Uric Acid Crystallization Interrupted with Competing Binding Agents

Abstract

Uric acid crystallization in humans is associated with undesirable medical conditions including the formation of gout deposits and kidney stones. A major contributing factor to uric acid biomineralization, most often as either monosodium urate (MSU) or anhydrous uric acid (UA), is its relatively low solubility in physiologic solutions. Using bidentate and tridentate binding patterns designed to disrupt the binding motifs observed in the major physiologic forms, several heterocycles were identified which (1) significantly delay the time required for visible uric acid crystals to appear and/or (2) yield new 1:1 uric acid cocrystal phases. All five of the new phases obtained exhibited a multidentate hydrogen bonding motif between components. Fluorescence assays showed that three of the cocrystals were 3–6× more soluble than the natural forms. The same competitive-binding approach was then extended to trimethoprim, an FDA-approved drug with the same substructure as the most effective binding agents. Addition of trimethoprim to uric acid solutions significantly delayed the crystallization times and also yielded a new cocrystal form with a solubility greater than MSU. These results serve to illustrate the potential benefits of repurposing existing pharmaceuticals to treat uric acid diseases.

Hydrate Transformation via Anhydrate Pairs

“…When its concentration exceeds the solubilizing capacity of physiologic fluid, it can precipitate in a variety of hydrated, , anhydrous, and salt − forms, which are the undesirable manifestations of gout and kidney stone formation. In large-scale studies of kidney stone composition, uric acid is most commonly found in anhydrate (UA) and dihydrate (UAD) forms. − Previous work has shown that although the dihydrate (UAD) precipitates rapidly from supersaturated aqueous solutions, , over time it can eventually transform to the more stable and less soluble UA via a dissolution–recrystallization process. , In the course of studies focused on identifying additives that might interrupt uric acid crystallization, we found that the addition of substoichiometric quantities of 2,4-diaminopyrimidine to the growth solution yielded UAD crystals with altered morphologies which transform via a highly unusual mechanism.…”

“…It was known from previous studies that 2,4-diaminopyrimidine (24-DAP) and some of its derivatives can cocrystallize with uric acid in 1:1 ratios. 16 In our experience, cocrystallization required that solutions contain equimolar or higher ratios of uric acid and 24-DAP; solutions with lower concentrations of 24-DAP yielded only UAD. On closer inspection, we observed that the morphologies of the UAD crystals grown in the presence of these substoichiometric 24-DAP concentrations were clearly altered compared to those obtained from pure aqueous solution.…”

“…9−11 Previous work has shown that although the dihydrate (UAD) precipitates rapidly from supersaturated aqueous solutions, 12,13 over time it can eventually transform to the more stable and less soluble UA via a dissolution− recrystallization process. 14,15 In the course of studies focused on identifying additives that might interrupt uric acid crystallization, 16 we found that the addition of substoichiometric quantities of 2,4-diaminopyrimidine to the growth solution yielded UAD crystals with altered morphologies which transform via a highly unusual mechanism.…”

“…It was known from previous studies that 2,4-diaminopyrimidine (24-DAP) and some of its derivatives can cocrystallize with uric acid in 1:1 ratios . In our experience, cocrystallization required that solutions contain equimolar or higher ratios of uric acid and 24-DAP; solutions with lower concentrations of 24-DAP yielded only UAD.…”

Investigation on the Mechanisms of Synchronous Interaction of K3Cit with Melamine and Uric Acid That Avoids the Formation of Large Clusters

“…The UA–Mel complex has a nonplanar structure that conforms to the most stable structure, as stabilized by several H-bonding interactions . π-Stacking is accountable for the self-association of UA. , Therefore, significant π-stacking interactions, together with multiple associations with hydrogen bonding, inevitably play a very vital and perhaps decisive role in the Mel and UA assembly and thus implies a high complexity . A straightforward yet realistic approach may indeed entail either devastation of UA aggregation or an impediment of a Mel and UA hydrogen-bonded cluster.…”