Structure-activity relationship study of sesquiterpene lactones and their semi-synthetic amino derivatives as potential anti-trypanosomal products

Stefanie Zimmermann; Gerda Fouche; Maria De Mieri; Yukiko Yoshimoto; Toyonobu Usuki; Rudzani Nthambeleni; Christopher Parkinson; Christiaan van der Westhuyzen; Marcel Kaiser; Matthias Hamburger; Michael Adams

doi:10.3390/molecules19033523

Structure-activity relationship study of sesquiterpene lactones and their semi-synthetic amino derivatives as potential anti-trypanosomal products

Stefanie Zimmermann, Gerda Fouche, Maria De Mieri, Yukiko Yoshimoto, Toyonobu Usuki, Rudzani Nthambeleni, Christopher Parkinson, Christiaan van der Westhuyzen, Marcel Kaiser, Matthias Hamburger, Michael Adams

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Abstract

Sesquiterpene lactones (STLs) are natural products that have potent antitrypanosomal activity in vitro and, in the case of cynaropicrin, also reduce parasitemia in the murine model of trypanosomiasis. To explore their structure-antitrypanosomal activity relationships, a set of 34 natural and semi-synthetic STLs and amino-STLs was tested in vitro against T. b. rhodesiense (which causes East African sleeping sickness) and mammalian cancer cells (rat bone myoblast L6 cells). It was found that the α-methylene-γ-lactone moiety is necessary for both antitrypanosomal effects and cytotoxicity. Antitrypanosomal selectivity is facilitated by 2-(hydroxymethyl)acrylate or 3,4-dihydroxy-2-methylenebutylate side chains, and by the presence of cyclopentenone rings. Semi-synthetic STL amines with morpholino and dimethylamino groups showed improved in vitro activity over the native STLs. The dimethylamino derivative of cynaropicrin was prepared and tested orally in the T. b. rhodesiense acute mouse model, where it showed reduced toxicity over cynaropicrin, but also lost antitrypanosomal activity.

Original language	English
Pages (from-to)	3523-3538
Number of pages	16
Journal	Molecules
Volume	19
Issue number	3
DOIs	https://doi.org/10.3390/molecules19033523
Publication status	Published - Mar 2014

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Zimmermann, S., Fouche, G., Mieri, M. D., Yoshimoto, Y., Usuki, T., Nthambeleni, R., Parkinson, C., Westhuyzen, C. V. D., Kaiser, M., Hamburger, M., & Adams, M. (2014). Structure-activity relationship study of sesquiterpene lactones and their semi-synthetic amino derivatives as potential anti-trypanosomal products. Molecules, 19(3), 3523-3538. https://doi.org/10.3390/molecules19033523

@article{43cb1c6b78404966abb893e206298144,

title = "Structure-activity relationship study of sesquiterpene lactones and their semi-synthetic amino derivatives as potential anti-trypanosomal products",

abstract = "Sesquiterpene lactones (STLs) are natural products that have potent antitrypanosomal activity in vitro and, in the case of cynaropicrin, also reduce parasitemia in the murine model of trypanosomiasis. To explore their structure-antitrypanosomal activity relationships, a set of 34 natural and semi-synthetic STLs and amino-STLs was tested in vitro against T. b. rhodesiense (which causes East African sleeping sickness) and mammalian cancer cells (rat bone myoblast L6 cells). It was found that the α-methylene-γ-lactone moiety is necessary for both antitrypanosomal effects and cytotoxicity. Antitrypanosomal selectivity is facilitated by 2-(hydroxymethyl)acrylate or 3,4-dihydroxy-2-methylenebutylate side chains, and by the presence of cyclopentenone rings. Semi-synthetic STL amines with morpholino and dimethylamino groups showed improved in vitro activity over the native STLs. The dimethylamino derivative of cynaropicrin was prepared and tested orally in the T. b. rhodesiense acute mouse model, where it showed reduced toxicity over cynaropicrin, but also lost antitrypanosomal activity. ",

keywords = "Cynaropicrin, Dimethylamino analogues, Sesquiterpene lactones, Antitrypanosomal, Cytotoxicity, Structure-activitity relationship, T. b. rhodesiense acute mouse model",

author = "Stefanie Zimmermann and Gerda Fouche and Mieri, {Maria De} and Yukiko Yoshimoto and Toyonobu Usuki and Rudzani Nthambeleni and Christopher Parkinson and Westhuyzen, {Christiaan van der} and Marcel Kaiser and Matthias Hamburger and Michael Adams",

note = "Includes bibliographical references.",

year = "2014",

month = mar,

doi = "10.3390/molecules19033523",

language = "English",

volume = "19",

pages = "3523--3538",

journal = "Molecules",

issn = "1420-3049",

publisher = "Multidisciplinary Digital Publishing Institute (MDPI)",

number = "3",

}

Zimmermann, S, Fouche, G, Mieri, MD, Yoshimoto, Y, Usuki, T, Nthambeleni, R, Parkinson, C, Westhuyzen, CVD, Kaiser, M, Hamburger, M & Adams, M 2014, 'Structure-activity relationship study of sesquiterpene lactones and their semi-synthetic amino derivatives as potential anti-trypanosomal products', Molecules, vol. 19, no. 3, pp. 3523-3538. https://doi.org/10.3390/molecules19033523

TY - JOUR

T1 - Structure-activity relationship study of sesquiterpene lactones and their semi-synthetic amino derivatives as potential anti-trypanosomal products

AU - Zimmermann, Stefanie

AU - Fouche, Gerda

AU - Mieri, Maria De

AU - Yoshimoto, Yukiko

AU - Usuki, Toyonobu

AU - Nthambeleni, Rudzani

AU - Parkinson, Christopher

AU - Westhuyzen, Christiaan van der

AU - Kaiser, Marcel

AU - Hamburger, Matthias

AU - Adams, Michael

N1 - Includes bibliographical references.

PY - 2014/3

Y1 - 2014/3

N2 - Sesquiterpene lactones (STLs) are natural products that have potent antitrypanosomal activity in vitro and, in the case of cynaropicrin, also reduce parasitemia in the murine model of trypanosomiasis. To explore their structure-antitrypanosomal activity relationships, a set of 34 natural and semi-synthetic STLs and amino-STLs was tested in vitro against T. b. rhodesiense (which causes East African sleeping sickness) and mammalian cancer cells (rat bone myoblast L6 cells). It was found that the α-methylene-γ-lactone moiety is necessary for both antitrypanosomal effects and cytotoxicity. Antitrypanosomal selectivity is facilitated by 2-(hydroxymethyl)acrylate or 3,4-dihydroxy-2-methylenebutylate side chains, and by the presence of cyclopentenone rings. Semi-synthetic STL amines with morpholino and dimethylamino groups showed improved in vitro activity over the native STLs. The dimethylamino derivative of cynaropicrin was prepared and tested orally in the T. b. rhodesiense acute mouse model, where it showed reduced toxicity over cynaropicrin, but also lost antitrypanosomal activity.

AB - Sesquiterpene lactones (STLs) are natural products that have potent antitrypanosomal activity in vitro and, in the case of cynaropicrin, also reduce parasitemia in the murine model of trypanosomiasis. To explore their structure-antitrypanosomal activity relationships, a set of 34 natural and semi-synthetic STLs and amino-STLs was tested in vitro against T. b. rhodesiense (which causes East African sleeping sickness) and mammalian cancer cells (rat bone myoblast L6 cells). It was found that the α-methylene-γ-lactone moiety is necessary for both antitrypanosomal effects and cytotoxicity. Antitrypanosomal selectivity is facilitated by 2-(hydroxymethyl)acrylate or 3,4-dihydroxy-2-methylenebutylate side chains, and by the presence of cyclopentenone rings. Semi-synthetic STL amines with morpholino and dimethylamino groups showed improved in vitro activity over the native STLs. The dimethylamino derivative of cynaropicrin was prepared and tested orally in the T. b. rhodesiense acute mouse model, where it showed reduced toxicity over cynaropicrin, but also lost antitrypanosomal activity.

KW - Cynaropicrin

KW - Dimethylamino analogues

KW - Sesquiterpene lactones

KW - Antitrypanosomal

KW - Cytotoxicity

KW - Structure-activitity relationship

KW - T. b. rhodesiense acute mouse model

U2 - 10.3390/molecules19033523

DO - 10.3390/molecules19033523

M3 - Article

C2 - 24662071

SN - 1420-3049

VL - 19

SP - 3523

EP - 3538

JO - Molecules

JF - Molecules

IS - 3

ER -

Structure-activity relationship study of sesquiterpene lactones and their semi-synthetic amino derivatives as potential anti-trypanosomal products

Abstract

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