A convenient chemical-microbial method for developing fluorinated pharmaceuticals

Biotransformation of fluorophenyl pyridine carboxylic acids by the model fungus Cunninghamella elegans

“…Extended incubation with C. elegans for a further 24 h resulted in the disappearance of these metabolites and the detection of the mono-hydroxy phenyl pyridine carboxylic acids (Figure 4). Similar reduction and oxidation of carboxyl groups has been observed in our previous study on biphenyl carboxylic acids (Bright et al, 2013).…”

“…None of the other compounds (2-4), which had fluorophenyl substituents meta to the carboxyl group, were reduced in this way. Interestingly, fluorinated biphenyl-4-carboxylic acids underwent similar reduction and re-oxidation of the carboxylate when incubated with C. elegans (Bright et al, 2013), but the hydroxylated alcohols were also detected as intermediates, whereas with the 1 and 5, only the hydroxylated carboxylic acids were identified. It is likely that a carboxylate reductase, which has been identified in other fungi (Winkler andWinkler, 2016, Ma et al, 2011) and requires ATP and NADPH as co-substrates, is responsible for the reduction.…”

“…Our previous studies on biphenyl systems , Bright et al, 2013, Shaughnessy et al, 2014 demonstrated that the hydroxylation typically occurs on the 4' (para) position. Furthermore, when this site is blocked by fluorine, no hydroxylation occurs, and the observation that 4 was not biotransformed by the fungus is consistent with this.…”

“…They also have enzymes associated with phase II (conjugative) metabolism, such as sulfotransferase, glucosyl transferase and glutathione S-transferase (Zhang et al, 1996). Furthermore, C. elegans can be employed in the design of fluorinated drugs, by identifying through biotransformation metabolically labile sites on non-fluorinated drug leads, which can then be modified by synthesis to contain fluorine at that specific position, thereby prolonging metabolic half-life (Bright et al, 2013, Shaughnessy et al, 2014. Amongst the many xenobiotics that Cunninghamella spp.…”

GRL-04810 and GRL-05010, Difluoride-Containing Nonpeptidic HIV-1 Protease Inhibitors (PIs) That Inhibit the Replication of Multi-PI-Resistant HIV-1 In Vitro and Possess Favorable Lipophilicity That May Allow Blood-Brain Barrier Penetration

“…The addition of fluorine atoms is generally expected to confer greater lipophilicity on nucleoside analogs and certain compounds (37)(38)(39). Thus, we determined the partition (log P) and distribution (log D) coefficients of GRL-04810 and GRL-05010.…”