Synthesis and Quantitative Structure-Property Relationships of Side Chain-Modified Hyodeoxycholic Acid Derivatives

Abstract

Bile acids have emerged as versatile signalling compounds of a complex network of nuclear and membrane receptors regulating various endocrine and paracrine functions. The elucidation of the interconnection between the biological pathways under the bile acid control and manifestations of hepatic and metabolic diseases have extended the scope of this class of steroids for in vivo investigations. In this framework, the design and synthesis of novel biliary derivatives able to modulate a specific receptor requires a deep understanding of both structure-activity and structure-property relationships of bile acids. In this paper, we report the preparation and the critical micellization concentration evaluation of a series of hyodeoxycholic acid derivatives characterized by a diverse side chain length and by the presence of a methyl group at the alpha position with respect to the terminal carboxylic acid moiety. The data collected are instrumental to extend on a quantitative basis, the knowledge of the current structure-property relationships of bile acids and will be fruitful, in combination with models of receptor activity, to design and prioritize the synthesis of novel pharmacokinetically suitable ligands useful in the validation of bile acid-responsive receptors as therapeutic targets.

Rice Bran and Probiotics Alter the Porcine Large Intestine and Serum Metabolomes for Protection against Human Rotavirus Diarrhea

“…Investigations have suggested that lower luminal levels of chenodeoxycholate are associated with decreased gastric emptying times and reduced expression of the pro-inflammatory cytokines TNF-a, IL-1B, IL-6, and IL-8 ( Goyal et al, 2015 ; Peleman et al, 2016 ). The decrease in chenodeoxycholate may be associated with metabolism of hyodeoxycholate a secondary bile acid resulting from bacterial metabolism of chenodeoxycholate ( Sabbatini et al, 2013 ; Theriot et al, 2016 ). In the colonic lumen, rodent studies suggest that hyodeoxycholate acts directly on goblet cells to increase mucus production, thereby modulating barrier function ( Barcelo et al, 2001 ).…”

Thermodynamic analysis and correlation of solid–liquid equilibrium of hyodeoxycholic acid in ethanol+(acetone, ethyl acetate) binary solvent mixtures

“…1, C 24 H 40 O 4 , CASRN: 83-49-8) is also known as 3α,6α-dihydroxy-5β-cholan-24-oic acid or HDCA, which is a secondary bile acid that is one of the metabolic byproducts of intestinal bacteria. It is widely used in treatment of hypertension and coronary artery disease [1,2]. Besides, HDCA was used as an anti-inflammatory drug to treat chronic bronchitis and infantile viral respiratory tract inflammation.…”

Ni-Electrocatalytic Enantioselective Doubly Decarboxylative C(sp3)–C(sp3) Cross Coupling

“…The enantioselective dDCC outlined herein can be applied to simplify the synthesis of both medicinally important structures and intermediates employed in natural product total synthesis (Figure ). For instance, the bile-acid derivative 49 (Figure A) was previously prepared from commercial hyodeoxycholic acid 47 as an inseparable mixture of diastereomers at C-24 in 15 steps with only one of those steps making a key C–C bond . In contrast, the same starting material could be enlisted to afford the desired product in only four steps as the major isomer (96:4 dr).…”

“…A vast array of RAEs derived from readily available alkyl carboxylic acids were tested. Aside from simple alkyl chains (3,5,6,18), a broad range of functional groups could be tolerated, such as terminal alkenes (4), internal alkenes (35, 37, 38), a trifluoromethyl group (8), terminal alkynes (9), internal alkynes (10,36), alkyl halides (15,17), aryl halides (7), ketones (16,41,42), silyl ethers (20), ethers (11,19), imides (14), heterocycles (12,13), lactones (38), carbamates (39, 40), and esters (39, 40). Several RAEs derived from malonate derivatives were also explored ranging from various substitutions on the phenyl ring (21−27) to substrates containing alkyl fluorides (32), nitriles (31), and internal alkenes (33, 34).…”

“…For instance, the bile-acid derivative 49 (Figure 2A) was previously prepared from commercial hyodeoxycholic acid 47 as an inseparable mixture of diastereomers at C-24 in 15 steps with only one of those steps making a key C−C bond. 15 In contrast, the same starting material could be enlisted to afford the desired product in only four steps as the major isomer (96:4 dr). The key dDCC proceeded in 34% yield with high diastereoselectivity (96:4 dr), thereby enabling this rapid route.…”