Synthesis of menarandroside A from dehydroepiandrosterone.

Menarandroside A, which bears a 12α-hydroxypregnenolone steroid backbone, was isolated from the plant, . Treatment of extracts from this plant containing menarandroside A against secretin tumor cell line (STC-1) intestinal cells, resulted in an increased secretion of glucagon-like peptide 1 (GLP-1), a peptide that plays a role in the regulation of blood sugar levels. Increase in GLP-1 is beneficial for the treatment of type 2 diabetes.

Pyridine-containing substrate analogs are restricted from accessing the human cytochrome P450 8B1 active site by tryptophan 281.

The human oxysterol 12α-hydroxylase cytochrome P450 8B1 (CYP8B1) is a validated drug target for both type 2 diabetes and nonalcoholic fatty liver disease, but effective selective inhibitors are not yet available. Herein, steroidal substrate-mimicking compounds with a pyridine ring appended to the C12 site of metabolism were designed as inhibitors, synthesized, and evaluated in terms of their functional and structural interactions with CYP8B1. While the pyridine nitrogen was intended to coordinate the CYP8B1 active site heme iron, none of these compounds elicited shifts in the CYP8B1 Soret absorbance consistent with this type of interaction.

Copper oxidation chemistry using a 19-iminopyridine-bearing steroidal ligand: (i) C5-C6 olefin difunctionalization and (ii) C1β-hydroxylation/C19-peroxidation.

The Schönecker oxidation involves the 12beta-hydroxylation of 17-imino pyridine DHEA derivatives using copper and either molecular oxygen or hydrogen peroxide as the oxidant. In this study, a 19-imino pyridine DHEA derivative was synthesized and was treated with copper nitrate and hydrogen peroxide. Our results showed the difunctionalization of an olefin for delta-5 steroid substrates to yield a 5beta-hydroxylated 6alpha-nitrate ester product.

A synthesis of a rationally designed inhibitor of cytochrome P450 8B1, a therapeutic target to treat obesity.

Mice that lack the gene for expression of cytochrome P450 8B1 (P450 8B1) resist weight gain and improve glucose tolerance when fed a high-fat diet. Thus, the inhibition of P450 8B1 is a target to treat obesity-associated metabolic disorders. P450 8B1 is the enzyme that hydroxylates its substrate, 7α-hydroxy-cholest-4-en-3-one to 7α-,12α-dihydroxycholest-4-en-3-one, which ultimately results in the formation of cholic acid.

Chemical synthesis of 7α-hydroxycholest-4-en-3-one, a biomarker for irritable bowel syndrome and bile acid malabsorption.

7α-Hydroxy-cholest-4-en-3-one is a biomarker for bile acid loss, irritable bowel syndrome, and other diseases associated with defective bile acid biosynthesis. Furthermore, 7α-hydroxy-cholest-4-en-3-one is the physiological substrate for cytochrome P450 8B1 (P450 8B1 or CYP8B1), the oxysterol 12α-hydroxylase enzyme implicated in obesity and cardiovascular health. We report the chemical synthesis of this physiologically important oxysterol beginning with cholesterol.

Chemical synthesis of 7-oxygenated 12α-hydroxy steroid derivatives to enable the biochemical characterization of cytochrome P450 8B1, the oxysterol 12α-hydroxylase enzyme implicated in cardiovascular health and obesity.

Cholic acid is the endogenous 12α-hydroxylated bile acid, which possesses enhanced cholesterol absorption properties compared to its 12-desoxy counterpart, chenodeoxycholic acid. The oxysterol 12α-hydroxylase enzyme is cytochrome P450 8B1 (P450 8B1), which regioselectively and stereoselectively incorporates the 12α-hydroxy group in 7α-hydroxycholest-4-en-3-one, the biosynthetic precursor of cholic acid. Despite the vital role of P450 8B1 activity in cardiovascular health, research studies of other 12α-hydroxy steroid derivatives are rare.