Synthesis and in vitro cholesterol dissolution by 23- and 24-phosphonobile acids
Introduction
Bile acids, which are essential for many physiological functions, are end-products of cholesterol metabolism. The physiological functions of bile salts result from their interesting physico-chemical properties, which have been studied extensively [1]. The glycine/taurine conjugates of bile acids form mixed micelles with phospholipids [2], [3], which solubilizes cholesterol. Impeding this function may cause the over saturation of cholesterol in the bile leading to its precipitation. The accumulation of cholesterol micro-crystals in the presence of glycoproteins leads to gallstone formation or cholelithiasis [4]. Chenodeoxy [5] and ursodeoxycholic acids [6] have been used with success for the dissolution of cholesterol gallstones. Two of the limitations of bile acid therapy are: (a) they undergo 7-dehydroxylation giving rise to hepatotoxic lithocholic acid and (b) low efficacy and prolonged treatment periods. There is growing interest in recent years to find a better gallstone-dissolving agent, which would be resistant to 7-dehydroxylation. The design of a few synthetic analogs of bile acids described in the literature has addressed this issue. N-methylated (sarcosine) glycocholate has been shown to possess therapeutic value, and is resistant to deconjugation and dehydroxylation [7]. The 7-methylated chenodeoxy and ursodeoxy derivatives were shown to be completely resistant to 7-dehydroxylation in hamsters [8]. Sulfonobile salts, side chain-modified analogs of natural bile salts, are resistant to 7-dehydroxylation, and do not interfere with endogenous bile acid synthesis [9], [10]. We have recently reported the synthesis of novel 23-phosphonobile acids [11]. In this paper, we report the synthesis of new 23- and 24-phosphonobile acids and a study of their in vitro cholesterol solubilizing efficiency as a model study for gallstone dissolution.
Section snippets
Materials and methods
Cholic, deoxycholic, chenodeoxycholic and lithocholic acids were purchased from Aldrich and were used as such. Ursodeoxycholic acid was also a commercial sample. Precoated silica gel glass plates with UV indicator on (0.25 mm thickness, Sigma–Aldrich) were used for thin layer chromatography and Liebermann–Burchard reagent was used as the spray reagent to visualize the steroids. Acme 100–200 mesh silica gel was used for gravity column chromatography. All the solvents used were of laboratory grade
Synthesis
The syntheses of 23-phosphonobile acids were accomplished as shown in Scheme 1. In addition, the one-carbon homologs were also synthesized starting from bile acids (Scheme 2). Cholic acid (CA), deoxycholic acid (DCA), chenodeoxycholic acid (CDCA), ursodeoxycholic acid (UDCA) and lithocholic acid (LCA) were converted to their corresponding performyl derivatives by heating with formic acid.
For the syntheses of 23-phosphonobile acids, formyl protected bile acids were subjected to a modified
Conclusions
We synthesized a new class of bile acid analogs. In vitro cholesterol solubilizing efficiency of 23- and 24-phosphonobile salts has been studied. The 24-PBSs solubilize cholesterol slightly better than 23-PBSs and bile salts. We believe that our preliminary results are encouraging to further explore a better medicinal therapy for cholesterol gallstone dissolution. The aggregation and gelation properties of these new compounds will be published elsewhere.
Acknowledgments
We thank the Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore for financial support of this work. Ponnusamy Babu thanks CSIR for fellowship.
References (18)
Physical-chemical properties of bile acids and their salts
- et al.
Roles of bile acids in intestinal lipid digestion and adsorption
- et al.
Synthesis of potential cholelitholytic agents: 3α, 7α, 12α-trihydroxy-7β-methyl-5β-cholanic acid, 3α, 7β, 12α-trihydroxy-7α-methyl-5β-cholanic acid, 3α, 12α-dihydroxy-7ɛ-methyl-5β-cholanic acid
J Lipid Res
(1985) - et al.
Metabolism of sulfonate analogs of ursodeoxycholic acid and their effects on biliary bile acid composition in hamsters
J Lipid Res
(1993) - et al.
First Synthesis of phosphonobile acids and preliminary studies on their aggregation properties
Steroids
(2003) - et al.
Synthesis of conjugated bile acids. II. Glycodesoxycholic acid
J Biol Chem
(1936) - et al.
The hydrophobic-hydrophilic balance of bile salts. Inverse correlation between reverse-phase high performance liquid chromatographic mobilities and micellar cholesterol-solubilizing capacities
J Lipid Res
(1982) Bile acid science (cholanology) at the dawn of a new millennium: past progress and challenges for the future
Formation and growth of cholesterol gallstones: the new synthesis
Cited by (18)
Haemolytic activity of formyl- and acetyl-derivatives of bile acids and their gramine salts
2017, SteroidsCitation Excerpt :Bile acids and their derivatives are also attractive compounds for synthetic chemists because they have a large, rigid skeleton and possess chemically different polar hydroxyl groups. It is often necessary to protect this hydroxyl groups using, for example, acetate or formate as protecting moieties [8–10]. According to Tsemg at al. [11], the formyl groups on these compounds are quite stable to various reaction conditions.
Self gelating isoracemosol A, new racemosaceramide A, and racemosol E from Barringtonia racemosa
2017, Natural Product ResearchAn efficient synthesis of 7α,12α-dihydroxy-4-cholesten-3-one and its biological precursor 7α-hydroxy-4-cholesten-3-one: Key intermediates in bile acid biosynthesis
2013, SteroidsCitation Excerpt :The 19-H3 signal (singlet) in 1a was appreciably shifted downfield by 0.19 ppm and resonated at 1.19 ppm, compared to that in 10a (1.00 ppm), whereas a signal appearing at 5.82 ppm as a singlet was assigned to the 4-H. These observations indicated that 1a has the 3-oxo-Δ 4-7α-hydroxy structure in the A/B-ring juncture [15]. Furthermore, the occurrence of the two quaternary 13C signals at 198.7 and 167.4 ppm and the tertiary 13C signal at 126.9 ppm in the 13C-NMR spectrum of 1a also indicated the presence of the conjugated enone moiety.
Synthesis, characterization and biological activity of hydroxyl- bisphosphonic analogs of bile acids
2012, European Journal of Medicinal ChemistryChemical synthesis of the (25R)- and (25S)-epimers of 3α,7α, 12α-trihydroxy-5α-cholestan-27-oic acid as well as their corresponding glycine and taurine conjugates
2011, Chemistry and Physics of LipidsCitation Excerpt :Our attempt to apply the reduction of 11 with LiAlH4 was discouraging; low yields of the desired 12 were obtained after a laborious chromatographic purification process, due to the concurrent formation of partial hydrolysis products at positions C-3, C-7 and/or C-12. However, a more mild reduction of 11 using the less basic NaBH4, in the presence of triethylamine and ethyl chloroformate (Babu and Maitra, 2005) in methanol at room temperature, proceeded smoothly to give the 3,7,12-triformyl-24-ol 12 in good yield (84%), without the problems of partial hydrolysis of protecting groups. Alkylation of alkyl halides with malonic diesters is a promising way to extend steroid side chains (Starchenkov et al., 2000; Komatsubara, 1954; Hayatsu, 1957).
Synthesis and olfactory activity of unnatural, sulfated 5β-bile acid derivatives in the sea lamprey (Petromyzon marinus)
2011, SteroidsCitation Excerpt :The analogous compounds 9b and 9c, derived from deoxycholic acid (10b) and chenodeoxycholic acid (10c) respectively, were synthesized using a very similar protocol. Lithocholic acid (10d) was converted to the primary alcohol 12d using a one-flask/two-reaction sequence (Scheme 2), presumably via the THP-ester 11d [19]. The primary alcohol 12d was sulfated (SO3·Py, Et3N) to give the THP-ether 13d, which was converted to the secondary alcohol 9d (pPTS, EtOH).