Biomedical research tools from the seabed

This review covers the applications of small-molecule and peptidic compounds isolated from marine organisms for biomedical research. Enzymes and proteins from marine sources are already on the market for biomedical applications, but the use of small-molecule biomedical research tools of marine origin is less developed. For many studies involving these molecules the ultimate goal is the application of small-molecule therapeutics in the clinic, but those that do not succeed in the clinic still have clearly defined biological activities, which may be of use as biomedical research tools. In other cases, the investigation of marine-derived compounds has led directly to the discovery of therapeutics with clinical applications. Both as tools and therapeutics, these small-molecule compounds are effective for investigating biological processes, and in this review the authors have chosen to concentrate on the ability of marine natural products to affect membrane processes, ion channels and intracellular processes.     

Lipid, sugar and liposaccharide based delivery systems 2

The vast majority of biologically active compounds will never be considered as potential drugs due to inherently poor bioavailability. This review discusses the progress in the development of chemical systems to improve the metabolic stability, absorption and physicochemical properties of potential drugs. Delivery systems that involve the conjugation of lipid and/or sugar moieties are highlighted, as well as novel methods of conjugation of these groups to drugs. The use of sugar molecules to target drugs to particular organs or cells is also discussed, as is the use of lipids in the growing area of gene delivery. This is an update of a previous review.     

Volatile Solvents as Drugs of Abuse: Focus on the Cortico-Mesolimbic Circuitry

Volatile solvents such as those found in fuels, paints, and thinners are found throughout the world and are used in a variety of industrial applications. However, these compounds are also often intentionally inhaled at high concentrations to produce intoxication. While solvent use has been recognized as a potential drug problem for many years, research on the sites and mechanisms of action of these compounds lags behind that of other drugs of abuse. In this review, we first discuss the epidemiology of voluntary solvent use throughout the world and then consider what is known about their basic pharmacology and how this may explain their use as drugs of abuse. We next present data from preclinical and clinical studies indicating that these substances induce common addiction sequelae such as dependence, withdrawal, and cognitive impairments. We describe how toluene, the most commonly studied psychoactive volatile solvent, alters synaptic transmission in key brain circuits such as the mesolimbic dopamine system and medial prefrontal cortex (mPFC) that are thought to underlie addiction pathology. Finally, we make the case that activity in mPFC circuits is a critical regulator of the mesolimbic dopamine system''s ability to respond to volatile solvents like toluene. Overall, this review provides evidence that volatile solvents have high abuse liability because of their selective effects on critical nodes of the addiction neurocircuitry, and underscores the need for more research into how these compounds induce adaptations in neural circuits that underlie addiction pathology.     

Complexes of gallium(III) and other metal ions and their potential in the treatment of neoplasia

The metal complexes of a variety of ligands show diverse pharmacological properties. The potential of these compounds as antineoplastic agents is underlined by the success of the clinically used platinum complex cisplatin (cis-[(NH(3))(2)PtCl(2)]). In the current review, specific examples of gallium, copper, ruthenium and titanium complexes are discussed with special relevance to their use in the treatment of cancer. Some of these complexes have demonstrated marked activity in a number of animal models and for some compounds, clinical trials are anticipated or have already begun. Collectively, the results in the literature indicate that the study of metal complexes as antineoplastic agents deserves continued intensive investigation.     

Exploring pharmacological significance of chalcone scaffold: a review

Chalcones (1,3-diaryl-2-propen-1-ones) and their heterocyclic analogues, belong to the flavonoid family, which possess a number of interesting biological properties such as antioxidant, cytotoxic, anticancer, antimicrobial, antiprotozoal, antiulcer, antihistaminic and anti-inflammatory activities. Several pure chalcones have been approved for clinical use or tested in humans. Clinical trials have shown that these compounds reached reasonable plasma concentration and are well-tolerated. For this reason they are an object of continuously growing interest amongst the scientists. However, much of the pharmacological potential of chalcones is still not utilized. The purpose of this review is to provide an overview of the pharmacological activity of naturally occurring and synthetic chalcones. This review highlights more recent pharmacological screening of these compounds, their mechanisms of action and relevant structure-activity relationships.     

Novel inhibitors of the early steps of the HIV-1 life cycle

Considerable advances have been made on compounds that are active as inhibitors of HIV entry and fusion. The discovery of chemokines a few years ago focused the attention on coreceptor inhibitors in addition to fusion and attachment blockers. During the last 5 years, there has been an intense research activity from both private companies and academic institutions to find effective compounds that are capable of inhibiting the initial steps in the HIV life cycle. Some of the presented compounds demonstrated in vitro synergism, thus there is the rationale of their combined use in HIV-infected individuals. Many entry and fusion inhibitors of HIV are being investigated in controlled clinical trials and there are a number of them that are bioavailable as oral formulations. This is an essential feature for an extended use of these compounds with the purpose of ameliorating patients' adherence to medications; therefore, preventing the development of drug resistance. Among the many compounds that are being investigated, some are in the preclinical arena and others are more advanced in development stages. Overall, the main aim is to establish the action of these compounds on the immune system (e.g., the balance of the system after shutting off CCR5 or CXCR4 coreceptors) and the possible burden of unexplained side effects. This review focuses on the recent developments in this field with a particular attention on promising compounds in preclinical and clinical trials.     

Novel inhibitors of the early steps of the HIV-1 life cycle

Considerable advances have been made on compounds that are active as inhibitors of HIV entry and fusion. The discovery of chemokines a few years ago focused the attention on coreceptor inhibitors in addition to fusion and attachment blockers. During the last 5 years, there has been an intense research activity from both private companies and academic institutions to find effective compounds that are capable of inhibiting the initial steps in the HIV life cycle. Some of the presented compounds demonstrated in vitro synergism, thus there is the rationale of their combined use in HIV-infected individuals. Many entry and fusion inhibitors of HIV are being investigated in controlled clinical trials and there are a number of them that are bioavailable as oral formulations. This is an essential feature for an extended use of these compounds with the purpose of ameliorating patients’ adherence to medications; therefore, preventing the development of drug resistance. Among the many compounds that are being investigated, some are in the preclinical arena and others are more advanced in development stages. Overall, the main aim is to establish the action of these compounds on the immune system (e.g., the balance of the system after shutting off CCR5 or CXCR4 coreceptors) and the possible burden of unexplained side effects. This review focuses on the recent developments in this field with a particular attention on promising compounds in preclinical and clinical trials.     

Entry and fusion inhibitors of HIV

Considerable advances have been made towards finding compounds that are active as inhibitors of the entry and fusion of HIV. The discovery of chemokines a few years ago focused the attention on coreceptor inhibitors, in addition to fusion and attachment blockers. During the past 5 years there has been intense research activity, both from private companies and academic institutions, in order to find effective compounds that are able to inhibit the initial steps in the HIV lifecycle. Some of the presented compounds demonstrated in vitro synergism, thus there is rationale for their combined use in HIV-infected individuals. Many entry and fusion inhibitors of HIV are currently under investigation in controlled clinical trials and a number of them are bioavailable as oral formulations. This is an essential feature for the extended use of these compounds with the purpose of ameliorating patients adherence to medications, thus preventing the development of drug resistance. The focus of this review will be on the most recent developments in this field, with particular attention focused on promising compounds in preclinical and clinical trials.     

Novel antitumor agents: marine sponge alkaloids, their synthetic analogs and derivatives

Present review describes research on novel natural antitumor agents isolated from marine sponges. More than 90 novel cytotoxic antitumor compounds and their synthetic analogs have shown confirmed activity in vitro tumor cell lines bioassay and are of current interest to NCI for further in vivo evaluation. A great problem, to use directly the reservoir of marine organisms for therapy is the very low availability and the isolation of only very small amounts of the biologically active substances from the natural materials. Thus, the synthetic chemistry is required to develop high yield synthetic methods, which are able to produce sufficient marine alkaloids for a broad biological screening. This review will present some of the aspects of the medicinal chemistry developed recently to introduce such modifications. The structures, origins, synthesis and biological activity of a selection of N-heterocyclic marine sponge alkaloids are reviewed. The emphasis is on compounds poised as potential anticancer drugs: pyrroles, pyrazines, imidazole, and other structural families. With computer program PASS some additional biological activities are also predicted, which point toward new possible applications of these compounds. This review emphasizes the role of marine sponge alkaloids as an important source of leads for drug discovery.     

Recent developments in the medicinal chemistry of single boron atom-containing compounds

Various boron-containing drugs have been approved for clinical use over the past two decades, and more are currently in clinical trials. The increasing interest in boron-containing compounds is due to their unique binding properties to biological targets; for example, boron substitution can be used to modulate biological activity, pharmacokinetic properties, and drug resistance. In this perspective, we aim to comprehensively review the current status of boron compounds in drug discovery, focusing especially on progress from 2015 to December 2020. We classify these compounds into groups showing anticancer, antibacterial, antiviral, antiparasitic and other activities, and discuss the biological targets associated with each activity, as well as potential future developments.     

Improvement of tumor localization of photosensitizers for photodynamic therapy and its application for tumor diagnosis

Photodynamic therapy (PDT) and photodynamic diagnosis of cancer are widely used in clinical fields. These are performed using photosensitizers. Many metalloporphyrin-related compounds have been developed as photosensitizers for use in PDT, and these tumor localization ability have been improved in recent research. Moreover, the precursor of porphyrin 5-aminolevulinic acid is used in fluorescence diagnosis using its tumor localization ability. In this review, these applications of photosensitizers in cancer therapy and diagnosis are summarized.     

Complexes of gallium(III) and other metal ions and their potential in the treatment of neoplasia

The metal complexes of a variety of ligands show diverse pharmacological properties. The potential of these compounds as antineoplastic agents is underlined by the success of the clinically used platinum complex cisplatin (₃)₂PtCl₂]). In the current review, specific examples of gallium, copper, ruthenium and titanium complexes are discussed with special relevance to their use in the treatment of cancer. Some of these complexes have demonstrated marked activity in a number of animal models and for some compounds, clinical trials are anticipated or have already begun. Collectively, the results in the literature indicate that the study of metal complexes as antineoplastic agents deserves continued intensive investigation.     

Toxins in anti-nociception and anti-inflammation.

The use of toxins as novel molecular probes to study the structure-function relationship of ion-channels and receptors as well as potential therapeutics in the treatment of wide variety of diseases is well documented. The high specificity and selectivity of these toxins have attracted a great deal of interest as candidates for drug development. This review highlights the involvement of the proteins and peptide toxins as well as non-proteinaceous compounds derived from both venomous and non-venomous animals, in anti-nociception and anti-inflammation. The possible mechanisms of these potential therapeutic agents and possible clinical applications in the treatment of pain and inflammation are also summarized.     

Depsipeptides from microorganisms: a new class of antimalarials

Depsipeptides are a large group of natural products produced by fungi, actinomycetes, cyanobacteria, higher plants and marine organisms. This family of compounds is known to exhibit a wide range of biological activities, and thanks to the progress of isolation techniques and the advances of methods for structure determination, the numbers of depsipeptides having both unique structures and attractive biological activities are increasing. Many of these compounds have shown a wide range of biological activities, and some are in clinical use or have entered human clinical trials as antibiotic or anticancer agents. However, only a handful of them have been evaluated for their antimalarial activity. This paper aims to review the recent advances in depsipeptides as potential antimalarial compounds.     

Metabolism of dietary polyphenols and possible interactions with drugs

Polyphenolic compounds are abundant in the human diet and gram quantities are ingested daily. The consumption of polyphenols is expected to rise due to the use of dietary supplements and public health initiatives promoting the consumption of more fruits and vegetables. It is known that these dietary polyphenols are extensively metabolized. Many of these compounds are therefore are expected to compete with other substrates of Phases I, II, III enzymes and transporters. In addition, some dietary polyphenols may induce certain drug metabolizing enzymes and affect the metabolism of important therapeutic agents. This review will discuss 1) the metabolism of dietary polyphenols using green tea polyphenols (catechins) as an example, 2) inhibition of drug metabolism by polyphenols, and 3) induction of drug metabolizing enzymes by dietary polyphenols. The potential consequences of these effects on drug metabolism will also be discussed.     

Potential and cytotoxicity of cis-platinum complex with anti-tumor activity in combination therapy

The use of anticancer agents forms an important part for treatment of cancer of various types. Complexes with cis-platinum compounds have been used for the prevention and treatment of cancers. Quite a number of these metal-containing complexes have been isolated, chemically prepared and characterized for the treatment of cancer. Many of these compounds display potent cytotoxic effects, although there is a considerable progress made in the design of novel anticancer agents. Some of these compounds showed strong inhibitory effects on cancer growth with a potential to become anti-cancer drugs. However, the unwanted deleterious effects hamper the common use of these agents as anticancer drugs. Nevertheless, the use of protective agents during, before or after treatment with anti-cancer agents in combination therapy has proven effective in the treatment. The results prompt the study of the biologic activities and the design of better modality for treatment and prevention of cancer. Here, we review the potential and reduction of cytotoxic properties of the prominent member of this class of metal compounds for the treatment of cancer.     

Computational strategies for metabolite identification in metabolomics

Most metabolomic data are characterized by complex spectra or chromatograms containing hundreds of peaks or features. While there are many methods for aligning or comparing these spectral features, there are few approaches for actually identifying which peaks match to which compounds. Indeed, one of the biggest unmet needs in the field of metabolomics lies in the problem of compound identification. This review describes some of the newly emerging computational strategies in metabolomics that are being used to aid in the identification of metabolites from biofluid mixtures analyzed by NMR and MS. The most successful compound-identification strategies typically involve matching spectral features of the unknown compound(s) to curated spectral databases of reference compounds. This approach is known as the identification of 'known unknowns'. However, the identification of truly novel compounds (the 'unknown unknowns') is particularly challenging and requires the use of computer-aided structure elucidation methods being applied to the purified compound. The strengths and limitations of these approaches as applied to different analytical technologies (GC-MS, LC-MS and NMR) will be discussed, as will prospects for potential improvements to existing strategies.     

The use of fluorescent probes in pharmaceutical analysis

Even though many pharmaceuticals show native fluorescence, there is also an important group of compounds which is not fluorescent. A main object of studies is to make them fluorescent, principally by using fluorescent probes through derivatisation reactions. An account of the fluorescent probes more widely used for the determination of drugs and related compounds is presented in this review paper. A wide variety of fluorescent probes is described on the basis of their ability to react specifically with various functional groups. Attention is focused on derivatisation reactions used in spectrofluorimetry and chromatographic techniques (HPLC, TLC) with fluorimetric detection. The review covers only those fluorescent probes whose use involves a chemical reaction with the analyte, and not those methods that involve physico-chemical interactions such as sensitised or charge transfer processes.

Many of these derivatisation reactions have been widely used in the detection of primary and secondary amines. Reagents such as dansyl chloride, fluorescamine, o-phtalaldehyde are very well known. Other reagents have also been developed for other functional groups, for example dansyl hydrazine for compounds with a carbonyl function or 4-bromomethyl-7-methoxy-coumarin for acidic compounds . Acid chlorides such as dansyl chloride may also react with different functional groups carrying active hydrogens as do phenols.

The use and development of new fluorescent probes in pharmaceutical analysis is a subject for further studies.     

The use of automated sequencing techniques to investigate the sequence selectivity of DNA-damaging agents

In this review, the use of automated DNA sequencing techniques to determine the sequence specificity of compounds that interact with DNA is discussed. The sequence specificity of a DNA-damaging agent is an essential element in determining the cellular mechanism of action of a drug. A number of DNA-damaging compounds are mutagenic, carcinogenic, as well as being widely used as cancer chemotherapeutic agents. The distribution of lesions in a sequence of DNA can give vital clues in the determination of the precise mechanism of interaction of the agent with DNA. The DNA sequence specificity of a number of DNA-damaging agents has been delineated using automated DNA sequencing technology, and these studies are discussed in this review. The current state-of-the-art methodology involves capillary electrophoresis with laser-induced fluorescence detection usually on an Applied Biosystems ABI 3730 capillary sequencer. This current technique has higher resolution, greater sensitivity, higher precision, more rapid separation times, is safer and easier to perform than previous methods. The two main methods to determine the DNA sequence selectivity of compounds that interact with DNA are described: end labelling and the polymerase stop assay. The interaction of the antitumour drug, bleomycin, with DNA is utilized to illustrate the recent technological advances.     

Natural products of dietary origin as lead compounds in virtual screening and drug design

Natural products have been found to be useful in the treatment of several diseases across the ages. In this article, we review the use of natural products, obtained from dietary sources, as lead compounds in developing novel therapeutic agents. These compounds have shown tremendous promise in the prevention and as well as treatment of a variety of chronic ailments. In addition, to being patentable and biocompatible, these compounds are a rich source of novel scaffolds to invigorate the pipelines of the pharmaceutical industry. In this communication, we also focus on studies which show how natural products have proved useful as lead compounds in virtual screening and structure-based drug design programs. Natural dietary constituents, such as resveratrol, curcumin and caffeine as well as other compounds, are discussed to illustrate this approach.