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Synthesis and structure-activity relationship study of cytotoxic germanicane- and lupane-type 3beta-O-monodesmosidic saponins starting from betulin.
Bioorg Med Chem. 2007 Sep 15; 15(18):6144-57.BM

Abstract

Germanicane-type triterpenes allobetulin (3) and 28-oxoallobetulin (4) can be obtained by the Wagner-Meerwein rearrangement of the more available lupane-type triterpenes betulin (1) and betulinic acid (2), respectively. The medical uses of betulinic acid (2) and its derivatives are limited because of their poor hydrosolubility and pharmacokinetics properties. In order to overcome this major problem, we synthesized and studied the in vitro anticancer activity of a series of 3beta-O-monodesmosidic saponins derived from betulin (14-16), betulinic acid (20-22), allobetulin (23-28) and 28-oxoallobetulin (29-34) based on six different natural sugar residues (d-glucose, l-rhamnose, d-arabinose, d-galactose, d-mannose and d-xylose). This structure-activity relationship study confirmed that betulinic acid saponins are generally better in vitro anticancer agents than those derived from betulin with the exception of betulin 3beta-O-alpha-d-mannopyranoside (15) which exerted a potent cytotoxic activity against lung carcinoma (A-549) and colorectal adenocarcinoma (DLD-1) human cell lines with IC(50) ranging from 7.3 to 10.1mumol/L. Furthermore, although the synthesis of novel germanicane-type saponins was carried out with success, the bioactivity measured for these glycosides was not as high as we anticipated since only the 3beta-O-beta-d-glucopyranoside and 3beta-O-beta-d-galactopyranoside of allobetulin (23,24) showed moderate anticancer activity (IC(50) 30-40 micromol/L).

Authors+Show Affiliations

Laboratoire d'Analyse et de Séparation des Essences Végétales, Département des Sciences Fondamentales, Université du Québec à Chicoutimi, 555 boul. de l'Université, Chicoutimi, Québec, Canada.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17614290

Citation

Thibeault, Dominic, et al. "Synthesis and Structure-activity Relationship Study of Cytotoxic Germanicane- and Lupane-type 3beta-O-monodesmosidic Saponins Starting From Betulin." Bioorganic & Medicinal Chemistry, vol. 15, no. 18, 2007, pp. 6144-57.
Thibeault D, Gauthier C, Legault J, et al. Synthesis and structure-activity relationship study of cytotoxic germanicane- and lupane-type 3beta-O-monodesmosidic saponins starting from betulin. Bioorg Med Chem. 2007;15(18):6144-57.
Thibeault, D., Gauthier, C., Legault, J., Bouchard, J., Dufour, P., & Pichette, A. (2007). Synthesis and structure-activity relationship study of cytotoxic germanicane- and lupane-type 3beta-O-monodesmosidic saponins starting from betulin. Bioorganic & Medicinal Chemistry, 15(18), 6144-57.
Thibeault D, et al. Synthesis and Structure-activity Relationship Study of Cytotoxic Germanicane- and Lupane-type 3beta-O-monodesmosidic Saponins Starting From Betulin. Bioorg Med Chem. 2007 Sep 15;15(18):6144-57. PubMed PMID: 17614290.
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TY - JOUR T1 - Synthesis and structure-activity relationship study of cytotoxic germanicane- and lupane-type 3beta-O-monodesmosidic saponins starting from betulin. AU - Thibeault,Dominic, AU - Gauthier,Charles, AU - Legault,Jean, AU - Bouchard,Jimmy, AU - Dufour,Philippe, AU - Pichette,André, Y1 - 2007/06/20/ PY - 2007/03/09/received PY - 2007/06/11/revised PY - 2007/06/13/accepted PY - 2007/7/7/pubmed PY - 2007/10/25/medline PY - 2007/7/7/entrez SP - 6144 EP - 57 JF - Bioorganic & medicinal chemistry JO - Bioorg Med Chem VL - 15 IS - 18 N2 - Germanicane-type triterpenes allobetulin (3) and 28-oxoallobetulin (4) can be obtained by the Wagner-Meerwein rearrangement of the more available lupane-type triterpenes betulin (1) and betulinic acid (2), respectively. The medical uses of betulinic acid (2) and its derivatives are limited because of their poor hydrosolubility and pharmacokinetics properties. In order to overcome this major problem, we synthesized and studied the in vitro anticancer activity of a series of 3beta-O-monodesmosidic saponins derived from betulin (14-16), betulinic acid (20-22), allobetulin (23-28) and 28-oxoallobetulin (29-34) based on six different natural sugar residues (d-glucose, l-rhamnose, d-arabinose, d-galactose, d-mannose and d-xylose). This structure-activity relationship study confirmed that betulinic acid saponins are generally better in vitro anticancer agents than those derived from betulin with the exception of betulin 3beta-O-alpha-d-mannopyranoside (15) which exerted a potent cytotoxic activity against lung carcinoma (A-549) and colorectal adenocarcinoma (DLD-1) human cell lines with IC(50) ranging from 7.3 to 10.1mumol/L. Furthermore, although the synthesis of novel germanicane-type saponins was carried out with success, the bioactivity measured for these glycosides was not as high as we anticipated since only the 3beta-O-beta-d-glucopyranoside and 3beta-O-beta-d-galactopyranoside of allobetulin (23,24) showed moderate anticancer activity (IC(50) 30-40 micromol/L). SN - 0968-0896 UR - https://www.unboundmedicine.com/medline/citation/17614290/Synthesis_and_structure_activity_relationship_study_of_cytotoxic_germanicane__and_lupane_type_3beta_O_monodesmosidic_saponins_starting_from_betulin_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0968-0896(07)00569-X DB - PRIME DP - Unbound Medicine ER -