Effects of α- and β-tigogenin cellobiosides on cholesterol absorption

Malinow, M. R.; Gardner, J.O.; Nelson, Jarrell T.; McLaughlin, P.; Upson, B.; Aigner-Held, Rosemarie

doi:10.1016/0039-128x(86)90003-6

Cited by 14 publications

(3 citation statements)

References 27 publications

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“…Through their earlier work with alfalfa saponins, they recognized the importance of isolating pure saponin components in order to better assess their pharmacological and toxicological properties (20). They prepared the synthetic spirostane saponins, diosgenin glucoside and tigogenin cellobioside, and demonstrated their effects on cholesterol absorption (21) and sterol balance in monkeys (22). Tigogenin cellobioside (tiqueside, CP-88,818) was later shown to decrease TPC concentrations in a variety of animals (23) and in humans (24).…”

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confidence: 99%

Comparison of synthetic saponin cholesterol absorption inhibitors in rabbits: evidence for a non-stoichiometric, intestinal mechanism of action

Morehouse

Bangerter

DeNinno

et al. 1999

Journal of Lipid Research

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The hypocholesterolemic activities of pamaqueside and tiqueside, two structurally similar saponins, were evaluated in cholesterol-fed rabbits. The pharmacological profiles of the saponins were virtually identical: both dosedependently decreased the intestinal absorption of labeled cholesterol 25-75%, increased fecal neutral sterol excretion up to 2.5-fold, and decreased hepatic cholesterol content 10-55%. High doses of pamaqueside ( Ͼ 5 mg/kg) or tiqueside ( Ͼ 125 mg/kg) completely prevented hypercholesterolemia. Decreases in plasma and hepatic cholesterol levels were strongly correlated with increased neutral sterol excretion. Ratios of neutral sterol excreted to pamaqueside administered were greater than 1:1 at all doses, in opposition to the formation of a stoichiometric complex previously suggested for tiqueside and other saponins. Ratios in tiqueside-treated rabbits were less than unity, a reflection of its lower potency. Pamaqueside-treated rabbits exhibited a more rapid decline in plasma cholesterol concentrations than control animals fed a cholesterol-free diet, indicating that the compound also inhibited the absorption of biliary cholesterol. Intravenous administration of pamaqueside had no effect on plasma cholesterol levels despite plasma levels twice those observed in rabbits given pamaqueside orally. These data indicate that pamaqueside and tiqueside induce hypocholesterolemia by blocking lumenal cholesterol absorption via a mechanism that apparently differs from the stoichiometric complexation of cholesterol hypothesized for other saponins. -Morehouse, L.

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confidence: 99%

Comparison of synthetic saponin cholesterol absorption inhibitors in rabbits: evidence for a non-stoichiometric, intestinal mechanism of action

Morehouse

Bangerter

DeNinno

et al. 1999

Journal of Lipid Research

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“…Enzymatic hydrolysis of 2 with naringinase gave 1a and d -glucose. The 1 H- and 13 C-NMR signals of the diglycoside moiety, which were assigned based on 1 H- 1 H correlation spectroscopy (COSY) and 1 H-detected heteronuclear multiple coherence (HMQC) spectra, indicated the presence of a terminal β- d -glucopyranosyl unit [δ H 5.20 (d, J = 7.9 Hz, H-1′′ of Glc (II)); δ C 104.9 (CH), 74.8 (CH), 78.2 (CH), 71.5 (CH), 78.4 (CH), 62.3 (CH 2 )] and a C-4 glycosylated β- d -glucopyranosyl unit [δ H 4.87 (d, J = 7.8 Hz, H-1′ of Glc (I)); δ C 106.4 (CH), 75.2 (CH), 76.9 (CH), 81.6 (CH), 76.2 (CH), 62.3 (CH 2 )] in the molecule of 2 [20] . In the HMBC spectrum of 2 , long-range correlations were observed between H-1′′ of Glc (II) and C-3′ of Glc (I), and between H-1′ of Glc (I) and C-3 of the aglycone moiety at δ C 88.7.…”

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confidence: 99%

Cycloartane and Oleanane Glycosides from the Tubers of Eranthis cilicica

et al. 2018

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Phytochemical analysis of the tubers of Eranthis cilicica was performed as part of our continuous study on the plants of the family Ranunculaceae, which resulted in the isolation of eleven new cycloartane glycosides (1–11) and one new oleanane glycoside (13), together with one known oleanane glycoside (12). The structures of the new compounds were determined by extensive spectroscopic analysis, including two-dimensional (2D) NMR, and enzymatic hydrolysis followed by either X-ray crystallographic or chromatographic analysis. The aglycone (1a) of 2 and its C-23 epimer (8a), and the oleanane glycosides (12 and 13) showed cytotoxic activity against HL-60 leukemia cells with IC50 values ranging from 10.6 μM to 101.6 μM. HL-60 cells were much more sensitive to 8a (IC50 14.8 μM) than 1a (IC50 101.1 μM), indicating that the C-23 configuration is associated with the cytotoxicity of these cycloartane derivatives. Compound 12 was revealed so as to partially induce apoptotic cell death in HL-60 cells, as was evident from morphology of HL-60 cells treated with 12.

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“…Recently, the inhibition of cholesterol absorption by steroid disaccharides has been studied at Pfizer Central Research for the treatment of atherosclerosis. Tiqueside, tigogenyl β- O -cellobioside 1 , which was first described by Rene Malinow et al, reached phase 2 clinical studies. While tiqueside was efficacious and well-tolerated, its relatively weak potency discouraged further development. Structural modification of the steroid nucleus led to the discovery of the more potent pamaqueside, 11-ketotigogenyl β- O -cellobioside 2 .…”

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Process Research and Large-Scale Synthesis of 4‘‘,6‘‘-Bis((2-fluorophenyl)carbamoyl)hecogenyl β-O-Cellobioside: A Potent Cholesterol Absorption Inhibitor

Urban¹,

Breitenbach²,

Buzon³

et al. 1998

Org. Process Res. Dev.

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This paper describes process research leading to the successful scale-up of a potent cholesterol absorption inhibitor 4‘‘,6‘‘-bis((2-fluorophenyl)carbamoyl)hecogenyl β-O-cellobioside 3. The synthesis of 3 from hecogenyl β-O-cellobioside 4 required five synthetic steps: (1) the selective protection of the 4‘‘,6‘‘-diol group, (2) acylation of the remaining five hydroxyl groups, (3) unmasking of the diol moiety, (4) carbamoylation with 2-fluorophenyl isocyanate, and finally, (5) deacylation. The synthesis by our discovery group utilized chloroacetate protecting groups for five of the sugar alcohols at step two, which led to problems on scale-up due to the instability of this group in solution and the poor crystallinity of the intermediates. Methoxyacetates were identified as the optimal acyl-protecting group. The identification of mild reaction conditions led to an efficient synthesis of bis(carbamate) 3 in very high purity and 42% yield from 4 over five synthetic steps and one recrystallization/polymorph conversion. The process was simple to operate and was carried out to provide 80 kg of 4‘‘,6‘‘-bis(2-fluorophenylcarbamoyl)hecogenyl β-O-cellobioside 3.

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Effects of α- and β-tigogenin cellobiosides on cholesterol absorption

Cited by 14 publications

References 27 publications

Comparison of synthetic saponin cholesterol absorption inhibitors in rabbits: evidence for a non-stoichiometric, intestinal mechanism of action

Comparison of synthetic saponin cholesterol absorption inhibitors in rabbits: evidence for a non-stoichiometric, intestinal mechanism of action

Cycloartane and Oleanane Glycosides from the Tubers of Eranthis cilicica

Process Research and Large-Scale Synthesis of 4‘‘,6‘‘-Bis((2-fluorophenyl)carbamoyl)hecogenyl β-O-Cellobioside: A Potent Cholesterol Absorption Inhibitor

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