Novel semisynthetic derivatives of betulin and betulinic acid with cytotoxic activity

Santos, Rosa M.; Salvador, Jorge A. R.; Marín, Silvia; Cascante, Marta

doi:10.1016/j.bmc.2009.07.050

Cited by 111 publications

(55 citation statements)

References 49 publications

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“…200 times more efficacious in HL-60 cells than the parent drug TQ (IC 50 ¼ 130 AE 20 nm). This finding is in line with recent reports by other groups on bioactive C(17)-esters of betulinic acid [28] [29]. Further investigations such as assessment of caspase kinetics and involvement of pro-/anti-apoptotic proteins are now underway to identify the precise mechanism of apoptosis induced by conjugates of type 3.…”

supporting

confidence: 91%

Terpene Conjugates of the Nigella sativa Seed‐Oil Constituent Thymoquinone with Enhanced Efficacy in Cancer Cells

Effenberger

Breyer

Schobert

2010

Chemistry & Biodiversity

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Thymoquinone (TQ; 1) is a weak anticancer constituent of black seed oil. Derivatives bearing terpene-terminated 6-alkyl residues were tested in cells of human HL-60 leukemia, 518A2 melanoma, multidrug-resistant KB-V1/Vbl cervix, and MCF-7/Topo breast carcinomas, as well as in non-malignant human foreskin fibroblasts. Derivatives with a short four-atom spacer between quinone and cyclic monoterpene moieties were more antiproliferative than analogues with longer spacers. 6-(Menthoxybutyryl)thymoquinone (3a) exhibited single-digit micromolar IC(50) (72 h) values in all four cell lines. It was seven times more active than TQ (1) in 518A2 melanoma cells and four times in KB-V1/Vbl cervix carcinoma cells, while only half as toxic in the fibroblasts. Compound 3a was also not a substrate for the P-gp and BCRP drug transporters of the resistant cancer cells. The caryophyllyl and germacryl conjugates 3e and 3f specifically inhibited the growth of the resistant MCF-7 breast carcinoma cells. Conjugation of TQ with the triterpene betulinic acid via the OH group as in 3g led to a loss in activity, while conjugation via the carboxylic acid afforded compound 4 with nanomolar IC(50) (72 h) activity against HL-60 cells. All anticancer-active derivatives of TQ (1) induced apoptosis associated with DNA laddering, a decrease in mitochondrial membrane potential and a slight increase in reactive oxygen species.

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supporting

confidence: 91%

Terpene Conjugates of the Nigella sativa Seed‐Oil Constituent Thymoquinone with Enhanced Efficacy in Cancer Cells

Effenberger

Breyer

Schobert

2010

Chemistry & Biodiversity

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“…The structures of the esters were elucidated using IR and NMR spectra and comparison of them with those of analogous compounds [5,9,10]. 13 C NMR spectra of synthesized 2-8 exhibited resonances for the betulin part of the molecule and the corresponding number of C resonances for the acyl components (Table 1).…”

Section: 597+547918mentioning

confidence: 99%

“…Esters 2-8 were prepared by reaction of 1 with the acid chlorides in Py (1:1.2 mole ratio) in the presence of dimethylaminopyridine (1.2 equivalents). The 28-O-monosubstituted betulin derivatives were isolated in 56-69% yields.The structures of the esters were elucidated using IR and NMR spectra and comparison of them with those of analogous compounds [5,9,10]. 13 C NMR spectra of synthesized 2-8 exhibited resonances for the betulin part of the molecule and the corresponding number of C resonances for the acyl components (Table 1).…”

mentioning

confidence: 99%

“…The most famous of these is betulin [2]. The high content, simple isolation methods, and presence of reactive functional groups make it an available and convenient starting material for synthesizing new biologically active compounds [3][4][5]. Compounds with anti-inflammatory, antioxidant, antibacterial, hepatoprotective, antiviral, antitumor, and immunostimulant properties were found among synthesized betulin derivatives [6,7].…”

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Synthesis and antibacterial activity of betulin esters

2011

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547.597+547.918Betulin isonicotinate, 6-chloronicotinate, 2-chlorocinnamate, and benzoates were synthesized by the reaction of betulin and the acid chlorides. It was shown that the 3,4-difluorobenzoate exhibited antibacterial activity against Ochrobactrum anthropi, Stenotrophomonas maltophilia, and S. nitritireducens whereas the 3,5-dinitrobenzoate was active against the last two microorganisms.The outer part of the bark of several white birch species is a rich source of pentacyclic lupane triterpenoids [1]. The most famous of these is betulin [2]. The high content, simple isolation methods, and presence of reactive functional groups make it an available and convenient starting material for synthesizing new biologically active compounds [3][4][5]. Compounds with anti-inflammatory, antioxidant, antibacterial, hepatoprotective, antiviral, antitumor, and immunostimulant properties were found among synthesized betulin derivatives [6,7]. The increasing number of publications in this area indicates that active research is continuing.Herein we present results from the synthesis of betulin esters and data on their antibacterial activity. Betulin (1) was obtained by extraction of birch (Betula platyphylla) bark collected in Chungbuk Province (South Korea). The structure of 1 was confirmed by comparison of its PMR and 13 C NMR spectra with those published [8]. Esters 2-8 were prepared by reaction of 1 with the acid chlorides in Py (1:1.2 mole ratio) in the presence of dimethylaminopyridine (1.2 equivalents). The 28-O-monosubstituted betulin derivatives were isolated in 56-69% yields.The structures of the esters were elucidated using IR and NMR spectra and comparison of them with those of analogous compounds [5,9,10]. 13 C NMR spectra of synthesized 2-8 exhibited resonances for the betulin part of the molecule and the corresponding number of C resonances for the acyl components (Table 1). A weak-field shift of the C-28 resonances and the appearance of resonances at 163.1-167.9 ppm indicated that the ester bonds had formed. This was also confirmed by the appearance of absorption bands at ~1700 cm -1 in the IR spectra of these compounds.Synthesized 2-8 were checked for antibacterial activity that was assessed using the diameter of the colony growth inhibition zone around paper disks with the applied compound (values are given below after the name of the bacteria). Betulin 3,4-difluorobenzoate (8) exhibited activity against Ochrobactrum anthropi (12 mm), Stenotrophomonas nitritireducens (13 mm), and S. maltophilia (11 mm) whereas the 3,5-dinitrobenzoate (5) inhibited growth of the last two test cultures (11 and 10 mm, respectively).

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“…1,2 It is also worth mentioning that BA itself, as well as some of its derivatives, have been described as potent anti-HIV agents. 3 A recent study revealed that a semi-synthetic oleanane-type saponin, 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid (CDDO) is a multi-functional molecule with promising clinical potential as a chemo-preventive agent and as a therapeutic agent for the treatment of cancer.…”

Section: Introductionmentioning

confidence: 99%

Cleavage of ring A and formation of an unusual nor-triterpene skeleton via the Baeyer–Villiger reaction

Tag̀

Çağır

Khan

et al. 2012

Tetrahedron Letters

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a b s t r a c tWith the aim to generate a compound library for our biological screening studies, cycloastragenol was subjected to chemical transformation studies. The Baeyer-Villiger oxidation experiments provided an interesting 3,5-seco-4-nor-triterpene skeleton via ring opening followed by an unusual rearrangement. A new methodology is described for transforming triterpenoids into 3,5-seco-4-nor derivatives.

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Novel semisynthetic derivatives of betulin and betulinic acid with cytotoxic activity

Cited by 111 publications

References 49 publications

Terpene Conjugates of the Nigella sativa Seed‐Oil Constituent Thymoquinone with Enhanced Efficacy in Cancer Cells

Terpene Conjugates of the Nigella sativa Seed‐Oil Constituent Thymoquinone with Enhanced Efficacy in Cancer Cells

Synthesis and antibacterial activity of betulin esters

Cleavage of ring A and formation of an unusual nor-triterpene skeleton via the Baeyer–Villiger reaction

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