Synthesis and biological activity of aloin derivatives.

Abstract

This project is focused on the synthesis and biological activity of aloin and derivatives. Aloin is a C-glucoside anthrone that is found in Aloe marlothii, a common Southern African plant used in traditional medicine. Aloin was isolated from A. marlothii, employing a selective chelation isolation procedure. This compound is known to have numerous biologically active properties, and can be used as a laxative, an anti-bacterial agent, an anti-oxidant, and as a cytotoxic drug against breast and ovarian tumour cell lines. More relevant to this research investigation, was the reported anti-inflammatory activity of aloin. Specifically, the inhibitory activity of aloin on matrix metalloproteinases, which when excessively secreted, can lead to the development of osteoarthritis and cancer metastasis. Aloin has also been reported to have antiplasmodial activity, which was also investigated. Aloin was synthetically transformed into several derivatives, which could be potentially useful medicinal compounds. The choice of derivatives to be made was based upon (i) known biologically active compounds (e.g. aloe-emodin) and (ii) interesting biologically active functional groups (e.g. amines). These aloin derivatives include aloe-emodin, rheinal, rhein and three amine derivatives. Homonataloin, an aloin-analogue, which was also isolated from A. marlothii, was synthetically transformed into nataloe-emodin. These two compounds serve as aloin structural analogues for the biological testing. Aloin and derivatives were characterised using NMR, HR-MS, UV and IR, which allowed for their unambiguous structural elucidation. Aloin and derivatives were all tested for (i) possible inhibition towards MMP-2 and MMP-9, which are the two most common MMPs in the blood, and (ii) antiplasmodial activity against chloroquine sensitive Plasmodium falciparum parasites. Doxycycline, a clinical tetracycline drug, was used as a reference compound for the biological assays, since it shares many common structural features with aloin and derivatives. 11-(Piperidin-1-yl)chrysophanol and 11-(morpholin-1-yl)chrysophanol proved to be the most potent selective MMP-2 inhibitors. 11-(Piperidin-1-yl)chrysophanol was also found to be the most potent against P. falciparum parasite, along with 11-(pyrrolidin-1-yl)chrysophanol. Aloin has been shown to be a cheap, easily obtainable lead compound that could facilitate the production of a range of powerful medicinal drugs.