RESUMO
This review focuses on the rare group of carbon-bridged steroids (CBS) and triterpenoids found in various natural sources such as green, yellow-green, and red algae, marine sponges, soft corals, ascidians, starfish, and other marine invertebrates. In addition, this group of rare lipids is found in amoebas, fungi, fungal endophytes, and plants. For convenience, the presented CBS and triterpenoids are divided into four groups, which include: (a) CBS and triterpenoids containing a cyclopropane group; (b) CBS and triterpenoids with cyclopropane ring in the side chain; (c) CBS and triterpenoids containing a cyclobutane group; (d) CBS and triterpenoids containing cyclopentane, cyclohexane or cycloheptane moieties. For the comparative characterization of the antitumor profile, we have added several semi- and synthetic CBS and triterpenoids, with various additional rings, to identify possible promising sources for pharmacologists and the pharmaceutical industry. About 300 CBS and triterpenoids are presented in this review, which demonstrate a wide range of biological activities, but the most pronounced antitumor profile. The review summarizes biological activities both determined experimentally and estimated using the well-known PASS software. According to the data obtained, two-thirds of CBS and triterpenoids show moderate activity levels with a confidence level of 70 to 90%; however, one third of these lipids demonstrate strong antitumor activity with a confidence level exceeding 90%. Several CBS and triterpenoids, from different lipid groups, demonstrate selective action on different types of tumor cells such as renal cancer, sarcoma, pancreatic cancer, prostate cancer, lymphocytic leukemia, myeloid leukemia, liver cancer, and genitourinary cancer with varying degrees of confidence. In addition, the review presents graphical images of the antitumor profile of both individual CBS and triterpenoids groups and individual compounds.
Assuntos
Antineoplásicos/farmacologia , Produtos Biológicos/farmacologia , Carcinogênese/efeitos dos fármacos , Esteroides/farmacologia , Triterpenos/farmacologia , Animais , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Organismos Aquáticos/química , Produtos Biológicos/química , Carbono/química , Proliferação de Células/efeitos dos fármacos , Clorófitas/química , Cicloparafinas/química , Cicloparafinas/farmacologia , Fungos/química , Humanos , Invertebrados/química , Metabolismo dos Lipídeos/efeitos dos fármacos , Rodófitas/química , Esteroides/química , Triterpenos/químicaRESUMO
The review focuses on sulfated steroids that have been isolated from seaweeds, marine sponges, soft corals, ascidians, starfish, and other marine invertebrates. Sulfur-containing steroids and triterpenoids are sourced from sedentary marine coelenterates, plants, marine sediments, crude oil, and other geological deposits. The review presents the pharmacological profile of sulfated steroids, sulfur-containing steroids, and triterpenoids, which is based on data obtained using the PASS program. In addition, several semi-synthetic and synthetic epithio steroids, which represent a rare group of bioactive lipids that have not yet been found in nature, but possess a high level of antitumor activity, were included in this review for the comparative pharmacological characterization of this class of compounds. About 140 steroids and triterpenoids are presented in this review, which demonstrate a wide range of biological activities. Therefore, out of 71 sulfated steroids, thirteen show strong antitumor activity with a confidence level of more than 90%, out of 50 sulfur-containing steroids, only four show strong antitumor activity with a confidence level of more than 93%, and out of eighteen epithio steroids, thirteen steroids show strong antitumor activity with a confidence level of 91% to 97.4%.
Assuntos
Antineoplásicos/farmacologia , Organismos Aquáticos/metabolismo , Esteroides/farmacologia , Compostos de Enxofre/farmacologia , Animais , Antineoplásicos/isolamento & purificação , Humanos , Estrutura Molecular , Esteroides/isolamento & purificação , Relação Estrutura-Atividade , Compostos de Enxofre/isolamento & purificaçãoRESUMO
Polycyclic endoperoxides are rare natural metabolites found and isolated in plants, fungi, and marine invertebrates. The purpose of this review is a comparative analysis of the pharmacological potential of these natural products. According to PASS (Prediction of Activity Spectra for Substances) estimates, they are more likely to exhibit antiprotozoal and antitumor properties. Some of them are now widely used in clinical medicine. All polycyclic endoperoxides presented in this article demonstrate antiprotozoal activity and can be divided into three groups. The third group includes endoperoxides, which show weak antiprotozoal activity with a reliability of up to 70%, and this group includes only 1.1% of metabolites. The second group includes the largest number of endoperoxides, which are 65% and show average antiprotozoal activity with a confidence level of 70 to 90%. Lastly, the third group includes endoperoxides, which are 33.9% and show strong antiprotozoal activity with a confidence level of 90 to 99.6%. Interestingly, artemisinin and its analogs show strong antiprotozoal activity with 79 to 99.6% confidence against obligate intracellular parasites which belong to the genera Plasmodium, Toxoplasma, Leishmania, and Coccidia. In addition to antiprotozoal activities, polycyclic endoperoxides show antitumor activity in the proportion: 4.6% show weak activity with a reliability of up to 70%, 65.6% show an average activity with a reliability of 70 to 90%, and 29.8% show strong activity with a reliability of 90 to 98.3%. It should also be noted that some polycyclic endoperoxides, in addition to antiprotozoal and antitumor properties, show other strong activities with a confidence level of 90 to 97%. These include antifungal activity against the genera Aspergillus, Candida, and Cryptococcus, as well as anti-inflammatory activity. This review provides insights on further utilization of polycyclic endoperoxides by medicinal chemists, pharmacologists, and the pharmaceutical industry.
Assuntos
Antineoplásicos/farmacologia , Antiprotozoários/farmacologia , Produtos Biológicos/farmacologia , Peróxidos/farmacologia , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Antifúngicos/química , Antifúngicos/farmacologia , Antineoplásicos/química , Antiprotozoários/química , Produtos Biológicos/química , Humanos , Peróxidos/químicaRESUMO
The review is devoted to the chemical diversity of steroids produced by soft corals and their determined and potential activities. There are about 200 steroids that belong to different types of steroids such as secosteroids, spirosteroids, epoxy- and peroxy-steroids, steroid glycosides, halogenated steroids, polyoxygenated steroids and steroids containing sulfur or nitrogen heteroatoms. Of greatest interest is the pharmacological activity of these steroids. More than 40 steroids exhibit antitumor and related activity with a confidence level of over 90 percent. A group of 32 steroids shows anti-hypercholesterolemic activity with over 90 percent confidence. Ten steroids exhibit anti-inflammatory activity and 20 steroids can be classified as respiratory analeptic drugs. Several steroids exhibit rather rare and very specific activities. Steroids exhibit anti-osteoporotic properties and can be used to treat osteoporosis, as well as have strong anti-eczemic and anti-psoriatic properties and antispasmodic properties. Thus, this review is probably the first and exclusive to present the known as well as the potential pharmacological activities of 200 marine steroids.
Assuntos
Antozoários/química , Esteroides/química , Esteroides/farmacologia , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Humanos , SecoesteroidesRESUMO
This review is dedicated to the comparative analysis of structure-activity relationships for more than 75 natural and synthetic derivatives of adamantane. Some of these compounds, such as amantadine and memantine, are currently used to treat dementia, Alzheimer's and Parkinson's diseases and other neurodegenerative diseases. The data presented show that the pharmacological potential of 1-fluoro- and 1-phosphonic acid adamantane derivatives against Alzheimer's and Parkinson's diseases and other neurodegenerative diseases exceeds those of well-known amantadine and memantine. The information presented in this review highlights the promising directions of studies for biochemists, pharmacologists, medicinal chemists, physiologists, and neurologists, as well as to the pharmaceutical industry.
Assuntos
Adamantano/uso terapêutico , Doenças Neurodegenerativas/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Adamantano/química , Adamantano/farmacologia , Animais , Halogênios/química , Halogênios/farmacologia , Halogênios/uso terapêutico , Humanos , Fármacos Neuroprotetores/farmacologiaRESUMO
Dementia is a major cause of disability and dependency among older people. If the lives of people with dementia are to be improved, research and its translation into druggable target are crucial. Ancient systems of healthcare (Ayurveda, Siddha, Unani and Sowa-Rigpa) have been used from centuries for the treatment vascular diseases and dementia. This traditional knowledge can be transformed into novel targets through robust interplay of network pharmacology (NetP) with reverse pharmacology (RevP), without ignoring cutting edge biomedical data. This work demonstrates interaction between recent and traditional data, and aimed at selection of most promising targets for guiding wet lab validations. PROTEOME, DisGeNE, DISEASES and DrugBank databases were used for selection of genes associated with pathogenesis and treatment of vascular dementia (VaD). The selection of new potential drug targets was made by methods of NetP (DIAMOnD algorithm, enrichment analysis of KEGG pathways and biological processes of Gene Ontology) and manual expert analysis. The structures of 1976 phytomolecules from the 573 Indian medicinal plants traditionally used for the treatment of dementia and vascular diseases were used for computational estimation of their interactions with new predicted VaD-related drug targets by RevP approach based on PASS (Prediction of Activity Spectra for Substances) software. We found 147 known genes associated with vascular dementia based on the analysis of the databases with gene-disease associations. Six hundred novel targets were selected by NetP methods based on 147 gene associations. The analysis of the predicted interactions between 1976 phytomolecules and 600 NetP predicted targets leaded to the selection of 10 potential drug targets for the treatment of VaD. The translational value of these targets is discussed herewith. Twenty four drugs interacting with 10 selected targets were identified from DrugBank. These drugs have not been yet studied for the treatment of VaD and may be investigated in this field for their repositioning. The relation between inhibition of two selected targets (GSK-3, PTP1B) and the treatment of VaD was confirmed by the experimental studies on animals and reported separately in our recent publications.
Assuntos
Demência Vascular/tratamento farmacológico , Avaliação Pré-Clínica de Medicamentos/métodos , Terapia de Alvo Molecular , Bases de Dados Factuais , Farmacologia , Interface Usuário-ComputadorRESUMO
Diepoxy-containing compounds are widely distributed in nature. These metabolites are found in plants and marine organisms and are also produced by many microorganisms, fungi, or fungal endophytes. Many of these metabolites are antibiotics and exhibit a wide variety of biological activities. More than 80 α,ß-diepoxy-containing compounds are presented in this article, which belong to different classes of chemical compounds including lipids, terpenoids, alkaloids, quinones, hydroquinones, and pyrones. The main activities that characterize α,ß-diepoxy-containing compounds are antineoplastic with confidence up to 99%, antifungal with confidence up to 94%, antiinflammatory with confidence up to 92%, or antibacterial with confidence up to 78%. In addition, these metabolites can be used as a lipid metabolism regulator with a certainty of up to 81%, antiviral (Arbovirus) activity with a certainty of up to 71%, or antiallergic activity with confidence up to 69%. These data on the biological activity of diepoxy-containing compounds are of considerable interest to pharmacologists, chemists, and medical professionals who are involved in phytomedicine and related areas of science and industry.
Assuntos
Produtos Biológicos/farmacologia , Compostos de Epóxi/farmacologia , Animais , Antialérgicos/química , Antialérgicos/farmacologia , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Produtos Biológicos/química , Compostos de Epóxi/química , Fungos/química , Insetos/química , Plantas/química , Plantas/microbiologiaRESUMO
Hydroperoxides (R-OOH) represent a small family of natural metabolites that have been isolated from higher plants, fungi, and marine organisms. This paper is devoted to the distribution of hydroperoxides in plants, fungi and terrestrial fungal endophytes and their biological activity. Hydroperoxides of plants demonstrate a wide range of biological activities however, antineoplastic and anti-ulcerative are most characteristic with confidence from 91 to 98 percent. For hydroperoxides from fungi, the dominant are antineoplastic and anti-hypercholesterolemic activities with confidence from 89 to 92 percent. Very interesting activity was found for some triterpenoid hydroperoxides, which is characterized as a treatment for the symptoms of dementia. The norlupane hydroperoxide shows activity for the treatment of dementia. It is interesting that the reliability of this activity was very high 97.2%. According to our preliminary data, the norlupane hydroperoxide is apparently the first natural metabolite that showed almost 100 percent activity for the treatment of dementia. However, to confirm these data requires practical and clinical experimental work.
Assuntos
Produtos Biológicos/química , Fungos/química , Peróxido de Hidrogênio/química , Plantas/química , Esteroides/química , Animais , Produtos Biológicos/farmacologia , Descoberta de Drogas , Humanos , Peróxido de Hidrogênio/farmacologia , Esteroides/farmacologiaRESUMO
Cyclobutanes containing one oxygen atom in a molecule are called oxetane-containing compounds (OCC). More than 600 different OCC are found in nature; they are produced by microorganisms, and also found in marine invertebrates and algae. The greatest number of them is found in plants belonging to the genus Taxus. Oxetanes are high-energy oxygen-containing non-aromatic heterocycles that are of great interest as new potential pharmacophores with a significant spectrum of biological activities. The biological activity of OCC that is produced by bacteria and Actinomycetes demonstrates antineoplastic, antiviral (arbovirus), and antifungal activity with confidence an angiogenesis stimulator, respiratory analeptic, and antiallergic activity dominate with confidence from 81 to 99%.
Assuntos
Produtos Biológicos/química , Éteres Cíclicos/química , Antifúngicos/isolamento & purificação , Antivirais/isolamento & purificação , Organismos Aquáticos/química , Bactérias/química , Produtos Biológicos/isolamento & purificação , Cianobactérias/química , Redes e Vias Metabólicas , Plantas/químicaRESUMO
Hydroperoxides are a small and interesting group of biologically active natural marine compounds. All these metabolites contain a group (R-O-O-H). In this mini-review, studies of more than 80 hydroperoxides isolated from bacteria, fungi, algae, and marine invertebrates are described. Hydroperoxides from the red, brown, and green algae exhibit high antineoplastic, anti-inflammatory, and antiprotozoal activity with a confidence of 73 to 94%. Hydroperoxides produced by soft corals showed antineoplastic and antiprotozoal activity with confidence from 81 to 92%. Metabolites derived from sea sponges, mollusks, and other invertebrates showed antineoplastic and antiprotozoal (Plasmodium) activity with confidence from 80 to 90%.
Assuntos
Anti-Infecciosos Locais/isolamento & purificação , Anti-Inflamatórios/isolamento & purificação , Antineoplásicos/isolamento & purificação , Organismos Aquáticos/química , Produtos Biológicos/isolamento & purificação , Peróxido de Hidrogênio/isolamento & purificação , Peróxido de Hidrogênio/farmacologia , Animais , Anti-Infecciosos Locais/farmacologia , Anti-Inflamatórios/farmacologia , Antineoplásicos/farmacologia , Bactérias/química , Produtos Biológicos/farmacologia , Fungos/química , Invertebrados/química , Microalgas/químicaRESUMO
This mini review is devoted to highly oxygenated isoprenoid lipids (HOIL) that are produced by fungi and fungal endophytes from various ecological niches, both terrestrial and aquatic. Steroids were distributed as from edible cultivated fungi, as well as fungi collected in forests. Fungal endophytes were generally isolated from plants and cultured to obtain sufficient biomass. Marine fungi were obtained from marine brown and red algae and marine invertebrates such as sponges, corals, worms, crustacea or from marine sediments. HOIL isolated from the terrestrial ecosystem have the pharmacological potential on anti-hypercholesterolemic, anti-neoplastic, anti-eczematic and anti-inflammatory activity estimated with a confidence of 84-90%. HOIL that produced by marine fungal species are predicted as having anti-inflammatory and anti-hypercholesterolemic activity with a confidence of 82-91%. In addition, they may have potential acetylcholinesterase and cell adhesion molecule inhibitors estimated with a confidence of 86-88%.
Assuntos
Endófitos/metabolismo , Fungos/metabolismo , Metabolismo dos Lipídeos , Oxigênio/metabolismo , Terpenos/metabolismo , Terpenos/farmacologiaRESUMO
Steroid phosphate esters are very rare natural lipids that have been comparatively recently isolated from fractions of polar lipids of marine sponges and starfish. These steroids exhibit interesting biological activities. When using the PASS computer program, we showed that many of steroid phosphate esters showed antifungal, antihypercholesterolemic, anesthetic, and other activities with a confidence of 73 to 93%. In addition, some of them can be used as inhibitors of cholesterol synthesis and show hepatoprotection properties. Phosphonosteroids demonstrate antineoplastic and antihypercholesterolemic activities with a certainty of 85 to 90%. And also, they can be used as ovulation inhibitors or female steroid contraceptives with confidence from 86 to 98%.
Assuntos
Organofosfonatos/metabolismo , Fosfatos/metabolismo , Esteroides/metabolismo , Animais , Anticolesterolemiantes/farmacologia , Antifúngicos/farmacologia , Antineoplásicos/farmacologia , Ésteres , Poríferos/metabolismo , Estrelas-do-Mar/metabolismoRESUMO
Peroxides represent a large and interesting group of biologically active natural compounds. All these metabolites contain a peroxide group (R-O-O-R). This review describes studies of more than 60 peroxides isolated from plants and fungi. Most of the plant peroxy steroids exhibit high antiprotozoal (Plasmodium) activity with a confidence of up to 95%, while steroids harvested from fungi show more antineoplastic activity with a confidence of up to 94%. In addition, more than 20 different activities of both groups of peroxides with a probability of 78 to 90% have also been predicted using computer program PASS.
Assuntos
Produtos Biológicos/isolamento & purificação , Produtos Biológicos/farmacologia , Fungos/química , Peróxidos/isolamento & purificação , Peróxidos/farmacologia , Plantas/química , Esteroides/isolamento & purificação , Esteroides/farmacologia , Antimaláricos/isolamento & purificação , Antimaláricos/farmacologia , Plasmodium/efeitos dos fármacosRESUMO
The present review describes the distribution and biological activities of natural mono-, di-, and triaromatic steroids. It is shown that the producers of aromatic steroids are microorganisms, fungi, and marine invertebrates, and also they were found in plants, animals, marine sediments, and karst deposits. Eighty biologically active aromatic steroids likely have an anti-tumor, anti-inflammatory, and neuroprotection activity with a confidence of 78 to 92%. The structures and predicted biological activities of aromatic steroids are available. This review emphasizes the role of aromatic steroids as an important source and potential leads for drug discovery and they are of great interest to chemists, physicians, biologists, pharmacologists, and the pharmaceutical industry.
Assuntos
Descoberta de Drogas , Esteroides/metabolismo , AnimaisRESUMO
In silico methods of phenotypic screening are necessary to reduce the time and cost of the experimental in vivo screening of anticancer agents through dozens of millions of natural and synthetic chemical compounds. We used the previously developed PASS (Prediction of Activity Spectra for Substances) algorithm to create and validate the classification SAR models for predicting the cytotoxicity of chemicals against different types of human cell lines using ChEMBL experimental data. A training set from 59,882 structures of compounds was created based on the experimental data (IG50, IC50, and % inhibition values) from ChEMBL. The average accuracy of prediction (AUC) calculated by leave-one-out and a 20-fold cross-validation procedure during the training was 0.930 and 0.927 for 278 cancer cell lines, respectively, and 0.948 and 0.947 for cytotoxicity prediction for 27 normal cell lines, respectively. Using the given SAR models, we developed a freely available web-service for cell-line cytotoxicity profile prediction (CLC-Pred: Cell-Line Cytotoxicity Predictor) based on the following structural formula: http://way2drug.com/Cell-line/.
Assuntos
Antineoplásicos/farmacologia , Antineoplásicos/toxicidade , Simulação por Computador , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Internet , Antineoplásicos/química , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular , Linhagem Celular Tumoral , Reposicionamento de Medicamentos , Ensaios de Seleção de Medicamentos Antitumorais/estatística & dados numéricos , Feminino , Humanos , Relação Estrutura-AtividadeRESUMO
This paper describes research on natural azo compounds isolated from fungi, plant, bacteria, and invertebrates. More than 120 biologically active diazene containing alkaloids demonstrate confirmed pharmacological activity, including antitumor, antimicrobial, and antibacterial effects. The structures, origin, and biological activities of azo compounds are reviewed. Utilizing the computer program PASS, some structure-activity relationship new activities are also predicted, pointing toward possible new applications of these compounds. This article emphasizes the role of natural azo compounds as an important source of drug prototypes and leads for drug discovery.
RESUMO
The present review describes research on novel natural isoquinoline alkaloids and their N-oxides isolated from different plant species. More than 200 biological active compounds have shown confirmed antimicrobial, antibacterial, antitumor, and other activities. The structures, origins, and reported biological activities of a selection of isoquinoline N-oxides alkaloids are reviewed. With the computer program PASS some additional SAR (structure-activity relationship) activities are also predicted, which point toward new possible applications of these compounds. This review emphasizes the role of isoquinoline N-oxides alkaloids as an important source of leads for drug discovery.
Assuntos
Alcaloides/química , Isoquinolinas/química , Alcaloides/farmacologia , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Descoberta de Drogas , Isoquinolinas/farmacologia , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
In silico approaches have been widely recognised to be useful for drug discovery. Here, we consider the significance of available databases of medicinal plants and chemo- and bioinformatics tools for in silico drug discovery beyond the traditional use of folk medicines. This review contains a practical example of the application of combined chemo- and bioinformatics methods to study pleiotropic therapeutic effects (known and novel) of 50 medicinal plants from Traditional Indian Medicine.
Assuntos
Descoberta de Drogas , Medicina Tradicional , Plantas Medicinais/química , Biologia Computacional , Bases de Dados Factuais , Estrutura MolecularRESUMO
Present review describes research on novel natural anticancer agents isolated from terrestrial and marine sources. More than 120 cytotoxic anticancer compounds have shown confirmed activity in vitro tumor cell lines bioassay and are of current interest to Natural Cancer Institute for further in vivo evaluation. Intensive searches for new classes of pharmacologically potent agents produced by terrestrial and marine organisms have resulted in the discovery of dozens of compounds possessing high cytotoxic activities. However, only a limited number of them have been tested in pre-clinical and clinical trials. One of the reasons is a limited supply of the active ingredients from the natural sources. However, the pre-clinical and clinical development of many terrestrial and/or marine-derived natural products into pharmaceuticals is often hampered by a limited supply from the natural source. Total synthesis is of vital importance in these situations, allowing for the production of useful quantities of the target compound for further biological evaluation. 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 terrestrial and marine peroxides as an important source of leads for drug discovery.
Assuntos
Antineoplásicos/farmacologia , Produtos Biológicos/farmacologia , Peróxidos/farmacologia , Animais , Antineoplásicos/química , Produtos Biológicos/química , Ácidos Graxos/química , Ácidos Graxos/farmacologia , Humanos , Peróxidos/química , Esteroides/química , Esteroides/farmacologia , Terpenos/química , Terpenos/farmacologiaRESUMO
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.