Protective effects of new antioxidant compositions of 4-methylcoumarins and related compounds with dl-α-tocopherol and l-ascorbic acid.

BACKGROUND: Coumarin derivatives possess a wide range of biological activities. By functionalization of the parent coumarin skeleton that has neither antioxidant nor biological activity, a series of new bio-antioxidants has been designed. RESULTS: New antioxidant compositions (equimolar binary and ternary mixtures) of eight 4-methylcoumarins and three related compounds have been tested and different effects between individual components have been observed: synergism (positive effect), additivism (summary effect) and antagonism (negative effect). Higher oxidative stability of the lipid substrate was obtained in the presence of the new antioxidant compositions of the studied compounds with dl-α-tocopherol and l-ascorbic acid. The role of each component in the antioxidant compositions of ternary mixtures has been identified by using new equations composed by the authors. CONCLUSION: All ternary mixtures demonstrate synergism as a result of continuous regeneration of dl-α-tocopherol from the studied antioxidants and l-ascorbic acid. Theoretical calculations have been probed as indicators of the expected effects between the individual components in a binary mixture. © 2018 Society of Chemical Industry.

Chemoenzymatic Synthesis, Nanotization, and Anti-Aspergillus Activity of Optically Enriched Fluconazole Analogues.

Despite recent advances in diagnostic and therapeutic methods in antifungal research, aspergillosis still remains a leading cause of morbidity and mortality. One strategy to address this problem is to enhance the activity spectrum of known antifungals, and we now report the first successful application of Candida antarctica lipase (CAL) for the preparation of optically enriched fluconazole analogues. Anti-Aspergillus activity was observed for an optically enriched derivative, (-)-S-2-(2',4'-difluorophenyl)-1-hexyl-amino-3-(1‴,2‴,4‴)triazol-1‴-yl-propan-2-ol, which exhibits MIC values of 15.6 µg/ml and 7.8 µg/disc in broth microdilution and disc diffusion assays, respectively. This compound is tolerated by mammalian erythrocytes and cell lines (A549 and U87) at concentrations of up to 1,000 µg/ml. When incorporated into dextran nanoparticles, the novel, optically enriched fluconazole analogue exhibited improved antifungal activity against Aspergillus fumigatus (MIC, 1.63 µg/ml). These results not only demonstrate the ability of biocatalytic approaches to yield novel, optically enriched fluconazole derivatives but also suggest that enantiomerically pure fluconazole derivatives, and their nanotized counterparts, exhibiting anti-Aspergillus activity may have reduced toxicity.

Synthesis of macromolecular systems via lipase catalyzed biocatalytic reactions: applications and future perspectives.

Enzymes, being remarkable catalysts, are capable of accepting a wide range of complex molecules as substrates and catalyze a variety of reactions with a high degree of chemo-, stereo- and regioselectivity in most of the reactions. Biocatalysis can be used in both simple and complex chemical transformations without the need for tedious protection and deprotection chemistry that is very common in traditional organic synthesis. This current review highlights the applicability of one class of biocatalysts viz."lipases" in synthetic transformations, the resolution of pharmaceutically important small molecules including polyphenols, amides, nucleosides and their precursors, the development of macromolecular systems (and their applications as drug/gene carriers), flame retardants, polymeric antioxidants and nanocrystalline solar cells, etc.

Neuroprotective and Antioxidant Activities of 4-Methylcoumarins: Development of Structure-Activity Relationships.

Coumarins are a major class of polyphenols that are abundantly present in many dietary plants and possess different biological activities. Neuroprotective effect of 28 variously substituted 4-methylcoumarins was evaluated in a cell model of oxidative stress-induced neurodegeneration, which measures viability in PC12 cells challenged with hydrogen peroxide by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The inhibitory activity of these compounds against intracellular reactive oxygen species (ROS) formation was also determined by 2',7'-dichlorofluorescein diacetate method in the same cells. Chemical redox-based assays including 2,2-diphenyl-1-picrylhydrazyl (DPPH) and ferric reducing antioxidant power (FRAP) tests were employed to explore structure-antioxidant activity relationships in a cell-free environment. The results demonstrated that 4-methylcoumarins containing ortho-dihydroxy or ortho-diacetoxy substituents on the benzenoid ring possess considerable neuroprotective effects. ortho-Dihydroxy compounds inhibited cytotoxicity (44.7-62.9%) and ROS formation (41.6-71.1%) at 50 µM and showed considerable antioxidant effects. We conclude that 4-methylcoumarins are promising neuroprotective and antioxidant scaffolds potentially usefull for management of neurodegenerative diseases.

Synthesis and anti-inflammatory activity evaluation of novel triazolyl-isatin hybrids.

New isatin-triazole based hybrids have been synthesized and evaluated for their inhibitory activity of TNF-α induced expression of Intercellular Adhesion Molecule-1 (ICAM-1) on the surface of human endothelial cells. Structure-activity relationship (SAR) studies revealed that the presence of the electron-attracting bromo substituent at position-5 of the isatin moiety played an important role in enhancing the anti-inflammatory potential of the synthesized compounds. Z-1-[3-(1H-1,2,4-Triazol-1-yl)propyl]-5-bromo-3-[2-(4-methoxyphenyl)hydrazono]indolin-2-one (19) with an IC50 = 20 µM and 89% ICAM-1 inhibition with MTD at 200 µM was found to be the most potent of all the synthesized derivatives. Introduction of 1,2,4-triazole ring and electron-donating methoxy group on the phenylhydrazone moiety resulted in four-fold increase of the anti-inflammatory activity.

Micro- and nanogels with labile crosslinks - from synthesis to biomedical applications.

Micro- or nanosized three-dimensional crosslinked polymeric networks have been designed and described for various biomedical applications, including living cell encapsulation, tissue engineering, and stimuli responsive controlled delivery of bioactive molecules. For most of these applications, it is necessary to disintegrate the artificial scaffold into nontoxic residues with smaller dimensions to ensure renal clearance for better biocompatibility of the functional materials. This can be achieved by introducing stimuli-cleavable linkages into the scaffold structures. pH, enzyme, and redox potential are the most frequently used biological stimuli. Moreover, some external stimuli, for example light and additives, are also used to trigger the disintegration of the carriers or their assembly. In this review, we highlight the recent progress in various chemical and physical methods for synthesizing and crosslinking micro- and nanogels, as well as their development for incorporation of cleavable linkages into the network of micro- and nanogels.

Biocatalytic Synthesis of Novel Partial Esters of a Bioactive Dihydroxy 4-Methylcoumarin by Rhizopus oryzae Lipase (ROL).

Highly regioselective acylation has been observed in 7,8-dihydroxy-4-methylcoumarin (DHMC) by the lipase from Rhizopus oryzae suspended in tetrahydrofuran (THF) at 45 °C using six different acid anhydrides as acylating agents. The acylation occurred regioselectively at one of the two hydroxy groups of the coumarin moiety resulting in the formation of 8-acyloxy-7-hydroxy-4-methylcoumarins, which are important bioactive molecules for studying biotansformations in animals, and are otherwise very difficult to obtain by only chemical steps. Six monoacylated, monohydroxy 4-methylcoumarins have been biocatalytically synthesised and identified on the basis of their spectral data and X-ray crystal analysis.

Synthesis of ß-C-Glycopyranosyl Aldehydes and 2,6-Anhydro-heptitols.

A convenient route has been developed for the diastereoselective synthesis of ß-C-glycopyranosyl aldehydes from D-glucose, D-mannose, and D-galactose. The key step in the synthesis of C-glycosyl aldehydes is the aryl driven reductive dehydration on 1-phenyl-2-(2',3',4',6'-tetra-O-acetyl-ß-D-glycopyranosyl)ethanone to afford alkenes, which on oxidation afford the desired compounds in good yield. ß-C-Glycopyranosyl aldehydes have been converted to 2,6-anhydro-heptitols in quantitative yields. The 2,6-anhydro-heptitols derived from D-mannose and D-galactose are enantiomeric and are useful linkers for the synthesis of macrocycles/amphiphiles of complementary chirality.

Monoclonal antibodies in breast cancer: A critical appraisal.

In breast cancer, mAbs can play multifunctional roles like targeting cancer cells, sometimes directly attacking them, helping in locating and delivering therapeutic drugs to targets, inhibiting cell growth and blocking immune system inhibitors, etc. Monoclonal antibodies are also one of the important successful treatment strategies especially against HER2 but they have not been explored much for other types of breast cancers especially in triple negative breast cancers. Monoclonal antibodies impact the feasibility of antigen specificity, bispecific and trispecific mAbs have opened new doors for more targeted specific efficacy. Monoclonal antibodies can be used diversly and with efficacy as compared to other methods of treatment thus maining it a suitable candidate for breast cancer treatment. However, mAbs treatment also causes various side effects such as fever, trembling, fatigue, headache and muscle pain, nausea/vomiting, difficulty in breathing, rashes and bleeding. Understanding the pros and cons of this strategy, we have explored in this review, the current and future potential capabilities of monoclonal antibodies with respect to diagnosis and treatment of breast cancer. DATA AVAILABILITY: Not applicable.

Biodegradable PEG-PCL Nanoparticles for Co-delivery of MUC1 Inhibitor and Doxorubicin for the Confinement of Triple-Negative Breast Cancer.

Combating triple-negative breast cancer (TNBC) is still a problem, despite the development of numerous drug delivery approaches. Mucin1 (MUC1), a glycoprotein linked to chemo-resistance and progressive malignancy, is unregulated in TNBC. GO-201, a MUC1 peptide inhibitor that impairs MUC1 activity, promotes necrotic cell death by binding to the MUC1-C unit. The current study deals with the synthesis and development of a novel nano-formulation (DM-PEG-PCL NPs) comprising of polyethylene glycol-polycaprolactone (PEG-PCL) polymer loaded with MUC1 inhibitor and an effective anticancer drug, doxorubicin (DOX). The DOX and MUC1 loaded nanoparticles were fully characterized, and their different physicochemical properties, viz. size, shape, surface charge, entrapment efficiencies, release behavior, etc., were determined. With IC50 values of 5.8 and 2.4 nm on breast cancer cell lines, accordingly, and a combination index (CI) of < 1.0, DM-PEG-PCL NPs displayed enhanced toxicity towards breast cancer cells (MCF-7 and MDA-MB-231) than DOX-PEG-PCL and MUC1i-PEG-PCL nanoparticles. Fluorescence microscopy analysis revealed DOX localization in the nucleus and MUC1 inhibitor in the mitochondria. Further, DM-PEG-PCL NPs treated breast cancer cells showed increased mitochondrial damage with enhancement in caspase-3 expression and reduction in Bcl-2 expression.In vivo evaluation using Ehrlich Ascites Carcinoma bearing mice explicitly stated that DM-PEG-PCL NPs therapy minimized tumor growth relative to control treatment. Further, acute toxicity studies did not reveal any adverse effects on organs and their functions, as no mortalities were observed. The current research reports for the first time the synergistic approach of combination entrapment of a clinical chemotherapeutic (DOX) and an anticancer peptide (MUC1 inhibitor) encased in a diblock PEG-PCL copolymer. Incorporating both DOX and MUC1 inhibitors in PEG-PCL NPs in the designed nanoformulation has provided chances and insights for treating triple-negative breast tumors. Our controlled delivery technology is biodegradable, non-toxic, and anti-multidrug-resistant. In addition, this tailored smart nanoformulation has been particularly effective in the therapy of triple-negative breast cancer. Supplementary Information: The online version contains supplementary material available at 10.1007/s10924-022-02654-4.

Glycine-terminated dendritic amphiphiles for nonviral gene delivery.

Development of nonviral vectors for the successful application of gene therapy through siRNA/DNA transfection of cells is still a great challenge in current research. (1, 2) In the present study, we have developed multivalent polyglycerol dendron based amphiphiles with well-defined molecular structures that express controlled glycine arrays on their surfaces. The structure-activity relationships with respect to the siRNA complexation, toxicity, and transfection profiles were studied with synthesized amphiphilic polycations. Our findings revealed that a second-generation amphiphilic dendrimer (G2-octaamine, 4) that has eight amine groups on its surface and a hydrophobic C-18 alkyl chain at the core of the dendron, acts as an efficient vector to deliver siRNA and achieve potent gene silencing by investigating the knockdown of luciferase and GAPDH gene activity in HeLa cells. Interestingly, the amphiphilic vector is nontoxic even at higher ratio of N/P 100. To the best of our knowledge this is the first example of successful in vitro siRNA transfection using dendritic amphiphiles. We believe that this supramolecular complex may serve as a new promising alternative for nonviral siRNA delivery systems and will be investigated for in vivo siRNA delivery in the future.

Arylalkyl ketones, benzophenones, desoxybenzoins and chalcones inhibit TNF-α induced expression of ICAM-1: structure-activity analysis.

The interaction between leukocytes and the vascular endothelial cells (EC) via cellular adhesion molecules plays an important role in the pathogenesis of various inflammatory and autoimmune diseases. Small molecules that block these interactions have been targeted as potential therapeutic agents against acute and chronic inflammatory diseases. In an effort to identify potent intercellular cell adhesion molecule-1 (ICAM-1) inhibitors, a large number of arylalkyl ketones, benzophenones, desoxybenzoins and chalcones and their analogs (54 in total) have been synthesized and screened for their ICAM-1 inhibitory activity. The structure-activity relationship studies of these compounds identified three potent chalcone derivatives and also demonstrated the possible mechanism for their ICAM-1 inhibitory activities. The most active compound was found to be 79.

Synthesis, Self-Assembly, and Biological Activities of Pyrimidine-Based Cationic Amphiphiles.

Pyrimidine-based cationic amphiphiles (PCAms), i.e., di-trifluoroacetic acid salts of N1-[1'-(1″,3″-diglycinatoxy-propane-2″-yl)-1',2',3'-triazole-4'-yl]methyl-N3-alkylpyrimidines have been synthesized utilizing naturally occurring biocompatible precursors, like glycerol, glycine, and uracil/ thymine in good yields. Synthesized PCAms consist of a hydrophilic head group comprising TFA salt of glyceryl 1,3-diglycinate and hydrophobic tail comprising of C-7 and C-12 N3-alkylated uracil or thymine conjugated via a 4-methylene-1,2,3-triazolyl linker. The physicochemical properties of all PCAms, such as critical aggregation concentration, hydrodynamic diameter, shape, and zeta potential (surface charge) were analyzed. These PCAms were also evaluated for their anti-proliferative and anti-tubercular activities. One of the synthesized PCAm exhibited 4- to 75-fold more activity than first-line anti-tubercular drugs streptomycin and isoniazid, respectively, against the multidrug resistant clinical isolate 591 of Mycobacterium tuberculosis.

Novel chemoenzymatic methodology for the regioselective glycine loading on polyhydroxy compounds.

In the present work, we have developed a highly efficient temperature-dependent chemo-enzymatic methodology for the regioselective synthesis of novel esters of glycerol, G1 tri-glycerol dendrons and related esters for the first time using 4-nitrophenyl 2-(tert-butoxycarbonyl)acetate (Boc-gly-Ph-pNO(2)) (2) as the acylating agent. This methodology offers efficient and controlled loading of amino acid (glycine) on polyhydroxy compounds.

Protective effects of 4-methylcoumarins and related compounds as radical scavengers and chain-breaking antioxidants.

The aim of this study is to determine, and to compare the protective effects of eight 4-methylcoumarins and four related compounds as radical scavengers and chain-breaking antioxidants. The main kinetic parameters of their radical scavenging activity (as % RSA, stoichiometry, n, and rate constants of reaction with DPPH radical, kRSA) and of chain breaking antioxidant activity (as antioxidant efficiency, PF and reactivity, ID), have been determined and discussed. The RSA study has been conducted at physiological temperature (37 °Ð¡) towards DPPH radical and the tested compounds are separated into three main groups: with strong activity (% RSA > 40%); with moderate activity (20% < % RSA > 40%) and with weak activity (% RSA < 20%). Chain-breaking antioxidant activities of the studied compounds have been evaluated during bulk phase lipid (triacylglycerols of sunflower oil, TGSO) autoxidation at 80 °C. All results obtained are compared with those for standard and known inhibitors of oxidation processes, e.g. caffeic and p-coumaric acids, α-tocopherol and butylated hydroxytoluene (BHT). On the basis of a comparative analysis with standard antioxidants, the differences in the radical scavenging and antioxidant abilities of the studied compounds have been discussed and reaction mechanisms proposed. All structures are optimized at UB3LYP/6-31 + G(d,p) level in gas phase and in acetone solution to study the solvation effects.

Sugar-based novel chiral macrocycles for inclusion applications and chiral recognition.

A convergent template assisted synthesis of sugar-based chiral macrocycles has been achieved. The host-guest inclusion studies have revealed significant interactions of the synthesized macrocycle with primary over secondary ammonium salt. The chiral macrocyle also discriminates between D- and L-phenylalanine methyl ester hydrochlorides as revealed by (1)H NMR spectral studies on the mixture of the host and the guest molecules.

Functionalized nanogels carrying an anticancer microRNA for glioblastoma therapy.

Glioblastoma Multiforme (GBM) is one of the most aggressive forms of all cancers. The median survival with current standard-of-care radiation and chemotherapy is about 14months. GBM is difficult to treat due to heterogeneity in cancer cell population. MicroRNA-based drugs have rapidly become a vast and burgeoning field due to the ability of a microRNA (miRNA) to target many genes involved in key cellular pathways. However, in vivo delivery of miRNA remains a crucial challenge for its therapeutic success. To bypass this shortcoming, we designed polymeric nanogels (NGs), which are based on a polyglycerol-scaffold, as a new strategy of miRNA delivery for GBM therapy. We focused on miR-34a, which is known for its key role in important oncogenic pathways and its tumor suppression ability in GBM and other cancers. We evaluated the capability of six NG derivatives to complex with miR-34a, neutralize its negative charge and deliver active miRNA to the cell cytoplasm. Human U-87 MG GBM cells treated with our NG-miR-34a nano-polyplexes showed remarkable downregulation of miR-34a target genes, which play key roles in the regulation of apoptosis and cell cycle arrest, and induce inhibition of cells proliferation and migration. Administration of NG-miR-34a nano-polyplexes to human U-87 MG GBM-bearing SCID mice significantly inhibited tumor growth as opposed to treatment with NG-negative control miR polyplex or saline. The comparison between different polyplexes highlighted the key features for the rational design of polymeric delivery systems for oligonucleotides. Taken together, we expect that this new therapeutic approach will pave the way for safe and efficient therapies for GBM.

Anti-inflammatory and antioxidant properties of Piper species: a perspective from screening to molecular mechanisms.

Identifying novel therapeutic agents from natural sources and their possible intervention studies has been one of the major areas in biomedical research in recent years. Piper species are highly important - commercially, economically and medicinally. Our groups have been working for more than two decades on the identification and characterization of novel therapeutic lead molecules from Piper species. We have extensively studied the biological activities of various extracts of Piper longum and Piper galeatum, and identified and characterized novel molecules from these species. Using synthetic chemistry, various functional groups of the lead molecules were modified and structure activity relationship (SAR) studies identified synthetic molecules with better efficacy and lower IC50 values. Moreover, the mechanisms of actions of some of these molecules were studied at the molecular level. The objective of this review is to summarize experimental data published from our laboratories and others on antioxidant and anti-inflammatory potentials of Piper species and their chemical constituents.

Nonviral gene delivery with dendritic self-assembling architectures.

In this review, we outline the concept and applicability of self-assembling dendrimers for gene-delivery applications. Low-molecular-weight, well-defined cationic dendritic arrays which have been modified with hydrophobic domains can form self-organized multivalent systems that have significant advantages over nonassembling, high-molecular-weight/polymeric gene vectors. Particular structural variations have been highlighted with respect to the individual components of the displayed dendritic amphiphiles, namely, the employed amine termini, the hydrophobic segment, the size of the dendritic array, and the integration of special features such as targeting ability and cleavability/degradability, which can all have a crucial effect on gene-transfection efficiencies. Accordingly, the scientific efforts to create new synthetic gene-delivery vectors to act as promising in vivo transfection agents in the future will be presented and discussed here.

Cascade N-Alkylation/Hemiacetalization for Facile Construction of the Spiroketal Skeleton of Acortatarin Alkaloids with Therapeutic Potentiality in Diabetic Nephropathy.

The concise building of the spiroketal core of acortatarin-type alkaloids as potential therapeutic agents in diabetic nephropathy was established in four steps, through a tandem N-alkylation/hemiacetalization between pyrrole units and the corresponding halo alcohols generated by convenient halomethylation of chiral lactones from natural aldoses.