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Anti-leukemia activity of semi-synthetic phenolic derivatives from Polygonum limbatum Meisn.

Nkuété AH, Kuete V, Gozzini D, Migliolo L, Oliveira AL, Wabo HK, Tane P, Vidari G, Efferth T, Franco OL - Chem Cent J (2015)

Bottom Line: We describe in the present paper four new semi-synthetic derivatives of A and B: 5-hydroxy-6-methoxy-7-O-(3'-methylbut-2'-enyl)chroman-4-one (1), trivially named metapchromone, 5-acetoxy-6-methoxy-7-O-[3'-methylbut-2'enyl]chroman-4-one (2), trivially named sargisin, 2'-hydroxy-3',6'-dimethoxy-4'-O-(3″-methylbut-2″-enyl)chalcone (3) trivially named limbachalcone A, and 2'-acetoxy-3',6'-dimethoxy-4'-O-(3″-methylbut-2″-enyl)chalcone (4) trivially named tsedengchalcone.The study clearly suggests that semi-synthesis involving O-prenylation and acetylation of chalcones or other chromanones should be avoided in a search for anticancer drugs.This conclusion should be helpful when selecting substituents for the synthesis of potential anticancer drugs.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, Faculty of Science, University of Dschang, Dschang, Cameroon ; Centro de Analises Proteômicas e Bioquimicas, Pós-Graduação em Ciencias Genomicas e Biotecnologia, Universidade Catolica de Brasilia, Brasilia, DF Brazil ; Dipartimento di Chimica, Laboratorio di Chimica delle Sostanze Organiche Naturali e Centro di Etnobiofarmacia (CISTRE), Università degli Studi di Pavia, Via Taramelli, 12-27100 Pavia, Italy.

ABSTRACT

Background: The present report describes the semi-synthesis of a few O-prenylated phenolic derivatives and their in vitro antitumor activities. These compounds were prepared by modifying two naturally occurring antitumor phenols, 5,7-dihydroxy-3-(1'-hydroxy-1'-phenyl-methyl)-6-methoxy-chroman-4-one (A) and 2',4'-dihydroxy-3',6'-dimethoxychalcone (B), previously isolated from Polygonum limbatum Meisn. (Polygonaceae). The structures were elucidated by spectroscopic means and comparison with published data. The cytotoxicity of compounds was determined by using the resazurin assay in the parental drug-sensitive CCRF-CEM cell line and its multidrug-resistant P-glycoprotein-over-expressing subline, CEM/ADR5000.

Results: We describe in the present paper four new semi-synthetic derivatives of A and B: 5-hydroxy-6-methoxy-7-O-(3'-methylbut-2'-enyl)chroman-4-one (1), trivially named metapchromone, 5-acetoxy-6-methoxy-7-O-[3'-methylbut-2'enyl]chroman-4-one (2), trivially named sargisin, 2'-hydroxy-3',6'-dimethoxy-4'-O-(3″-methylbut-2″-enyl)chalcone (3) trivially named limbachalcone A, and 2'-acetoxy-3',6'-dimethoxy-4'-O-(3″-methylbut-2″-enyl)chalcone (4) trivially named tsedengchalcone. Their preliminary cytotoxic activities have been determined. We also report herein the isolation of 1-methylhydantoin (C) and betulinic acid (D) from Polygonum limbatum for the first time.

Conclusions: The study clearly suggests that semi-synthesis involving O-prenylation and acetylation of chalcones or other chromanones should be avoided in a search for anticancer drugs. This conclusion should be helpful when selecting substituents for the synthesis of potential anticancer drugs.

No MeSH data available.


Related in: MedlinePlus

Cytotoxicity activity of compounds on leukaemia CCRF-CEM cells at 125 μM.5,7-dihydroxy-3-(1′-hydroxy-1′-phenyl-methyl)-6-methoxy-chroman-4-one (A), 2′,4′-dihydroxy-3′,6′-dimethoxychalcone (B); 5-hydroxy-6-methoxy-7-O-(3′,3′-dimethylprop-2′-enyl)chroman-4-one (1), 5-acetyl-6-methoxy-7-O-(3′,3′-dimethylprop-2′-enyl)chroman-4-one (2), 2′-hydroxy-3′,6′-dimethoxy-4′-O-(3″,3″-dimethylprop-2″-enyl)chalcone (3), 2′-acetyl-3′,6′-dimethoxy-4′-O-(3″,3″-dimethylprop-2″-enyl)chalcone (4). Doxorubicin was used as a positive control
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Fig4: Cytotoxicity activity of compounds on leukaemia CCRF-CEM cells at 125 μM.5,7-dihydroxy-3-(1′-hydroxy-1′-phenyl-methyl)-6-methoxy-chroman-4-one (A), 2′,4′-dihydroxy-3′,6′-dimethoxychalcone (B); 5-hydroxy-6-methoxy-7-O-(3′,3′-dimethylprop-2′-enyl)chroman-4-one (1), 5-acetyl-6-methoxy-7-O-(3′,3′-dimethylprop-2′-enyl)chroman-4-one (2), 2′-hydroxy-3′,6′-dimethoxy-4′-O-(3″,3″-dimethylprop-2″-enyl)chalcone (3), 2′-acetyl-3′,6′-dimethoxy-4′-O-(3″,3″-dimethylprop-2″-enyl)chalcone (4). Doxorubicin was used as a positive control

Mentions: In this study, we determined the cytotoxicity of the natural compound A as well as the semi-synthetic compounds 1–4. We previously reported the cytotoxicity of compound B [3, 4], and the data were also reported herein for a better understanding of the structure-activity relationship (SAR). As shown in Fig. 4, the two natural compounds A and B were much more active than the semi-synthetic ones, inducing less than 20 % growth of CCRF-CEM leukaemia cells. This was confirmed in the dose–response assays, as IC50 values below 20 μM were recorded for the two natural compounds. Among the synthetic compounds (Table 2), 3 displayed the highest activity with IC50 values below 20 μM on the two tested leukaemia cell lines. Interestingly, the resistant cell line was more sensitive to compound 3 as well as to A and B than to doxorubicin. Nonetheless, the cytotoxicity can be considered moderate [8]. In contrast to doxorubicin, which was about 1000 times less active in multidrug-resistant CEM/ADR5000 cells than in parental CCRF-CEM cells, compounds A and B, as well as the semi-synthetic compound 3, showed minor cross-resistance in the otherwise highly drug-resistant CEM/ADR5000 cells. Regarding the structure-activity relationship, it clearly appeared that O-prenylation at position C4′ of B to afford 3 considerably reduced the cytotoxic activity. In addition to the O-prenylation, acetylation at C-2′ of 3 to afford 4 or at C5 of 1 to yield 2, further reduced the antiproliferative activity. These data clearly suggest that semi-synthesis involving O-prenylation and acetylation of chalcones or chromones should be avoided in the search for potential anticancer drugs. Usually it has been found that C-prenylation of the flavonoid nucleus increases the cytotoxic activity [9]. Moreover, as an additional benefit, prenylated flavonoids are relatively non-toxic to non-cancer cells [9]. In our case, O-prenylation was accompanied by a decrease in bioactivity, indicating the importance of free phenolic groups. This conclusion is further supported by the observation that, after prenylation, acetylation of the remaining free phenolic groups further reduced the cytotoxicity.Fig. 4


Anti-leukemia activity of semi-synthetic phenolic derivatives from Polygonum limbatum Meisn.

Nkuété AH, Kuete V, Gozzini D, Migliolo L, Oliveira AL, Wabo HK, Tane P, Vidari G, Efferth T, Franco OL - Chem Cent J (2015)

Cytotoxicity activity of compounds on leukaemia CCRF-CEM cells at 125 μM.5,7-dihydroxy-3-(1′-hydroxy-1′-phenyl-methyl)-6-methoxy-chroman-4-one (A), 2′,4′-dihydroxy-3′,6′-dimethoxychalcone (B); 5-hydroxy-6-methoxy-7-O-(3′,3′-dimethylprop-2′-enyl)chroman-4-one (1), 5-acetyl-6-methoxy-7-O-(3′,3′-dimethylprop-2′-enyl)chroman-4-one (2), 2′-hydroxy-3′,6′-dimethoxy-4′-O-(3″,3″-dimethylprop-2″-enyl)chalcone (3), 2′-acetyl-3′,6′-dimethoxy-4′-O-(3″,3″-dimethylprop-2″-enyl)chalcone (4). Doxorubicin was used as a positive control
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4493792&req=5

Fig4: Cytotoxicity activity of compounds on leukaemia CCRF-CEM cells at 125 μM.5,7-dihydroxy-3-(1′-hydroxy-1′-phenyl-methyl)-6-methoxy-chroman-4-one (A), 2′,4′-dihydroxy-3′,6′-dimethoxychalcone (B); 5-hydroxy-6-methoxy-7-O-(3′,3′-dimethylprop-2′-enyl)chroman-4-one (1), 5-acetyl-6-methoxy-7-O-(3′,3′-dimethylprop-2′-enyl)chroman-4-one (2), 2′-hydroxy-3′,6′-dimethoxy-4′-O-(3″,3″-dimethylprop-2″-enyl)chalcone (3), 2′-acetyl-3′,6′-dimethoxy-4′-O-(3″,3″-dimethylprop-2″-enyl)chalcone (4). Doxorubicin was used as a positive control
Mentions: In this study, we determined the cytotoxicity of the natural compound A as well as the semi-synthetic compounds 1–4. We previously reported the cytotoxicity of compound B [3, 4], and the data were also reported herein for a better understanding of the structure-activity relationship (SAR). As shown in Fig. 4, the two natural compounds A and B were much more active than the semi-synthetic ones, inducing less than 20 % growth of CCRF-CEM leukaemia cells. This was confirmed in the dose–response assays, as IC50 values below 20 μM were recorded for the two natural compounds. Among the synthetic compounds (Table 2), 3 displayed the highest activity with IC50 values below 20 μM on the two tested leukaemia cell lines. Interestingly, the resistant cell line was more sensitive to compound 3 as well as to A and B than to doxorubicin. Nonetheless, the cytotoxicity can be considered moderate [8]. In contrast to doxorubicin, which was about 1000 times less active in multidrug-resistant CEM/ADR5000 cells than in parental CCRF-CEM cells, compounds A and B, as well as the semi-synthetic compound 3, showed minor cross-resistance in the otherwise highly drug-resistant CEM/ADR5000 cells. Regarding the structure-activity relationship, it clearly appeared that O-prenylation at position C4′ of B to afford 3 considerably reduced the cytotoxic activity. In addition to the O-prenylation, acetylation at C-2′ of 3 to afford 4 or at C5 of 1 to yield 2, further reduced the antiproliferative activity. These data clearly suggest that semi-synthesis involving O-prenylation and acetylation of chalcones or chromones should be avoided in the search for potential anticancer drugs. Usually it has been found that C-prenylation of the flavonoid nucleus increases the cytotoxic activity [9]. Moreover, as an additional benefit, prenylated flavonoids are relatively non-toxic to non-cancer cells [9]. In our case, O-prenylation was accompanied by a decrease in bioactivity, indicating the importance of free phenolic groups. This conclusion is further supported by the observation that, after prenylation, acetylation of the remaining free phenolic groups further reduced the cytotoxicity.Fig. 4

Bottom Line: We describe in the present paper four new semi-synthetic derivatives of A and B: 5-hydroxy-6-methoxy-7-O-(3'-methylbut-2'-enyl)chroman-4-one (1), trivially named metapchromone, 5-acetoxy-6-methoxy-7-O-[3'-methylbut-2'enyl]chroman-4-one (2), trivially named sargisin, 2'-hydroxy-3',6'-dimethoxy-4'-O-(3″-methylbut-2″-enyl)chalcone (3) trivially named limbachalcone A, and 2'-acetoxy-3',6'-dimethoxy-4'-O-(3″-methylbut-2″-enyl)chalcone (4) trivially named tsedengchalcone.The study clearly suggests that semi-synthesis involving O-prenylation and acetylation of chalcones or other chromanones should be avoided in a search for anticancer drugs.This conclusion should be helpful when selecting substituents for the synthesis of potential anticancer drugs.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, Faculty of Science, University of Dschang, Dschang, Cameroon ; Centro de Analises Proteômicas e Bioquimicas, Pós-Graduação em Ciencias Genomicas e Biotecnologia, Universidade Catolica de Brasilia, Brasilia, DF Brazil ; Dipartimento di Chimica, Laboratorio di Chimica delle Sostanze Organiche Naturali e Centro di Etnobiofarmacia (CISTRE), Università degli Studi di Pavia, Via Taramelli, 12-27100 Pavia, Italy.

ABSTRACT

Background: The present report describes the semi-synthesis of a few O-prenylated phenolic derivatives and their in vitro antitumor activities. These compounds were prepared by modifying two naturally occurring antitumor phenols, 5,7-dihydroxy-3-(1'-hydroxy-1'-phenyl-methyl)-6-methoxy-chroman-4-one (A) and 2',4'-dihydroxy-3',6'-dimethoxychalcone (B), previously isolated from Polygonum limbatum Meisn. (Polygonaceae). The structures were elucidated by spectroscopic means and comparison with published data. The cytotoxicity of compounds was determined by using the resazurin assay in the parental drug-sensitive CCRF-CEM cell line and its multidrug-resistant P-glycoprotein-over-expressing subline, CEM/ADR5000.

Results: We describe in the present paper four new semi-synthetic derivatives of A and B: 5-hydroxy-6-methoxy-7-O-(3'-methylbut-2'-enyl)chroman-4-one (1), trivially named metapchromone, 5-acetoxy-6-methoxy-7-O-[3'-methylbut-2'enyl]chroman-4-one (2), trivially named sargisin, 2'-hydroxy-3',6'-dimethoxy-4'-O-(3″-methylbut-2″-enyl)chalcone (3) trivially named limbachalcone A, and 2'-acetoxy-3',6'-dimethoxy-4'-O-(3″-methylbut-2″-enyl)chalcone (4) trivially named tsedengchalcone. Their preliminary cytotoxic activities have been determined. We also report herein the isolation of 1-methylhydantoin (C) and betulinic acid (D) from Polygonum limbatum for the first time.

Conclusions: The study clearly suggests that semi-synthesis involving O-prenylation and acetylation of chalcones or other chromanones should be avoided in a search for anticancer drugs. This conclusion should be helpful when selecting substituents for the synthesis of potential anticancer drugs.

No MeSH data available.


Related in: MedlinePlus