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)

A call for using natural compounds in the development of new antimalarial treatments – an introduction

Natural compounds, mostly from plants, have been the mainstay of traditional medicine for thousands of years. They have also been the source of lead compounds for modern medicine, but the extent of mining of natural compounds for such leads decreased during the second half of the 20th century. The advantage of natural compounds for the development of drugs derives from their innate affinity for biological receptors. Natural compounds have provided the best anti-malarials known to date. Recent surveys have identified many extracts of various organisms (mostly plants) as having antiplasmodial activity. Huge libraries of fractionated natural compounds have been screened with impressive hit rates. Importantly, many cases are known where the crude biological extract is more efficient pharmacologically than the most active purified compound from this extract. This could be due to synergism with other compounds present in the extract, that as such have no pharmacological activity. Indeed, such compounds are best screened by cell-based assay where all potential targets in the cell are probed and possible synergies identified. Traditional medicine uses crude extracts. These have often been shown to provide many concoctions that deal better with the overall disease condition than with the causative agent itself. Traditional medicines are used by ~80 % of Africans as a first response to ailment. Many of the traditional medicines have demonstrable anti-plasmodial activities. It is suggested that rigorous evaluation of traditional medicines involving controlled clinical trials in parallel with agronomical development for more reproducible levels of active compounds could improve the availability of drugs at an acceptable cost and a source of income in malaria endemic countries

Natural and synthetic homoisoflavonoids and related compounds for the treatment of macular degeneration

The inhibition of angiogenesis is a drug target with widespread application. Macular conditions affect around 1.5 million people in the UK, with most of them suffering from age-related macular degeneration. AMD is the biggest cause of sight loss in the UK, affecting about 600 000 people. Wet age-related macular degeneration it is characterized by extensive neovascularisation of the retina. Current treatments include the use of anti-VEGF agents such as Bevacizumab (Avastin) and Ranibizumab (Lucentis). Due to the cost of these treatments and the variable outcomes, the possibility of a small molecule treatment is very attractive. Homoisoflavonoids are C-16 natural products isolated primarily from the Asparagaceae family. These compounds have shown promising activity in vitro and in some initial in vivo analyses. A wide range of homoisoflavonoids, both extracted from natural sources as well as of synthetic origin have been screened for selectivity towards human retinal microvascular endothelial (HREC) cells, as well as being assessed for their ability to inhibit tube formation using a Matrigel assay. The work has highlighted some key structural features that are important for activity and selectivity. Synthetic methodology has been developed and optimised to allow for the production of a range of structurally diverse homoisoflavonoids showing good activity and promise for further development as therapeutic agents

Phytochemical Investigations of Three Rhodocodon (Hyacinthaceae Sensu APG II) Species

The genus Rhodocodon (Hyacinthaceae sensu APG II) is endemic to Madagascar and its phytochemistry has not been described previously. The phytochemistry of three species in this genus has been investigated and eight compounds, including three bufadienolides (compounds 1, 4, and 5), a norlignan (2), and four homoisoflavonoids (compounds 3 and 6-8) have been isolated and identified. Compounds 1-3 and 6-8 have not been described previously. The COX-2 inhibitory activity of compound 6 and compound 7 acetate (compound 7A) were investigated on isolated colorectal cancer cells. Compounds 6 and 7A inhibited COX-2 by 10% and 8%, respectively, at a concentration of 12.5 M compared to 12% for 1 mM aspirin (the positive control)