160242-89-7Relevant academic research and scientific papers
Mitochondrial affinity of guanidine-rich molecular transporters built on monosaccharide scaffolds: Stereochemistry and lipophilicity
Lee, Woo Sirl,Kim, Wanil,Kim, Kyong-Tai,Chung, Sung-Kee
experimental part, p. 2286 - 2300 (2012/06/16)
We synthesized eight G8 molecular transporters (MTs) based on 4 different monosaccharide scaffolds, and studied their biological properties with a special focus on possible mitochondrial targeting and tissue selectivity. The mitochondrial affinity of these MTs was found to be clearly related to the scaffold stereochemistry and also tenuously with the lipophilicity. It may be suggested that in the practical delivery strategy of drugs for the brain and mitochondrial diseases the BBB permeability and mitochondrial affinity should be considered as key parameters, and that an enhanced mitochondrial affinity appears possible by further research on the structure-property relationship of guanidine-rich molecular transporters.
Synthesis and enzyme-specific activation of carbohydrate-geldanamycin conjugates with potent anticancer activity
Cheng, Hao,Cao, Xianhua,Xian, Ming,Fang, Lanyan,Cai, Tingwei Bill,Ji, Jacqueline Jia,Tunac, Josefino B.,Sun, Duxin,Wang, Peng George
, p. 645 - 652 (2007/10/03)
Geldanamycin (GA) is a potent anticancer antibiotic that inhibits Hsp90. Its potential clinical utility is hampered by its severe toxicity. To alleviate this problem, we synthesized a series of carbohydrate-geldanamycin conjugates for enzyme-specific activation to increase tumor selectivity. The conjugation was carried out at the C-17-position of GA. Their anticancer activity was tested in a number of cancer cell lines. The enzyme-specific activation of these conjugates was evaluated with β-galactosidase and β-glucosidase. Evidently, glycosylation of C-17-position converted GA to an inactive prodrug before enzyme cleavage. Glucose-GA, as positive control, showed anticancer activity with IC50 of 70.2-380.9 nM in various cancer cells by β-glucosidase activation inside of the tumor cells, which was confirmed by 3-fold inhibition using β-glucosidase specific inhibitor [2,5-dihydroxyniethy-3,4-dihydroxypyrrolidine (DMDP)]. Compared to glucose-GA, galactose- and lactose-GA conjugates exhibited much less activity with IC 50 greater than 8000-25 000 nM. However, when galactose- and lactose-GA were incubated with β-galactosidase in the cells, their anticancer activity was enhanced by 3- to 40-fold. The results suggest that GA can be inactivated by glycosylation of C-17-position and reactivated for anticancer activity by β-galactosidase. Therefore, galactose-GA can be exploited in antibody-directed enzyme prodrug therapy (ADEPT) with β-galactosidase for enzyme-specific activation in tumors to increase tumor selectivity.
Synthesis of the 5-aminopentyl glycoside of β-D-Galp-(1->4)-β-D-GlcpNAc-(1->3)-L-Fucp and fragments thereof related to glycopeptides of human Christmas factor and the marine sponge Microciona prolifera
Ziegler, Thomas
, p. 195 - 212 (2007/10/02)
The marine sponge Microciona prolifera and human coagulation factor IX (Christmas factor)-related mono- to tri-saccharide 5-aminopentyl glycosides β-D-Galp-R (5), β-D-GlcpNAc-R (16), β-D-Galp-(1->4)-β-D-GlcpNAc-R (26), β-D-GlcpNAc-(1->3)-β-L-Fucp-R (39), β-D-GlcpNAc-(1->3)-α-L-Fucp-R (43), β-D-Galp-(1->4)-β-D-GlcpNAc-(1->3)-β-L-Fucp-R (45), and β-D-Galp-(1->4)-β-D-GlcpNAc-(1->3)-α-L-Fucp-R (47), where R is a 5-aminopentyloxy spacer moiety, which allowed the construction of glycoconjugates, were prepared.Thus 3,4,6-tri-O-acetyl-2-deoxy-2-(2,2,2-trichloroethoxycarbonylamino)-α-D-glucopyranosyl trichloroacetimidate (10) and 1,3,4,6-tetra-O-acetyl-2-chloroacetamido-2-deoxy-β-D-glucopyranose (13) were condensed with N-Z-protected 5-aminopentanol (2) followed by conversion of the coupling products into the corresponding N-acetylglucosamine derivatives, to give compound 16 after deblocking.Similarly, the donors 10 and 13 were coupled to position 3 of suitably protected aminopentyl β- (32) and α- (37) -L-fucopyranosides, to give the disaccharides 39 and 43, respectively.Starting from lactose, O-(2,3,4,6-tetra-O-benzoyl-β-D-galactopyranosyl)-(1->4)-3,6-di-O-benzoyl-2-deoxy-2-(2,2,2-trichloroethoxycarbonylamino)-α-D-glucopyranosyl trichloroacetimidate (23) was prepared and used as an efficient disaccharide donor for the construction of ligand 26 from 2 and of the trisaccharide ligands 45 and 47 from fucosides 32 and 37, respectively.Key words: Christmas factor, human; Coagulation factor IX; Human marine sponge Microciona prolifera; Aminopentyl glycoside
