Evidence for natural products as alternative wound-healing therapies

Chronic, non-healing wounds represent a significant area of unmet medical need and are a growing problem for healthcare systems around the world. They affect the quality of life for patients and are an economic burden, being difficult and time consuming to treat. They are an escalating problem across the developed world due to the increasing incidence of diabetes and the higher prevalence of ageing populations. Effective treatment options are currently lacking, and in some cases chronic wounds can persist for years. Some traditional medicines are believed to contain bioactive small molecules that induce the healing of chronic wounds by reducing excessive inflammation, thereby allowing re-epithelisation to occur. Furthermore, many small molecules found in plants are known to have antibacterial properties and, although they lack the therapeutic selectivity of antibiotics, they are certainly capable of acting as topical antiseptics when applied to infected wounds. As these molecules act through mechanisms of action distinct from those of clinically used antibiotics, they are often active against antibiotic resistant bacteria. Although there are numerous studies highlighting the effects of naturally occurring small molecules in wound-healing assays in vitro, only evidence from well conducted clinical trials can allow these molecules or the remedies that contain them to progress to the clinic. With this in mind, we review wound-healing natural remedies that have entered clinical trials over a twenty-year period to the present. We examine the bioactive small molecules likely to be in involved and, where possible, their mechanisms of action

Bufadienolides and anti-angiogenic homoisoflavonoids from 'Rhodocodon cryptopodus', 'Rhodocodon rotundus' and 'Rhodocodon cyathiformis'

Background: Homoisoflavonoids have been shown to have potent anti-proliferative activities in endothelial cells over other cell types and have demonstrated a strong antiangiogenic potential in vitro and in vivo in animal models of ocular neovascularization. Three species of Rhodocodon (Scilloideaea subfamily of the Asparagaceae family), endemic to Madagascar, R. cryptopodus, R. rotundus and R. cyathiformis, were investigated. Purpose: To isolate and test homoisoflavonoids for their antiangiogenic activity against human retinal microvascular endothelial cells (HRECs), as well as specificity against other ocular cell lines. Methods: Plant material was extracted at room temperature with EtOH. Compounds were isolated using flash column chromatography and were identified using NMR and CD spectroscopy and HRESIMS. Compounds were tested for antiproliferative effects on primary human microvascular retinal endothelial cells (HRECs), ARPE19 retinal pigment epithelial cells, 92–1 uveal melanoma cells, and Y79 retinoblastoma cells. HRECs exposed to compounds were also tested for migration and tube formation ability. Results: Two homoisoflavonoids, 3S-5,7-dihydroxy-(3′-hydroxy-4′-methoxybenzyl)-4-chromanone (1) and 3S-5,7-dihydroxy-(4′-hydroxy-3′-methoxybenzyl)-4-chromanone (2), were isolated along with four bufadienolides. Compound 1 was found to be non-specifically antiproliferative, with GI50 values ranging from 0.21–0.85 μM across the four cell types, while compound 2 showed at least 100-fold specificity for HRECs over the other tested cell lines. Compound 1, with a 3S configuration, was 700 times more potent that the corresponding 3R enantiomer recently isolated from a Massonia species. Conclusion: Select homoisoflavonoids have promise as antiangiogenic agents that are not generally cytotoxic

The antiangiogenic activity of naturally occurring and synthetic homoisoflavonoids from the Hyacinthaceae (sensu APGII)

Excessive blood vessel formation in the eye is implicated in wet age-related macular degeneration, proliferative diabetic retinopathy, neovascular glaucoma, and retinopathy of prematurity, which are major causes of blindness. Small molecule antiangiogenic drugs are strongly needed to supplement existing biologics. Homoisoflavonoids have been previously shown to have potent antiproliferative activities in endothelial cells over other cell types. Moreover, they demonstrated a strong antiangiogenic potential in vitro and in vivo in animal models of ocular neovascularization. Here, we tested the antiangiogenic activity of a group of naturally occurring homoisoflavonoids isolated from the family Hyacinthaceae and related synthetic compounds, chosen for synthesis based on structure–activity relationship observations. Several compounds showed interesting antiproliferative and antiangiogenic activities in vitro on retinal microvascular endothelial cells, a disease-relevant cell type, with the synthetic chromane, 46, showing the best activity (GI50 of 2.3 × 10–4 μM)

Melanin production inhibitors from the West African 'Cassipourea congoensis'

Cassipourea congoensis (syn. Cassipourea malosana) is used in African countries as a skin-lightening agent. Two previously unreported cycloartane triterpenoids, 26-hydroxy-3-keto-24-methy lenecycloartan-30-oic acid 1 and 24-methylene-cycloartan-3β,26,30-triol 2 along with the known mahuannin B 3, 7-methoxymahuannin B 4, 7-methoxygeranin A 5, methyl-3-(4-hydroxy-3-methoxyphenyl)-2E-propenoate, glycerol-1-alkanoate, (E)-3-(4-hydroxy-3-methoxyphenyl)prop-2-enal 6, (-)-syringaresinol 7, and stigmast-5-en-3-O-β-D-glucoside, were isolated from the roots of C. congoensis. The crude extract and compounds 1 and 5 were found to inhibit the production of melanin at 10 μM with low cytotoxicity validating the ethno-medicinal use of this plan

Design and synthesis of pyrrolidine-based nucleotide mimetics for use as inhibitors of the DNA repair enzyme AAG.

The action of the DNA repair enzyme alkyladenine DNA glycosylase (AAG), as part of the Base Excision Repair pathway, on alkylation-induced DNA damage has been shown in mice to lead to cell death in the retina, spleen, thymus and cerebellum. The action of AAG has also been linked to damage caused by ischaemia/reperfusion (I/R) events in liver, brain and kidney. As a result, small molecule inhibitors of AAG are required for ongoing studies into the biological mechanism of this cellular damage, as well as to become potential drug leads for some types of retinal degeneration, I/R-related tissue damage, or as protective agents for patients undergoing alkylative chemotherapy and showing an increased AAG activity. They could also serve the opposite effect, acting as an alkylating agent (TMZ) sensitiser in paediatric glioblastoma (GBM). Two DNA oligomers, containing etheno-cytidine or an abasic pyrrolidine, are reported in the literature to show potent AAG inhibition in vitro. Unfortunately, their size and the charged nature of DNA chains makes them unsuitable for use as potential drug leads in vivo, as they would show low membrane permeability and face degradation by nucleases. However, the motifs present in these oligomers, together with examination of the enzyme active site, led to the conception of two types of small drug-like pyrrolidine-based inhibitor candidates termed 2-(hydroxymethyl)pyrrolidines and 4-(hydroxymethyl)pyrrolidines. The synthetic routes to these inhibitor candidates have been studied and optimised. That to the 2-(hydroxymethyl)pyrrolidines failed at the final step of attachment of DNA base-mimicking aryl groups. However, five 4-(hydroxymethyl)pyrrolidines nucleoside mimetics were successfully synthesised, bearing imidazole and pyridine groups to represent a DNA base. These were subsequently tested in vitro against AAG in a surface-bound hairpin loop colorimetric DNA oligomer assay. The most promising candidate, (+)-395, showed an IC50 of 157 µM corresponding to a ligand efficiency of 0.37 kcal·mol-1·heavy atom-1. Due to its low molecular weight (197 g·mol-1), this inhibitor constitutes a viable starting point for a future lead optimisation programme

Fungal Drug Discovery for Chronic Disease: History, New Discoveries and New Approaches.

Fungal-derived drugs include some of the most important medicines ever discovered, and have proved pivotal in treating chronic diseases. Not only have they saved millions of lives, but they have in some cases changed perceptions of what is medically possible. However, now the low-hanging fruit have been discovered it has become much harder to make the kind of discoveries that have characterised past eras of fungal drug discovery. This may be about to change with new commercial players entering the market aiming to apply novel genomic tools to streamline the discovery process. This review examines the discovery history of approved fungal-derived drugs, and those currently in clinical trials for chronic diseases. For key molecules, we discuss their possible ecological functions in nature and how this relates to their use in human medicine. We show how the conservation of drug receptors between fungi and humans means that metabolites intended to inhibit competitor fungi often interact with human drug receptors, sometimes with unintended benefits. We also plot the distribution of drugs, antimicrobial compounds and psychoactive mushrooms onto a fungal tree and compare their distribution to those of all fungal metabolites. Finally, we examine the phenomenon of self-resistance and how this can be used to help predict metabolite mechanism of action and aid the drug discovery process

Chemistry of pollen

<p>Students missing in co-authorship in this version</p><p>Aminoacids, PSM, Fatty Acids. </p><p>Sterols missing in this version</p&gt

HIV-1 Integrase Inhibitory Effects of Major Compounds Present in CareVid™: An Anti-HIV Multi-Herbal Remedy

In our continued study on the anti-HIV activity of compounds present in CareVidTM, we report the HIV-1 integrase ((HIV-1 IN) inhibitory effects of pellitorine (1), oleuropein (2), magnoflorine (3), crotepoxide (4), ent-kaurane-16β,17-diol (5), crotocorylifuran (6), lupeol (7), betulin (8), and ellagic acid (9) in an in vitro enzyme assay, and in an in silico study. Ellagic acid, pellitorine, lupeol, and betulin showed an in vitro percentage inhibition against HIV-1 IN of 21.1%, 19.0%, 18.5%, and 16.8%, respectively, at a standard concentration of 25 μg/mL. However, from a pharmacokinetic perspective, ellagic acid has poor bioavailability, due to rapid elimination in metabolism in the gut microbiome. It was postulated that known gut catabolites of ellagic acid, urolithin A (10) and urolithin B (11) could be more promising candidates in exploring the anti-HIV activity of ellagic acid-rich medicinal species consumed orally. On the contrary, urolithin A and urolithin B demonstrated lower activity with comparison to ellagic acid. The binding affinity of compounds 1–9, urolithin A, and urolithin B against the catalytic domain of HIV-1 IN was also explored by in silico methods. Docking studies showed oleuropein as the best candidate, with a predicted energy of binding of ΔG −5.81 kcal/mol, while ellagic acid showed moderate predicted inhibition (ΔG −4.38 kcal/mol) caused by the interaction between the carbonyl and the key Mg2+ ion in the active site