Emerging technologies for metabolite generation and structural diversification

Abstract

Multiple technologies have emerged for structural diversification and efficient production of metabolites of drug molecules. These include expanded use of enzymatic and bioorganic transformations that mimic biological systems, biomimetic catalysis and electrochemical techniques. As this field continues to mature the breadth of transformations is growing beyond simple oxidative processes due in part to parallel development of more efficient catalytic methods for functionalization of unactivated scaffolds. These technologies allow for efficient structural diversification of both aromatic and aliphatic substrates in many cases via single step reactions without the use of protecting groups.

Application of engineered cytochrome P450 mutants as biocatalysts for the synthesis of benzylic and aromatic metabolites of fenamic acid NSAIDs

“…12 Enzymes which are capable of introducing an oxygen atom in a highly regioselective manner are of high demand in organic synthesis. 13 The use of engineered bacterial cytochrome P450s for the production of drug metabolites has gained importance over the years. 14,15 Among the bacterial P450s, cytochrome CYP102A1 (Cytochrome P450 BM3) from Bacillus megaterium is a well known fatty acid hydroxylase.…”

Cytochrome P450 Enzyme Metabolites in Lead Discovery and Development

“…Understanding the role of the CYP in the orcinol and phloroglucinol ring coupling reactions opens up the possibility of creating griseofulvin analogs that may have useful applications as antifungal or antineoplastic agents. A number of exciting technologies to combine CYP active metabolite generation with structural elucidation and activity studies have recently surfaced, all of which will no doubt be a boon for novel lead discovery 10,27 .…”

“…One of the more innovative and exciting approaches to the identification and exploitation of active CYP metabolites has been the development of microscale and microfluidic technologies for the production and analysis of CYP metabolic products 10 . Using these technologies, it is possible to screen a number of CYP generated metabolites simultaneously.…”

“…Additionally, several of the drugs derived from natural products are further transformed by drug metabolizing CYPs in vivo into biologically active metabolites, some of which are more potent than the parent compound 9 . More recently, microscale analytical technologies have been employed for the generation and identification of CYP metabolites as lead compounds 10 . In conjunction with the development of bioreactor technology, whereby CYP oxidative transformations may be scaled-up for quantitative production of metabolites, this has ushered in the possibility of utilizing CYPs as a platform for lead discovery and development 10,11 .…”

“…More recently, microscale analytical technologies have been employed for the generation and identification of CYP metabolites as lead compounds 10 . In conjunction with the development of bioreactor technology, whereby CYP oxidative transformations may be scaled-up for quantitative production of metabolites, this has ushered in the possibility of utilizing CYPs as a platform for lead discovery and development 10,11 . This review will highlight some of the recent examples of drug leads identified from CYP metabolites and the intriguing possibilities of using CYPs as catalysts for future drug discovery and development.…”