The Chemical Space of Marine Antibacterials: Diphenyl Ethers, Benzophenones, Xanthones, and Anthraquinones.

The emergence of multiresistant bacteria and the shortage of antibacterials in the drug pipeline creates the need to search for novel agents. Evolution drives the optimization of the structure of marine natural products to act as antibacterial agents. Polyketides are a vast and structurally diverse family of compounds that have been isolated from different marine microorganisms. Within the different polyketides, benzophenones, diphenyl ethers, anthraquinones, and xanthones have shown promising antibacterial activity. In this work, a dataset of 246 marine polyketides has been identified. In order to characterize the chemical space occupied by these marine polyketides, molecular descriptors and fingerprints were calculated. Molecular descriptors were analyzed according to the scaffold, and principal component analysis was performed to identify the relationships among the different descriptors. Generally, the identified marine polyketides are unsaturated, water-insoluble compounds. Among the different polyketides, diphenyl ethers tend to be more lipophilic and non-polar than the remaining classes. Molecular fingerprints were used to group the polyketides according to their molecular similarity into clusters. A total of 76 clusters were obtained, with a loose threshold for the Butina clustering algorithm, highlighting the large structural diversity of the marine polyketides. The large structural diversity was also evidenced by the visualization trees map assembled using the tree map (TMAP) unsupervised machine-learning method. The available antibacterial activity data were examined in terms of bacterial strains, and the activity data were used to rank the compounds according to their antibacterial potential. This potential ranking was used to identify the most promising compounds (four compounds) which can inspire the development of new structural analogs with better potency and absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties.

Bioactive Marine Xanthones: A Review.

The marine environment is an important source of specialized metabolites with valuable biological activities. Xanthones are a relevant chemical class of specialized metabolites found in this environment due to their structural variety and their biological activities. In this work, a comprehensive literature review of marine xanthones reported up to now was performed. A large number of bioactive xanthone derivatives (169) were identified, and their structures, biological activities, and natural sources were described. To characterize the chemical space occupied by marine-derived xanthones, molecular descriptors were calculated. For the analysis of the molecular descriptors, the xanthone derivatives were grouped into five structural categories (simple, prenylated, O-heterocyclic, complex, and hydroxanthones) and six biological activities (antitumor, antibacterial, antidiabetic, antifungal, antiviral, and miscellaneous). Moreover, the natural product-likeness and the drug-likeness of marine xanthones were also assessed. Marine xanthone derivatives are rewarding bioactive compounds and constitute a promising starting point for the design of other novel bioactive molecules.

A Pyranoxanthone as a Potent Antimitotic and Sensitizer of Cancer Cells to Low Doses of Paclitaxel.

Microtubule-targeting agents (MTAs) remain a gold standard for the treatment of several cancer types. By interfering with microtubules dynamic, MTAs induce a mitotic arrest followed by cell death. This antimitotic activity of MTAs is dependent on the spindle assembly checkpoint (SAC), which monitors the integrity of the mitotic spindle and proper chromosome attachments to microtubules in order to ensure accurate chromosome segregation and timely anaphase onset. However, the cytotoxic activity of MTAs is restrained by drug resistance and/or toxicities, and had motivated the search for new compounds and/or alternative therapeutic strategies. Here, we describe the synthesis and mechanism of action of the xanthone derivative pyranoxanthone 2 that exhibits a potent anti-growth activity against cancer cells. We found that cancer cells treated with the pyranoxanthone 2 exhibited persistent defects in chromosome congression during mitosis that were not corrected over time, which induced a prolonged SAC-dependent mitotic arrest followed by massive apoptosis. Importantly, pyranoxanthone 2 was able to potentiate apoptosis of cancer cells treated with nanomolar concentrations of paclitaxel. Our data identified the potential of the pyranoxanthone 2 as a new potent antimitotic with promising antitumor potential, either alone or in combination regimens.

Yicathins B and C and Analogues: Total Synthesis, Lipophilicity and Biological Activities.

Natural products have always been an important source of new hits and leads in drug discovery, with the marine environment being regarded as a significant source of novel and exquisite bioactive compounds. Yicathins B and C are two marine-derived xanthones that have shown antibacterial and antifungal activity. Herein, the total synthesis of these yicathins and six novel analogues is reported for the first time. As marine natural products tend to have very lipophilic scaffolds, the lipophilicity of yicathins and their analogues was evaluated in the classical octanol/water system and a biomimetic model-based system. As the xanthonic nucleus is a "privileged structure", other biological activities were evaluated, namely antitumor and anti-inflammatory activities. An interesting anti-inflammatory activity was identified for yicathin analogues that paves the way for the design of dual activity (anti-infective and anti-inflammatory) marine-inspired xanthone derivatives.

Structures, Activities and Drug-Likeness of Anti-Infective Xanthone Derivatives Isolated from the Marine Environment: A Review.

Marine organisms represent almost half of total biodiversity and are a very important source of new bioactive substances. Within the varied biological activities found in marine products, their antimicrobial activity is one of the most relevant. Infectious diseases are responsible for high levels of morbidity and mortality and many antimicrobials lose their effectiveness with time due to the development of resistance. These facts justify the high importance of finding new, effective and safe anti-infective agents. Among the variety of biological activities of marine xanthone derivatives, one that must be highlighted is their anti-infective properties. In this work, a literature review of marine xanthones with anti-infective activity, namely antibacterial, antifungal, antiparasitic and antiviral, is presented. Their structures, biological activity, sources and the methods used for bioactivity evaluation are described. The xanthone derivatives are grouped in three sets: xanthones, hydroxanthones and glycosylated derivatives. Moreover, molecular descriptors, biophysico-chemical properties, and pharmacokinetic parameters were calculated, and the chemical space occupied by marine xanthone derivatives is recognized. The chemical space was compared with marketed drugs and framed accordingly to the drug-likeness concept in order to profile the pharmacokinetic of anti-infective marine xanthone derivatives.

Accessing lipophilicity of drugs with biomimetic models: A comparative study using liposomes and micelles.

Lipophilicity is a physicochemical property of crucial importance in drug discovery and drug design. Biomimetic models, such as liposomes and micelles, constitute a valuable tool for the assessment of lipophilicity through the determination of partition coefficients (log Kp). However, the lack of standardization hampers the judgment about which model or method has the best and broadest passive drug permeation predictive capacity. This work provides a comparative analysis between the methodologies based on biomimetic models to determine the partition coefficient (log Kp). For that purpose, a set of reference substances preconized by the Organization for Economic Cooperation and Development (OECD) guidelines was used. The biomimetic models employed were liposomes and micelles composed by 1,2-dimyristoyl-sn-glycero-3-phosphorylcholine (DMPC) and hexadecylphosphocholine (HePC), respectively. Both lipids were used as representative phospholipids of natural membranes. The partition coefficients between biomimetic models and aqueous phases were determined by derivative spectroscopy at physiological conditions (37 °C and pH 7.4). The partition coefficients obtained using biomimetic models are quite different and more reliable than the ones obtained using an octanol/water system. Comparing the performance of the two biomimetic models, micelles revealed to be suitable only for substances with high molar absorption coefficient and log Kp > 3, but in general liposomes are the best model for accessing lipophilicity of drugs. Furthermore, a comparison between experimental data and the partition coefficients determined by the computational method COSMOmic is also provided and discussed. As a final summarizing result, a decision tree is provided in order to guide the selection of a tool for assessing the lipophilicity of drugs.