We report the synthesis of a series of diphenylmethane-based oligomers containing anionic and lipophilic functionalities that are potent inhibitors of human leukocyte elastase (HLE). The enzyme inhibition is regulated by the size of the oligomer, as well as, the number of charges. Lipophilicity is an important element in determining potency and specificity against other basic enzymes. Compounds whose scaffolds contain three phenoxyacetic acid groups and three alkyl ethers are competitive and specific inhibitors of HLE with Ki = 20 nM. The mechanism of action of this class of compounds is believed to involve multidendate interactions with the surface of HLE near the active site which prevents substrate access to the catalytic site.
An efficient synthesis of the functionalized diphenylmethane
system 1 is described. Selective
unmasking of the latent phenol groups on 1 allowed the
introduction of various appendages onto
the diphenylmethane scaffold via simple alkylation, Mitsunobu
etherification, and transition-metal-mediated C−C bond formation. Conversion of 1 to iodide
18 and benzylic zinc reagent 28
followed
by palladium(0)-mediated coupling of these derivatives provided
homologue 29. Repetitive
application of this homologation protocol was used to prepare oligomers
of chain length up to 16.
Several examples of functional group manipulations on these higher
order oligomers are presented.
Diphenylmethane 1 was also employed as a key building
block in the synthesis of the elastase
inhibitor 67. The potential application of extended
aromatic oligomers to the field of drug discovery
is discussed.
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