Year: 2015
Type: dissertation
Abstract: Betulin is a triterpene class natural product present, for example, in the outer layer of birch bark, which is a low-value waste product of the forestry industry in Northern Hemisphere. Oxidation products of betulin, namely betulinic acid and betulonic acid, have been shown to have several biological activities. This makes betulin an interesting starting point for drug discovery projects. In this work, mainly ring A-fused heterocyclic derivatives of betulin were synthesized, and their structure-activity relationships against a protozoan parasite Leishmania donovani, prostate cancer cell lines, a serine hydrolase enzyme (ABHD12), and inflammatory factors were studied. The heterocycles used included pyridine, pyrazine, pyrazole, indole, isoxazole, and oxazole rings. Also, positions C-28 and C-20 of these compounds were modified and the resulting structure-activity relationships (SAR) were studied. Among the tested compounds, two heterocyclic betulin derivatives showed significant inhibition against L. donovani amastigotes growth. These compounds showed improved activity compared to the heterocyclic betulin derivatives tested previously. Also, a betulinderived potent anti-HIV compound, bevirimat, showed L. donovani growth inhibition at a similar level to the ring A-fused heterocyclic betulin derivatives. However, further optimization is needed to get more potent betulin derivative activity against L. donovani. In prostate cancer studies some of the betulin derivatives displayed dose-dependent anti-invasive activity at nanomolar concentrations with negligible cytotoxicity. The most potent compounds were betulin derivatives with a ring A-fused heterocycle. Also, the carboxyl group at C-28 seemed to be important for activity. These compounds showed considerably improved anti-invasive effects compared to betulinic acid. Betulin derivatives were found to selectively inhibit the ABHD12 serine hydrolase enzyme without inhibiting other endocannabinoid hydrolases and without activity towards cannabinoid receptors. In mechanistic studies, the inhibition type was shown to be reversible. Important structural features required for ABHD12 inhibition were revealed based on our SAR studies. Heterocyclic betulin derivatives were shown to suppress the expression of several inflammation mediators, such as iNOS, IL-6, and MCP-1, a pyrazole derivative being the most potent compound. With further improvement and development, more potent betulin derivatives could be found. The betulin derivatives show different activity with different targets, which means they are selective. Selectivity and potency could be further improved to obtain a potential betulin-derived compound for further development. In this work, betulin has been shown to be a good starting point for several different drug discovery projects.
Source: Työväentutkimus Vuosikirja
Author: Raisa Haavikko
Language: English
Subfield: Organic Chemistry
Field: Chemistry
Domain: Physical Sciences
Open Access status: green
OpenAlex ID: W1908152191