Halogenating Enzymes for Active Agent Synthesis: First Steps Are Done and Many Have to Follow

Abstract

Halogens can be very important for active agents as vital parts of their binding mode, on the one hand, but are on the other hand instrumental in the synthesis of most active agents. However, the primary halogenating compound is molecular chlorine which has two major drawbacks, high energy consumption and hazardous handling. Nature bypassed molecular halogens and evolved at least six halogenating enzymes: Three kind of haloperoxidases, flavin-dependent halogenases as well as α-ketoglutarate and S-adenosylmethionine (SAM)-dependent halogenases. This review shows what is known today on these enzymes in terms of biocatalytic usage. The reader may understand this review as a plea for the usage of halogenating enzymes for fine chemical syntheses, but there are many steps to take until halogenating enzymes are reliable, flexible, and sustainable catalysts for halogenation.

Deploying Microbial Synthesis for Halogenating and Diversifying Medicinal Alkaloid Scaffolds

“…Although the prevalence of these elements in nature is becoming increasingly understood, they are not often found naturally in plant alkaloids (Runguphan et al, 2010). Conversely, halogens are highly prevalent in licensed pharmaceuticals, and often have beneficial effects on the ligand binding and their pharmacokinetic properties of human therapeutics (Fejzagić et al, 2019). This is due to a unique combination of chemical properties-bulkiness alters the sterics of ligand binding, the high electronegativity can alter the charge interactions of ligand binding, their specific orbital architectures support unique intermolecular interactions and their hydrophobicity can improve bioavailability (Figure 2).…”

“…This is due to a unique combination of chemical properties-bulkiness alters the sterics of ligand binding, the high electronegativity can alter the charge interactions of ligand binding, their specific orbital architectures support unique intermolecular interactions and their hydrophobicity can improve bioavailability (Figure 2). These properties and their effects on drugs have been recently reviewed (Fejzagić et al, 2019). As a consequence of these properties, organohalogens make up roughly 25% of licensed drugs (Xu et al, 2014) and 40% of all new drugs being tested (Fejzagić et al, 2019).…”

“…These properties and their effects on drugs have been recently reviewed (Fejzagić et al, 2019). As a consequence of these properties, organohalogens make up roughly 25% of licensed drugs (Xu et al, 2014) and 40% of all new drugs being tested (Fejzagić et al, 2019). Of these, 57% contain fluorine, 38% contain chlorine, whereas bromine and iodine make up just 5% between them (Xu et al, 2014;Fejzagić et al, 2019).…”

“…As a consequence of these properties, organohalogens make up roughly 25% of licensed drugs (Xu et al, 2014) and 40% of all new drugs being tested (Fejzagić et al, 2019). Of these, 57% contain fluorine, 38% contain chlorine, whereas bromine and iodine make up just 5% between them (Xu et al, 2014;Fejzagić et al, 2019). In addition to directly altering pharmacokinetic properties of a compound, halogens can act as "chemical handles" for targeting further drug derivatization (Runguphan and O'Connor, 2013;Frese et al, 2016;Corr et al, 2017).…”

“…The complex chemistries of natural products that make halogenation so useful for targeting cross-coupling reactions ( Figure 1D) also makes it extremely difficult to selectively halogenate the desired site in the first place (Chung and Vanderwal, 2016). Where it is possible chemically, this requires expensive catalysts (palladium) and elemental halogen, which is both toxic and energetically expensive to produce (Schnepel and Sewald, 2017;Fejzagić et al, 2019). The intrinsically high selectivity of enzymes therefore makes enzymatic halogenation a tempting alternative for achieving FIGURE 1 | Deploying synthetic biology to access novel regions of chemical space.…”