https://pubs.rsc.org/en/content/articlepdf/2019/NP/C8NP00092A

Marine natural products.

Curcumin as “Curecumin”: From kitchen to clinic

Nanoparticle interaction with plasma proteins as it relates to particle biodistribution, biocompatibility and therapeutic efficacy.

Turmeric, derived from the plant Curcuma longa, is a gold-colored spice commonly used in the Indian subcontinent, not only for health care but also for the preservation of food and as a yellow dye for textiles. Curcumin, which gives the yellow color to turmeric, was first isolated almost two centuries ago, and its structure as diferuloylmethane was determined in 1910. Since the time of Ayurveda (1900 Bc) numerous therapeutic activities have been assigned to turmeric for a wide variety of diseases and conditions, including those of the skin, pulmonary, and gastrointestinal systems, aches, pains, wounds, sprains, and liver disorders. Extensive research within the last half century has proven that most of these activities, once associated with turmeric, are due to curcumin. Curcumin has been shown to exhibit antioxidant, anti-inflammatory, antiviral, antibacterial, antifungal, and anticancer activities and thus has a potential against various malignant diseases, diabetes, allergies, arthritis, Alzheimer's disease, and other chronic illnesses. These effects are mediated through the regulation of various transcription factors, growth factors, inflammatory cytokines, protein kinases, and other enzymes. Curcumin exhibits activities similar to recently discovered tumor necrosis factor blockers (e.g., HUMIRA, REMICADE, and ENBREL), a vascular endothelial cell growth factor blocker (e.g., AVASTIN), human epidermal growth factor receptor blockers (e.g., ERBITUX, ERLOTINIB, and GEFTINIB), and a HER2 blocker (e.g., HERCEPTIN). Considering the recent scientific bandwagon that multitargeted therapy is better than monotargeted therapy for most diseases, curcumin can be considered an ideal "Spice for Life".

Curcumin: The Indian solid gold

Electronic excitations in small aggregates, thin films, and crystals of conjugated organic molecules play a fundamental role in the operation of a wide array of organic-based devices including solar cells, transistors, and light-emitting diodes. Such excitations, or excitons, are generally spread out over several molecules: a balance between the delocalizing influence of resonant intermolecular coupling and the localizing influence of static and dynamic disorder determines the coherence range of the exciton. Because of the "soft" nature of organic materials, significant nuclear relaxation in the participating molecules also accompanies the electronic excitations. To properly understand energy or charge transport, one must treat intermolecular (excitonic) coupling, electron-vibrational coupling, and disorder on equal footing. In this Account, we review the key elements of a theoretical approach based on a multiparticle representation that describes electronic excitations in organic materials as vibronic excitations surrounded by a field of vibrational excitations. Such composite excitations are appropriately called Frenkel excitonic polarons. For many conjugated molecules, the bulk of the nuclear reorganization energy following electronic excitation arises from the elongation of a symmetric vinyl stretching mode with energy approximately 1400 cm(-1). To appreciate the impact of aggregation, we study how the vibronic progression of this mode, which dominates the isolated (solvated) molecule absorption and emission spectra, is distorted when molecules are close enough to interact with each other. As we demonstrate in this Account, the nature of the distortion provides a wealth of information about how the molecules are packed, the strength of the excitonic interactions between molecules, the number of molecules that are coherently coupled, and the nature of the disorder. We show that the aggregation-induced deviations from the Poissonian distribution of vibronic peak intensities take on two extremes identified with ideal H- and J-aggregates. The sign of the nearest neighbor electronic coupling, positive for H and negative for J, distinguishes the two basic aggregate forms. For several decades, researchers have known that H-aggregates exhibit blue-shifted absorption spectra and are subradiant while J-aggregates exhibit the opposite behavior (red-shifted absorption and superradiance). However, the exact inclusion of exciton-vibrational coupling reveals several more distinguishing traits between the two aggregate types: in H(J)-aggregates the ratio of the first two vibronic peak intensities in the absorption spectrum decreases (increases) with increasing excitonic coupling, while the ratio of the 0-0 to 0-1 emission intensities increases (decreases) with disorder and increases (decreases) with increasing temperature. These two extreme behaviors provide the framework for understanding absorption and emission in more complex morphologies, such as herringbone packing in oligo(phenylene vinylene)s, oligothiophenes and polyacene crystals, as well as the polymorphic packing arrangements observed in carotenoids.

The spectral signatures of Frenkel polarons in H- and J-aggregates.

Probing the binding of the flavonoid, quercetin to human serum albumin by circular dichroism, electronic absorption spectroscopy and molecular modelling methods.

Five unique metabolites, xyloketals A (1), B (2), C (3), D (4), and E (5), and the known 6 were isolated from mangrove fungus Xylaria sp. (no. 2508), obtained from the South China Sea. The structures of these compounds were elucidated by spectroscopic and X-ray diffraction experiments. Xyloketal A is a ketal compound with a C3 symmetry and xyloketals B−E are its analogues. It was found that xytoketal C slowly rearranged to xytoketal B in DMSO-d6 solution at room temperature. Xyloketal A exhibited the activity of inhibiting acetylcholine esterase.

Five unique compounds: xyloketals from mangrove fungus Xylaria sp. from the South China Sea coast.

According to the conventional view, noncovalent association of small molecules with human serum albumin (HSA) occurs principally at the so-called Sudlow's sites located in subdomain IIA and IIIA. By employing a circular dichroism (CD) spectroscopic approach, it is shown that biliverdin is the specific CD label of an additional drug binding area in subdomain IB. CD competition experiments disclosed the entrapment of a diverse assortment of acidic, neutral, and basic molecules within subdomain IB including anticancer agents (camptothecin, doxorubicin, daunorubicin, teniposide, suramin, tyrosine kinase inhibitors), anticoagulants (dicoumarol), various steroids (bile acids, carbenoxolone), nonsteroidal antiinflammatory drugs, natural substances (aristolochic acid, glycyrrhetinic acid), and synthetic dyes (methyl orange, azocarmine B). These finding imply that subdomain IB can be considered as the third major drug binding region of HSA featured with promiscuous ligand recognition ability. Additionally, subdomain IB is allosterically coupled with the Sudlow's sites, the ligand binding of which is shown to alter the HSA binding mode and affinity of biliverdin and hemin. Brief case studies are presented to illustrate how the evaluation of spectral changes of tetrapyrrole CD probes gains new insight into the HSA binding properties of endogenous as well as pharmaceutical compounds.

Subdomain IB is the third major drug binding region of human serum albumin: toward the three-sites model.

Motivation: Human serum albumin (HSA), the most abundant plasma protein is well known for its extraordinary binding capacity for both endogenous and exogenous substances, including a wide range of drugs. Interaction with the two principal binding sites of HSA in subdomain IIA (site 1) and in subdomain IIIA (site 2) controls the free, active concentration of a drug, provides a reservoir for a long duration of action and ultimately affects the ADME (absorption, distribution, metabolism, and excretion) profile. Due to the continuous demand to investigate HSA binding properties of novel drugs, drug candidates and drug-like compounds, a support vector machine (SVM) model was developed that efficiently predicts albumin binding. Our SVM model was integrated to a free, web-based prediction platform ( http://albumin.althotas.com). Automated molecular docking calculations for prediction of complex geometry are also integrated into the web service. The platform enables the users (i) to predict if albumin binds the query ligand, (ii) to determine the probable ligand binding site (site 1 or site 2), (iii) to select the albumin X-ray structure which is complexed with the most similar ligand and (iv) to calculate complex geometry using molecular docking calculations. Our SVM model and the potential offered by the combined use of in silico calculation methods and experimental binding data is illustrated.

Contact: eszter.hazai@virtuadrug.com

Supplementary information:Supplementary data are available at Bioinformatics online.

/pdf/evaluation-of-drug-human-serum-albumin-binding-interactions-2rin5qqmaa.pdf

Evaluation of drug–human serum albumin binding interactions with support vector machine aided online automated docking

For the first time, an interaction between the non-toxic, cancer chemopreventive agent curcumin and both natural and synthetic DNA duplexes has been demonstrated by using circular dichroism (CD) and absorption spectroscopy techniques. Upon addition of curcumin to calf thymus DNA, poly(dG-dC)·poly(dG-dC) and poly(dA-dT)·poly(dA-dT) solutions, an intense positive induced CD band centered around 460–470 nm was observed depending on the actual pH and Na+ ion concentration of the medium; no CD signal was obtained, however, with single stranded poly(dC). Interaction of curcumin with calf thymus DNA was observed already at pH 6.5 in contrast with poly(dG-dC)·poly(dG-dC) which induces no extrinsic Cotton effect above a pH value of 5. The protonated, Hoogsteen base-paired structure of poly(dG-dC)·poly(dG-dC) is necessary for curcumin binding while the alternating AT-rich polymer formed complexes with curcumin only at certain Na+ concentrations. Evaluation of the spectral data and molecular modeling calculations suggested that curcumin, this dietary polyphenolic compound binds in the minor groove of the double helix. The mechanism of the induced CD activity, the effects of the pH and Na+ ions on the ligand binding and conformation of the double helix are discussed in detail. As well as being an essentially new phenolic minor groove binder agent curcumin is also a promising molecular probe to study biologically important, pH and cation induced conformational polymorphisms of nucleic acids.

Ferenc Zsila

Papers

Probing the binding of the flavonoid, quercetin to human serum albumin by circular dichroism, electronic absorption spectroscopy and molecular modelling methods.

Five unique compounds: xyloketals from mangrove fungus Xylaria sp. from the South China Sea coast.

Subdomain IB is the third major drug binding region of human serum albumin: toward the three-sites model.

Evaluation of drug–human serum albumin binding interactions with support vector machine aided online automated docking

Circular dichroism spectroscopic studies reveal pH dependent binding of curcumin in the minor groove of natural and synthetic nucleic acids