Synthesis of 24-(Piperidin-1-yl, Morpholin-4-yl and 4-Methylpiperazin-1-yl)-5β-cholan-3α-ols and Four Hydroxylated 23-(4,5-Dihydroimidazol-2-yl)-24-nor-5β-cholanes

Abstract

Lithocholic (1a), chenodeoxycholic (1b), deoxycholic (1c) and cholic acid (1d) were used for the synthesis of the title compouds. Reactions of O-acetyllithocholic acid chloride with piperidine, morpholine and 1-methylpiperazine gave the corresponding amides 2a-2c which were reduced with lithium aluminium hydride to 24-(piperidin-1-yl)-5β-cholan-3α-ol (3a) and analogues 3b and 3c. Heating of the acids 1a-1d with ethylenediamine monotosylate afforded 23-(4,5-dihydroimidazol-2-yl)-24-nor-5β-cholan-3α-ol (4a) and analogues 4b-4d. Compound 4a was similarly obtained from 3α-acetoxy-24-nor-5β-cholane-23-carbonitrile. Identity of the products was corroborated by spectral characterization. Some of the products (in the form of salts) were tested for cancerostatic and antimicrobial activities in vitro with partially promising results.

Hierarchical Self-Assembly of Bile-Acid-Derived Dicationic Amphiphiles and Their Toxicity Assessment on Microbial and Mammalian Systems

“…33−37 In most of the cases, bile salts has been synthesized with a cationic group at the side chain by introducing a bis (amine) through amide conjugation chemistry and converting the second amine to a quaternary ammonium salt. 34,38 On the other hand, Maitra and co-workers has reported cationic bile salts without amide linkage at the side chain and studied their aggregation and gelation behavior. 39 Recently, Galantini and co-workers has reported the self-assembly of a tryptophan and phenylalanine substituted bile acids.…”

“…Over the last few decades, researchers have worked on the synthesis and studies of cationic bile acid derivatives owing to their wide range of applications as cancerostatic, cholesterol dissolution agents, gallstone dissolution enhancers, and DNA transfection agents. − Moreover, these derivatives were found to be potent antibacterial agents in biomedical applications. , Many reports are available on the synthesis of cationic bile salts through ether, ester, and amide linkages in both facial and side chain of the bile acids and the level of difficulty varies widely in these syntheses. − In most of the cases, bile salts has been synthesized with a cationic group at the side chain by introducing a bis (amine) through amide conjugation chemistry and converting the second amine to a quaternary ammonium salt. , On the other hand, Maitra and co-workers has reported cationic bile salts without amide linkage at the side chain and studied their aggregation and gelation behavior . Recently, Galantini and co-workers has reported the self-assembly of a tryptophan and phenylalanine substituted bile acids …”

Novel Cationic and Neutral Analogues of Bile Acids: Synthesis and Preliminary Study of Their Aggregation Properties

“…Bile salts formed by the conjugation of bile acids with taurine and glycine are biologically important surfactants involved in a number of biological functions such as solubilization of cholesterol, absorption of dietary fats and fat soluble vitamins, and removal of pancreatic hydrolysis products such as fatty acids by their detergent action. 1 Cationic bile salts have attracted the attention of medicinal chemists during the last two decades as cancerostatic, 2 antimicrobial, 3 and cholesterol-lowering agents, 4 gallstone dissolution enhancers, 5 and DNA transfection agents. 6 Most of these analogues have been synthesized by attaching a bis(amine) to the bile acid through an amide bond, and converting the other amine to a quaternary ammonium salt.…”

“…6 Most of these analogues have been synthesized by attaching a bis(amine) to the bile acid through an amide bond, and converting the other amine to a quaternary ammonium salt. [2][3][4][5][6] In some cases the amide group was reduced to an amine. Our recent discovery 7 of a tripodal cationic bile acid derivative as a powerful gelator of aqueous liquids led us to design simpler, monomeric analogues of bile acids as potential hydrogelators.…”

Calcium‐ and Voltage‐Gated Potassium (BK) Channel Activators in the 5β‐Cholanic Acid‐3α‐ol Analogue Series with Modifications in the Lateral Chain

“…[33] Compound 10 was stirred with p-toluene sulfonic acid (p-TsOH) in methanol at room temperature for three days to procure deacetylated derivative 11. [34] The desired 3a-hydroxy-23tetrazole (12) was conveniently prepared in good yield by refluxing the nitrile derivative (11) with sodium azide and triethylamine hydrochloride in toluene (Scheme 2). Scheme 3 shows the synthesis of several final products from a key sulfonate intermediate (13).…”