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Stability and antioxidant activity of semi-synthetic derivatives of 4-nerolidylcatechol.

Silva Lima E, Silva Pinto AC, Nogueira KL, Rocha e Silva LF, Oliveira de Almeida PD, Carvalho de Vasconcellos M, Chaves FC, Tadei WP, Pohlit AM.

Molecules. 2012 Dec 24;18(1):178-89.

Universidade Federal do Amazonas, Avenida General Rodrigo Otavio Jordao Ramos 3000, 69077-000 Campus Universitario, Manaus, Amazonas, Brazil.

 

Abstract

4-nerolidylcatechol (4-NC) is an unstable natural product that exhibits important antioxidant, anti-inflammatory and other properties. It is readily obtainable on a multi-gram scale through straightforward solvent extraction of the roots of cultivated Piper peltatum or P. umbellatum, followed by column chromatography on the resulting extract. Semi-synthetic derivatives of 4-NC with one or two substituent groups (methyl, acetyl, benzyl, benzoyl) on the O atoms have been introduced that have increased stability compared to 4-NC and significant in vitro inhibitory activity against the human malaria parasite Plasmodium falciparum. Antioxidant and anti-inflammatory properties may be important for the antiplasmodial mode of action of 4-NCderivatives. Thus, we decided to investigate the antioxidant properties, cytotoxicity and stability of 4-NC derivatives as a means to explore the potential utility of these compounds. 4-NC showed high antioxidant activity in the DPPH and ABTS assays and in 3T3-L1 cells (mouse embryonic fibroblast), however 4-NC was more cytotoxic (IC50 = 31.4 µM) and more unstable than its derivatives and lost more than 80% of its antioxidant activity upon storage in solution at -20 °C for 30 days. DMSO solutions of mono-O-substituted derivatives of 4-NC exhibited antioxidant activity and radical scavenging activity in the DPPH and ABTS assays that was comparable to that of BHA and BHT. In the cell-based antioxidant model, most DMSO solutions of derivatives of 4-NC were less active on day 1 than 4-NC, quercetin and BHA and more active antioxidants than BHT. After storage for 30 days at -20 °C, DMSO solutions of most of the derivatives of 4-NC were more stable and exhibited more antioxidant activity than 4-NC, quercetin and BHA and exhibited comparable antioxidant activity to BHT. These findings point to the potential of derivatives of 4-NC as antioxidant compounds.

 

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Additional Information

4-NC is a pharmacologically active natural product that can be produced on a large scale for research and industrial applications. In a lab situation, dry, ground roots (see inset image) can be extracted and several grams of pure 4-NC can be obtained after chromatography in a single day providing isolated yields of 4-NC of >5% w/w based on extracted roots. In published agronomic studies, we have shown that ca. 1,200 kg of dry caapeba root can be produced per hectare in ca. 450 days of cultivation (see image, cultivated caapeba). This corresponds to a potentially isolable yield of ca. 27 kg of 4-NC per hectare. A study on the costs of the production of caapeba root and 4-NC per hectare in the cultivation conditions found in Amazonas State, Brazil, is currently underway.

4-NC exhibits a number of interesting chemical and pharmacological properties. It has been shown by others to have in vitro antioxidant activity that is 20× that of vitamin E. 4-NC is the active component of caapeba extracts that exhibit a strong in vivo photoprotective and anti-inflammatory effect against UV radiation-induced skin damage. We have described the significant in vitro antimalarial activity of 4-NC (IC50 < 1 microM) against Plasmodium falciparum and have demonstrated that significant in vivo suppression of Plasmodium berghei in mice occurs only at high doses (600 mg/kg) in the 4-day suppressive test. This in vivo assay also provided evidence for a lack of acute toxicity at least up to 600 mg/kg in mice. 4-NC in pure form or solutions is highly labile even under freezer conditions and decomposes over several days to a couple of weeks.

The O-monosubstituted and O,O-disubstituted 4-NC derivatives that are the focus of the present work are prepared using simple one or two-step reaction sequences and 4-NC as the substrate. They have been introduced in an attempt to improve stability and pharmacological properties over those of 4-NC. These 4-NC derivatives exhibit longer storage lives in the freezer than 4-NC. Some derivatives can be stored for 2 years with minimal degradation (by TLC). These derivatives exhibit in vitro antimalarial activity against P. falciparum that is comparable or lower than that of 4-NC itself. Furthermore, in unpublished work, the O,O-diacetyl 4-NC derivative exhibited 60× more activity in vivo against Plasmodium berghei than 4-NC, exhibiting significant inhibition at doses of 10 mg/kg/day in the 4-day suppressive test. Also, in unpublished work in collaboration with others, derivatives of 4-NC have been shown to inhibit the biosynthesis of polyprenylated metabolites that is known to occur within the apicoplast of Plasmodium falciparum as part of their mechanism of antimalarial activity. This represents a very rare mechanism of action there being no example among the arsenal of currently available antimalarial drugs exhibiting this biological activity. In the future, these and new derivatives of 4-NC should be prepared on gram scales for in vivo testing for antioxidant and antiamalarial activity, toxicity and other properties.

 

Stability and Antioxidant Activity of Semi-synthetic Derivatives of 4-Nerolidylcatechol.