5840-67-5

Upstream product

• 22479-95-4 dimethyl 4-hydroxyphthalate 
• 100-39-0 benzyl bromide 
• 610-35-5 4-hydroxyphthalic acid 

Downstream Products

• 174728-80-4 1-benzyloxy-3,4-dihydroxymethylbenzene 
• 522609-31-0 4-benzyloxy-benzene-1,2-dicarbaldehyde 

Relevant academic research and scientific papers

Small Molecule Inhibitors of the BfrB-Bfd Interaction Decrease Pseudomonas aeruginosa Fitness and Potentiate Fluoroquinolone Activity

The iron storage protein bacterioferritin (BfrB) is central to bacterial iron homeostasis. The mobilization of iron from BfrB, which requires binding by a cognate ferredoxin (Bfd), is essential to the regulation of cytosolic iron levels in P. aeruginosa. This paper describes the structure-guided development of small molecule inhibitors of the BfrB-Bfd protein-protein interaction. The process was initiated by screening a fragment library and followed by obtaining the structure of a fragment hit bound to BfrB. The structural insights were used to develop a series of 4-(benzylamino)- A nd 4-((3-phenylpropyl)amino)-isoindoline-1,3-dione analogs that selectively bind BfrB at the Bfd binding site. Challenging P. aeruginosa cells with the 4-substituted isoindoline analogs revealed a dose-dependent growth phenotype. Further investigation determined that the analogs elicit a pyoverdin hyperproduction phenotype that is consistent with blockade of the BfrB-Bfd interaction and ensuing irreversible accumulation of iron in BfrB, with concomitant depletion of iron in the cytosol. The irreversible accumulation of iron in BfrB prompted by the 4-substituted isoindoline analogs was confirmed by visualization of BfrB-iron in P. aeruginosa cell lysates separated on native PAGE gels and stained for iron with Ferene S. Challenging P. aeruginosa cultures with a combination of commercial fluoroquinolone and our isoindoline analogs results in significantly lower cell survival relative to treatment with either antibiotic or analog alone. Collectively, these findings furnish proof of concept for the usefulness of small molecule probes designed to dysregulate bacterial iron homeostasis by targeting a protein-protein interaction pivotal for iron storage in the bacterial cell.

Convenient syntheses of fluorous phenols of the formula triarylphosphites

The aldehydic benzyl ethers PhCH2OC6H4CHO (2; a/b = paralmeta series) are readily available from the corresponding phenols and react with Wittig reagents derived from [Ph3PCH2CH2Rf8]+- (Rf8 = (CF2)7CF3) to give PhCH2OC6H4CH=CHCH2Rf8 (86-93%, Z major). Reactions with H2 over Pd/C give the fluorous phenols HOC6H4(CH2)3Rf8 (4a,b; 87-91%). Condensations with PCl3 and NEt3 (3.0:1:0:3.3 mol ratio) give the flourous phosphites P[OC6H4(CH2)3Rf8] 3 (5a,b; 92-94%), but traces of 4a,b are difficult to remove. The phthalate-based benzyl ethers PhCH2OC6H3COOR 2 (7; c/d = 3,5/3,4 -OC6H3-3,n-(R)2 series) are easily accessed and reduced with LiAlH4 to the diols PhCH2OC6H3(CH2OH)2 (8c,d; 89-90%). Diol 8c and the Dess-Martin periodinane react to give the dialdehyde PhCH2OC6H3(CHO)2 (9C; 95%). This is elaborated by a sequence analogous to 2 → 4 → 5 to the flourous phenol HOC6H3((CH2)3Rf8) 2 (11c; 97%/96%, two steps) and phosphite P[OC6H3((CH2)3Rf8) 2]3 (12C, 92%), from which traces of 11c are difficult to remove. Diol 8d can be similarly elaborated to 11d, but the dialdehyde 9d is labile and combined yield of the Dess-Martin/Wittig steps is 32%. The CF3C6F11/ toluene partition coefficients of 11c,d, and 12c (two pony tails; 70:30,72:28, 92:8) are much higher than those of 4a and b (one pony tail; 12:88, 14:86).