Novel Derivatives of Kaurenoic Acid

Abstract

O ácido caurenóico, um diterpeno caurânico, mostrou-se ativo in vitro contra formas tripomastigotas do Trypanosoma cruzi. Uma ação lítica sobre os eritrócitos foi uma das limitações encontradas para esta atividade. A síntese de doze derivados deste ácido: quatro amidas, quatro aminas (e três cloridratos) e quatro oximas foi realizada, com o objetivo de se tentar diminuir ou eliminar esse efeito secundário e, se possível, aumentar a atividade em relação ao material de partida. Dentre esses compostos, um mostrou-se mais ativo que o ácido caurenóico, mas também apresentou lise discreta de eritrócitos; outro não apresentou este efeito, mas a atividade não foi aumentada em relação àquela apresentada pelo ácido caurenóico.Kaurenoic acid, a kauranic diterpenoid, presents in vitro activity against trypomastigote forms of Trypanosoma cruzi, showing, however, lytic activity on blood erythrocytes, as a side effect. The syntheses of twelve new derivatives of kaurenoic acid, four amides, four amines (and three hydroclorides) and four oximes, was carried out aiming at the improvement of the therapeutic activity and without the side effect. Among the derivatives prepared, one compound showed enhanced trypanocidal activity in vitro towards Trypanosoma cruzi trypomastigote erythrocytic forms, when compared to kaurenoic acid, but continued to show discrete lytic activity on erythrocytes; another compound showed a level of activity similar to that of kaurenoic acid, but without lysis.

A simple synthesis of kaurenoic esters and other derivatives and evaluation of their antifungal activity

“…18 Oxidative cleavage 19,20 of the olefin moiety in 1 gave the keto acid 15 which was methylated with CH 3 I in KOH-acetone to afford methyl norkauranoate 16 quantitatively (Scheme 3). To carry out the antifungal evaluation, concentrations of kaurenoic acid and its derivatives up to 250 μg mL -1 were incorporated to growth media according to NCCLS guidelines.…”

“…[8][9][10][11][12][13][14][15][16] The relatively high natural abundance of kaurenoic acid (1) and the inexistence of a general method for the synthesis of alkyl kaurenoates by esterification of 1 provides further motivation to investigate its chemical modification 17 in order to obtain derivatives and test their pharmacological activity. 18 This paper describes a general synthesis of kaurenoic esters and derivatives as well as their antifungal activity, evaluated against a panel of human opportunistic pathogenic fungi including yeasts, hialohyphomycetes and dermatophytes.…”

Occurrence, Biological Activities and Synthesis of Kaurane Diterpenes and their Glycosides

“…Aiming to reduce or eliminate the lytic effect of kaurenoic acid (1) on the erythrocytes of infected blood [40], which are usually used in the in vitro assays against trypomastigote forms of Trypanosoma cruzi, Vieira and collaborators [85] synthesized 19 kaurane derivatives containing a ketone or an oxime group at C-16, and alcohol, methyl ester, amine or amide functions at C-19. Of these, only the oxime 48 was more active than 1, presenting trypanosomicidal activity in all the concentrations tested (2.27 -0.57 mM) along with a slight lysis of the red cells.…”

Rhodium catalyzed hydroformylation of kaurane derivatives: A route to new diterpenes with potential bioactivity

“…It has been reported that some kaurenic acid derivatives present a higher biological activity or a lesser toxic effect than the natural diterpene. For instance, the C16 oxime derivative shows an enhanced trypanocidal activity with respect to the natural diterpene, while the derivative produced via the substitution of the acid at C1 by the N-pyrrolidinylmethyl group shows a similar trypanocidal activity, but a reduced lytic activity on blood erythrocytes in comparison to the unmodified terpene [17]. More recently, it has been demonstrated that the dihydroxylation at the double bond of kaurenic acid enhances its inhibitory activity against a-glucosidase [18].…”