescine (PUT), spermidine (SPD) and spermine (SPM), dopamine and aliphatic amines and substituted benzylamines producing a series of DTR-PA hybrids, after acid-mediated deprotection, as well as simple amides. The compounds were tested as antioxidants and inhibitors of lipoxygenase (LOX). The amides 4,4'-dimethoxybenzhydrylamide 13 (86% and 95%), 2,4-dimethoxybenzylamide 12 (87% and 81%) and dodecylamide 9 (98% and 74%), and the hybrid DTR-SPM (7) (93% and 87%), showed the highest antioxidant activity in the DPPH and AAPH assays, whereas the most potent inhibitors of LOX were amide 13 (IC50=7 µM), the benzylamide 10 (IC50=7.9 µM) and the butylamide 8 (IC50=10 µM). Molecular binding studies showed that binding of these derivatives into the hydrophobic domain blocks approach of substrate to the active site, inhibiting soybean LOX. Amide 13 presented the highest anti-inflammatory activity (79.7%). The DTR moiety was absolutely necessary for securing high anti-inflammatory potency. Ethyl ester 3 (IC50=0.357 µM) and the amides 9 (IC50=0.022 µM) and 13 (IC50=0.56 µM) exhibited higher antiproliferative activity than DTR (IC50=0.945 µM) on HaCaT keratinocytes whereas amide 13 generally presented better cytocompatibility. Amide 13 is a very promising lead compound for further development as an anti-inflammatory and antiproliferative agent.

Synthesis and evaluation of chloramphenicol homodimers: molecular target, antimicrobial activity, and toxicity against human cells.

As fight against antibiotic resistance must be strengthened, improving old drugs that have fallen in reduced clinical use because of toxic side effects and/or frequently reported resistance, like chloramphenicol (CAM), is of special interest. Chloramphenicol (CAM), a prototypical wide-spectrum antibiotic has been shown to obstruct protein synthesis via binding to the bacterial ribosome. In this study we sought to identify features intensifying the bacteriostatic action of CAM. Accordingly, we synthesized a series of CAM-dimers with various linker lengths and functionalities and compared their efficiency in inhibiting peptide-bond formation in an Escherichia coli cell-free system. Several CAM-dimers exhibited higher activity, when compared to CAM. The most potent of them, compound 5, containing two CAM bases conjugated via a dicarboxyl aromatic linker of six successive carbon-bonds, was found to simultaneously bind both the ribosomal catalytic center and the exit-tunnel, thus revealing a second, kinetically cryptic binding site for CAM. Compared to CAM, compound 5 exhibited comparable antibacterial activity against MRSA or wild-type strains of Staphylococcus aureus, Enterococcus faecium and E. coli, but intriguingly superior activity against some CAM-resistant E. coli and Pseudomonas aeruginosa strains. Furthermore, it was almost twice as active in inhibiting the growth of T-leukemic cells, without affecting the viability of normal human lymphocytes. The observed effects were rationalized by footprinting tests, crosslinking analysis, and MD-simulations.

Synthesis and antimicrobial activity of chloramphenicol-polyamine conjugates.

A series of chloramphenicol (CAM) amides with polyamines (PAs), suitable for structure-activity relationship studies, were synthesized either by direct attachment of the PA chain on the 2-aminopropane-1,3-diol backbone of CAM, previously oxidized selectively at its primary hydroxyl group, or from chloramphenicol base (CLB) through acylation with succinic or phthalic anhydride and finally coupling with a PA. Conjugates 4 and 5, in which the CLB moiety was attached on N4 and N1 positions, respectively, of the N(8),N(8)-dibenzylated spermidine through the succinate linker, were the most potent antibacterial agents. Both conjugates were internalized into Escherichia coli cells by using the spermidine-preferential uptake system and caused decrease in protein and polyamine content of the cells. Noteworthy, conjugate 4 displayed comparable activity to CAM in MRSA or wild-type strains of Staphylococcus aureus and Escherichia coli, but superior activity in E. coli strains possessing ribosomal mutations or expressing the CAM acetyltransferase (cat) gene. Lead compounds, and in particular conjugate 4, have been therefore discovered during the course of the present work with clinical potential.

Synthesis and evaluation of anticancer activity in cells of novel stoichiometric pegylated fullerene-doxorubicin conjugates.

PURPOSE: To synthesize pegylated stoichiometrically and structurally well-defined conjugates of fullerene (C60) with doxorubicin (DOX) and investigate their antiproliferative effect against cancer cell lines. METHODS: Stoichiometric (1:1 and 1:2) pegylated conjugates of C60 with DOX were synthesized using the Prato reaction to create fulleropyrrolidines equipped with a carboxyl function for anchoring a polyethylene glycol (PEG) moiety and either a hydroxyl group for attaching one molecule of DOX or a terminal alkyne group for attaching two molecules of DOX through a click reaction. In both conjugates, the DOX moieties are held through a urethane-type bond. Drug release was studied in phosphate buffer (PBS, pH 7.4) and MCF-7 cancer cells lysate. The uptake of the conjugates by MCF-7 cancer cells and their intracellular localization were studied with fluorescence microscopy. The antiproliferative activity of the conjugates was investigated using the WST-1 test. RESULTS: One or two DOX molecules were anchored on pegylated C60 particles to form DOX-C60-PEG conjugates. Drug liberation from the conjugates was significantly accelerated in the presence of tumor cell lysate compared to PBS. The conjugates could be internalized by MCF-7 cells. DOX from the conjugates exhibited much delayed, compared to free DOX, localization in the nucleus and antiproliferative activity. CONCLUSION: Pegylated DOX-C60 conjugates (1:1) and (2:1) with well-defined structure were successfully synthesized and found to exhibit comparable, but with a delayed onset, antiproliferative activity with free DOX against MCF-7 cancer cells. The results obtained justify further investigation of the potential of these conjugates as anticancer nanomedicines.

Bioinspired syntheses of dimeric hydroxycinnamic acids (lignans) and hybrids, using phenol oxidative coupling as key reaction, and medicinal significance thereof.

Lignans are mainly dimers of 4-hydroxycinnamic acids (HCAs) and reduced analogs thereof which are produced in Nature through phenol oxidative coupling (POC) as the primary C-C or C-O bond-forming reaction under the action of the enzymes peroxidases and laccases. They present a large structural variety and particularly interesting biological activities, therefore, significant efforts has been devoted to the development of efficient methodologies for the synthesis of lignans isolated from natural sources, analogs and hybrids with other biologically interesting small molecules. We summarize in the present review those methods which mimic Nature for the assembly of the most common lignan skeleta by using either enzymes or one-electron inorganic oxidants to effect POC of HCAs and derivatives, such as esters and amides, or cross-POC of pairs of HCAs or HCAs with 4-hydrocycinnamyl alcohols. We, furthermore, provide outlines of mechanistic schemes accounting for the formation of the coupled products and, where applicable, indicate their potential application in medicine.