Terpene Esters from Natural Products: Synthesis and Evaluation of Cytotoxic Activity

VICTOR, MAURICIO M.; DAVID, JORGE M.; SAKUKUMA, MARIA C.K.; COSTA-LOTUFO, LETÍCIA V.; MOURA, ANDREA F.; ARAÚJO, ANA J.

doi:10.1590/0001-3765201720160780

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Chemical Sciences • An. Acad. Bras. Ciênc. 89 (03) • Jul-Sep 2017 • https://doi.org/10.1590/0001-3765201720160780 linkcopy

Terpene Esters from Natural Products: Synthesis and Evaluation of Cytotoxic Activity

Authorship SCIMAGO INSTITUTIONS RANKINGS

ABSTRACT

Natural steroids and triterpenes such as b-sitosterol, stigmasterol, lupeol, ursolic and betulinic acids were transformed into its hexanoic and oleic esters, to evaluate the influence of chemical modification towards the cytotoxic activities against tumor cells. The derivatives were evaluated against five tumor cell lines [OVCAR-8 (ovarian carcinoma); SF-295 (glioblastoma); HCT-116 (colon adenocarcinoma); HL-60 (leukemia); and PC-3 (prostate carcinoma)] and the results showed only betulinic acid hexyl ester exhibits cytotoxic potential activity.

Key words:
antitumor activity; chemical modification; derivative synthesis; natural products esters

Authorship

MAURICIO M. VICTOR

Instituto de Química, Universidade Federal da Bahia, Depto de Química Orgânica, Rua Barão do Jeremoabo, s/n, Campus de Ondina, Ondina, 40170-115 Salvador, BA, Brazil Universidade Federal da BahiaBrazilSalvador, BA, BrazilInstituto de Química, Universidade Federal da Bahia, Depto de Química Orgânica, Rua Barão do Jeremoabo, s/n, Campus de Ondina, Ondina, 40170-115 Salvador, BA, Brazil

Instituto Nacional de Ciência e Tecnologia/INCT de Energia e Ambiente,Universidade Federal da Bahia/UFBA, Rua Barão de Geremoabo, 147, Campus de Ondina, 40170-290 Salvador, BA, BrazilUniversidade Federal da BahiaBrazilSalvador, BA, BrazilInstituto Nacional de Ciência e Tecnologia/INCT de Energia e Ambiente,Universidade Federal da Bahia/UFBA, Rua Barão de Geremoabo, 147, Campus de Ondina, 40170-290 Salvador, BA, Brazil

JORGE M. DAVID

MARIA C.K. SAKUKUMA

LETÍCIA V. COSTA-LOTUFO

Departamento de Fisiologia e Farmacologia, Universidade Federal do Ceará, Centro de Ciências da Saúde, Av. Coronel Nunes de Melo, 1127, Rodolfo Teófilo, 60430-270 Fortaleza, CE, BrazilUniversidade Federal do CearáBrazilFortaleza, CE, BrazilDepartamento de Fisiologia e Farmacologia, Universidade Federal do Ceará, Centro de Ciências da Saúde, Av. Coronel Nunes de Melo, 1127, Rodolfo Teófilo, 60430-270 Fortaleza, CE, Brazil

Departamento de Farmacologia, Universidade de São Paulo, Av. Professor Lineu Prestes, 1524, Cidade Universitária, Butantã, 05508-900 São Paulo, SP, BrazilUniversidade de São PauloBrazilSão Paulo, SP, BrazilDepartamento de Farmacologia, Universidade de São Paulo, Av. Professor Lineu Prestes, 1524, Cidade Universitária, Butantã, 05508-900 São Paulo, SP, Brazil

ANDREA F. MOURA

ANA J. ARAÚJO

Universidade Federal do Piauí, Av. São Sebastião, 2819, São Benedito, Campus Ministro Reis Velloso, 64202-020 Parnaíba, PB, BrazilUniversidade Federal do PiauíBrazilParnaíba, PB, BrazilUniversidade Federal do Piauí, Av. São Sebastião, 2819, São Benedito, Campus Ministro Reis Velloso, 64202-020 Parnaíba, PB, Brazil

Correspondence to: Mauricio Moraes Victor E-mail: mmvictor@ufba.br

SCIMAGO INSTITUTIONS RANKINGS

Figures | Tables

Figures (4)
Tables (3)

Thumbnail

Figure 1
Betulinic acid and its derivative Bevirimat^® (2 and 1, respectively).

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Figure 2
Structures of betulinic and ursolic acids (2 and 3, respectively), lupeol (4), stigmasterol (5) and b-sitosterol (6).

Thumbnail

Scheme 1
Condition to syntheses of esters: DMAP (2 eq.), DIC (2 eq.) in CH₂Cl₂, then acid (2 eq.) in CH₂Cl₂, 24-48h.

Thumbnail

Figures S1-S40
describing characterization data (IR, 1H and 13C NMR spectra) of compounds 2a,b-6a,b.

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TABLE I
Cytotoxic activity of betulinic acid 2 and its hexanoate derivative 2a against HCT-116 (colon adenocarcinoma), SF-295 (glioblastoma), HL-60 (leukemia) and PC-3 (prostate carcinoma) cells using MTT assay after 72 h incubation. Doxorubicin was used as positive control.

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Table SI
Percentual inhibition of cell growth in three human tumor cell lines. Data are presented as media ± standard deviation.

Thumbnail

Table SII
Cytotoxic activity of triterpenic esters derivatives 6a.b-10a.b against HCT-116 (colon adenocarcinoma), SF-295 (glioblastoma), HL-60 (leukemia) and PC-3 (prostate carcinoma) cells using MTT assay after 72 h incubation. Doxorubicin was used as positive control.

imageFigure 1 Betulinic acid and its derivative Bevirimat^® (2 and 1, respectively). open_in_new

imageFigure 2 Structures of betulinic and ursolic acids (2 and 3, respectively), lupeol (4), stigmasterol (5) and b-sitosterol (6). open_in_new

imageScheme 1 Condition to syntheses of esters: DMAP (2 eq.), DIC (2 eq.) in CH₂Cl₂, then acid (2 eq.) in CH₂Cl₂, 24-48h. open_in_new

table_chartTABLE I Cytotoxic activity of betulinic acid 2 and its hexanoate derivative 2a against HCT-116 (colon adenocarcinoma), SF-295 (glioblastoma), HL-60 (leukemia) and PC-3 (prostate carcinoma) cells using MTT assay after 72 h incubation. Doxorubicin was used as positive control.

Compound	HL-60	HCT-116	SF-295	PC-3
Compound	IC₅₀ (95% confidence interval) µg mL^-1 (mM)			PC-3
2	0.84 (1.84) (0.74-0.97)	2.05 (4.49) (1.73-2.42)	6.10 (13.36) (4.89-7.62)	1.78 (3.9) (1.42-2.23)
2a	10.86 (19.57) (8.54-13.81)	9.50 (17.12) (8.31-10.88)	17.43 (31.41) (12.91-23.54)	14.17 (25.54) (10.31-19.47)
Doxorubicin	0.02 (0.03) (0.01-0.02)	0.12 (0.21) (0.09-0.17)	0.24 (0.41) (0.2-0.27)	0.26 (0.44) (0.18-0.29)

IC₅₀ values and its 95% confidence interval were obtained by non-linear regression from two independent experiments performed in duplicate.

imageFigures S1-S40 describing characterization data (IR, 1H and 13C NMR spectra) of compounds 2a,b-6a,b.

table_chartTable SI Percentual inhibition of cell growth in three human tumor cell lines. Data are presented as media ± standard deviation.

Table SI Percentual inhibition of cell growth in three human tumor cell lines. Data are presented as media ± standard deviation.

table_chartTable SII Cytotoxic activity of triterpenic esters derivatives 6a.b-10a.b against HCT-116 (colon adenocarcinoma), SF-295 (glioblastoma), HL-60 (leukemia) and PC-3 (prostate carcinoma) cells using MTT assay after 72 h incubation. Doxorubicin was used as positive control.

Table SII Cytotoxic activity of triterpenic esters derivatives 6a.b-10a.b against HCT-116 (colon adenocarcinoma), SF-295 (glioblastoma), HL-60 (leukemia) and PC-3 (prostate carcinoma) cells using MTT assay after 72 h incubation. Doxorubicin was used as positive control.

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