Metabolite Synthesis

Synthesis of sulfated metabolites

Sulfate metabolite synthesis

Sulfate metabolite synthesis is achieved using a variety of scalable techniques in Hypha’s one-stop metabolite shop.

Sulfation is an important phase 2 reaction in the biotransformation of structurally diverse compounds containing aromatic or aliphatic hydroxyl and amine groups. These reactions are undertaken by sulfotransferases (SULTs) which are widely distributed in tissues. During the process of sulfation by these enzymes, a sulfonate moiety is transferred from the 3′-phosphoadenosine-5′-phosphosulfate (PAPS) to the substrates. In humans there are three SULT families; SULT1, SULT2, and SULT4.

Generally the addition of a sulfonate moiety to a compound increases its water solubility and decreases its biological activity. However, many of these SULTs are also capable of bioactivation producing carcinogenic reactive electrophiles (Gamage et al., 2006), and thus these metabolites are important to characterise.

Sulfated metabolites can be screened for and scaled-up using a number of techniques, including microbial biotransformation, liver S9 fractions and late-stage chemical synthesis. Metabolites can be supplied at microgram to multi mg scale, and at gram scale via the microbial and chemical synthesis route..

Case studies

A project for a pharma client involved synthesis of two sulfated metabolites in mg amounts. Following a dual system screening approach, more than 50 mg of an O-sulfate was produced from porcine S9 fraction incubations and more than 10 mg of an N-sulfate via a microbial biocatalytic route. Employing the best yielding path for synthesising each sulfated metabolite meant that requirements were successfully met for supply of both metabolites at high purity.

In another client project, a sulfated metabolite was required which was produced in humans through an aryl hydroxylated intermediate. Hypha used microbial biotransformation to produce the intermediate metabolite followed by late-stage chemical synthesis to make and purify hundreds of milligrams of both the unlabelled and deuterated O-sulfated metabolite.

Resources

Explore our library of resources comprising brochures, case studies, posters and publications about the work we do.

Phase 2 conjugated metabolites such as sulfates can be screened for and scaled-up using a variety of methods including microbial biotransformation, mammalian biotransformation and chemical synthesis. The chemical sulfation screens work well for both aliphatic and aromatic alcohols. Metabolites can be supplied at microgram to multi mg scale, and at gram scale via the microbial and chemical synthesis routes.

Interested in metabolite synthesis? Download this useful resource on how Hypha approach making metabolites of drugs and agrochemicals, featuring a variety of interesting case studies.

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Hypha Discovery has been a valuable metabolite ID partner. Hypha have provided biotransformation, metabolite purification and structure elucidation answers to some of our most challenging metabolism and metabolite ID problems. We really appreciate the breadth of expertise available at Hypha Discovery and will definitely reach out for future work.

Director of DMPK

US Pharma Company

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