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. 2013 Nov 14;56(24):9982–10002. doi: 10.1021/jm401251p

Table 1. Modulatory Effect of the Library of Small Molecule Analogues on TLR-Dependent Cytokine Productiona.

graphic file with name jm-2013-01251p_0014.jpg

(A) phosphonates and phosphates
SMA X Y n Z LPS IL-12 LPS IL-6 BLP IL-12 BLP IL-6 CPG IL-12 CPG IL-6
5a CH2PO3– 4-Br 2 NMe3+ ↓ ↑ ↓      
5b CH2PO3– 4-Br 2 NMe2   ↑       ↑
5c CH2PO3– 4-Me 2 NMe2 ↑          
5d CH2PO3– 4-NO2 2 NMe3+ ↑ ↑        
5e CH2PO3– 4-Me 2 NMe2 ↑   ↑      
6 OPO3– 4-BOCNH 3 NMe2   ↑       ↑
(B) sulfones
SMA X Y n Z LPS IL-12 LPS IL-6 BLP IL-12 BLP IL-6 CpG IL-12 CpG IL-6
11a CH2SO2 4-Br 2 Me2N ↓ ↓ ↓   ↓ ↓
11b CH2SO2 4-Me 2 Me2N ↓ ↓        
11c CH2SO2 4-Me 2 pyrrol ↓ ↓ ↓ ↓    
11d CH2SO2 4-Br 2 pyrrol ↓          
11e CH2SO2 3-F 2 NMe2 ↑ ↑        
11f CH2SO2 3-F 2 diam            
11g CH2SO2 3-F 2 morph     ↑      
11h CH2SO2 3-F 2 pyrrol   ↑ ↓      
11i CH2SO2 4-F 2 NMe2     ↓ ↓    
11j CH2SO2 4-F 2 morph   ↓ ↑ ↑    
11k CH2SO2 4-F 2 pyrrol ↑   ↓      
11l CH2SO2 4-F 2 diam     ↓      
11m CH2SO2 3-F 2 S-2-Me-but            
11n CH2SO2 3-F 2 R-2-Me-but     ↓ ↓    
11o CH2SO2 4-Br 2 S-2-Me-but     ↓      
11p CH2SO2 4-Br 2 R-2-Me-but            
12a CH2SO2 4-Br 2 Me3N+            
12b CH2SO2 4-Me 2 Me3N+ ↓   ↓   ↓ ↓
12c CH2SO2 4-Me 2 pyrrol Me+ ↓   ↓      
12d CH2SO2 4-Br 2 pyrrol Me+ ↓ ↓ ↓      
16a CH2SO2 4-Br 3 pyrrol            
16b CH2SO2 4-Br 3 NMe2   ↓        
16c CH2SO2 4-Br 3 morph     ↑ ↓    
16d CH2SO2 4-Me 3 pyrrol            
16e CH2SO2 4-Me 3 NMe2            
16f CH2SO2 4-Me 3 morph            
17a CH2SO2 4-Br 3 morph Me+     ↑      
17b CH2SO2 4-Br 3 Me3N+   ↓   ↓    
17c CH2SO2 4-Br 3 pyrrol Me+            
17d CH2SO2 4-Me 3 pyrrol Me+            
17e CH2SO2 4-Me 3 Me3N+            
18a SO2 H 2 diam       ↑    
18b SO2 H 2 thiomorph ↓ ↓   ↑    
18c SO2 H 2 morph   ↑ ↓      
18d SO2 H 2 pyrrol   ↑ ↓      
18e SO2 H 2 R-2-Me-but ↑ ↑        
18f SO2 H 2 S-2-Me-but            
18g SO2 H 2 diam (−Me)            
18h SO2 H 2 n-Pr ↑ ↑ ↓ ↓    
18i SO2 H 2 i-Pr     ↓      
18j SO2 H 2 3-OH-n-Pr ↑ ↑ ↓      
18k SO2 H 2 t-Bu   ↑ ↓      
18l SO2 H 2 4-Me-pip            
(C) sulfonamides and carboxamides
SMA X Y n Z LPS IL-12 LPS IL-6 BLP IL-12 BLP IL-6 CpG IL-12 CpG IL-6
19a CH2SO2NH H 2 NMe2         ↑  
19b CH2SO2NH H 2 pyrrol            
19c CH2SO2NH H 2 morph            
19e CH2SO2NH 4-Br 2 NMe2     ↑   ↑  
19d CH2SO2NH 4-Br 2 pyrrol         ↑  
19f CH2SO2NH 4-Br 2 morph         ↑ ↑
19g CH2SO2NH 4-F 2 NMe2         ↑ ↑
19h CH2SO2NH 4-F 2 pyrrol ↑   ↑   ↑ ↑
19i CH2SO2NH 4-F 2 morph         ↑ ↑
19j CH2SO2NH 4-Me 2 NMe2 ↑          
19k CH2SO2NH 4-Me 2 pyrrol            
19l CH2SO2NH 4-Me 2 morph            
19m CH2SO2NH 4-NO2 2 NMe2       ↓    
19n CH2SO2NH 4-NO2 2 pyrrol            
19o CH2SO2NH 4-NO2 2 morph            
19p CH2SO2NH 4-Br 3 NMe2            
19q CH2SO2NH 4-NO2 3 NMe2       ↓    
19r CH2SO2NH 4-Me 3 NMe2            
19s CH2SO2NH 4-F 3 NMe2            
19t CH2SO2NH H 3 NMe2 ↑          
19u CH2SO2NH 2-naphthyl 2 morph   ↓ ↓   ↓ ↓
19v CH2SO2NH 2-naphthyl 2 pyrrol       ↓    
19w CH2SO2NH 2-naphthyl 2 NMe2            
19x CH2SO2NH 4-stilbenyl 2 NMe2     ↓      
21a CH2NHSO2 H 2 pyrrol            
21b CH2NHSO2 H 2 morph            
21c CH2NHSO2 H 2 NMe2     ↑      
21d CH2NHSO2 4-Br 2 morph            
21e CH2NHSO2 4-Br 2 pyrrol ↑ ↑ ↑ ↑    
21f CH2NHSO2 4-Br 2 NMe2           ↑
21g CH2NHSO2 4-Me 2 morph            
21h CH2NHSO2 4-Me 2 pyrrol   ↑   ↑   ↑
21i CH2NHSO2 4-Me 2 NMe2       ↑   ↑
21j CH2NHSO2 4-NO2 2 morph            
21k CH2NHSO2 4-NO2 2 pyrrol            
21l CH2NHSO2 4-NO2 2 NMe2   ↓ ↓ ↓ ↓ ↓
21m CH2NHSO2 4-F 2 morph   ↓   ↓ ↓ ↓
21n CH2NHSO2 4-F 2 pyrrol   ↓     ↓ ↓
21o CH2NHSO2 4-F 2 NMe2         ↓  
21p CH2NHSO2 4-Me 2 diam ↓ ↓   ↓   ↓
21q CH2NHSO2 4-Br 2 diam ↓     ↓ ↓  
21r CH2SO2NH ‘coumarin’ 2 morph ↓   ↓      
21s CH2SO2NH ‘coumarin’ 2 pyrrol ↓   ↓      
21t CH2SO2NH ‘coumarin’ 2 NMe2 ↓   ↓      
23a NHSO2 H 2 NMe2 ↓          
23b NHSO2 H 2 pyrrol ↓       ↓  
23c NHSO2 H 2 morph            
23d NHSO2 4-F 2 NMe2 ↓         ↑
23e NHSO2 4-F 2 pyrrol ↓          
23f NHSO2 4-F 2 morph ↓         ↑
23g NHSO2 4-F 2 diam ↓         ↑
23h NHSO2 H 2 diam ↓         ↑
24a CH2CONH H 2 NMe2 ↓         ↓
24b CH2CONH H 2 pyrrol ↓ ↓   ↓ ↓ ↓
24c CH2CONH H 2 morph ↓       ↓ ↓
24d CH2CONH H 3 NMe2            
24e CH2NHCO 5-isoquinolyl 2 morph     ↓      
25a CONH 3-MeO-C6H4 2 NMe2 ↓   ↓     ↓
25b CONH 3-MeO-C6H4 2 pyrrol ↓   ↓     ↓
25c CONH 3-MeO-C6H4 2 Morph ↓   ↓     ↓
25d CONH 3-MeO-C6H4 3 NMe2 ↓     ↑   ↓
a

Bone marrow-derived macrophages preincubated for 18 h with 5 μg/mL of compounds were stimulated with 100 ng/mL LPS, 10 ng/mL BLP, or 0.01 μM CpG in the continued presence of the compounds. After 24 h, supernatants were collected and measured for their IL-12p40 and IL-6 content by ELISA. Arrows down (↓) indicate statistically significant (at least p < 0.05) down-regulation and arrows up (↑) statistically significant up-regulation of the levels of cytokine versus control; blank squares = no significant change. Abbreviations used in structural formulas: ‘coumarin’ = (7-methoxy-2-oxo-2H-chromen-4-yl)methyl; diam = N,N,N-1,1,2-tetramethylethylenediamino2-Me-but = 2-methylbutylamino; 4-Me-pip = 4-methylpiperazinyl; morph = morpholino; 3-OH-n-propyl = 3-hydroxypropylamino; pyrrol = pyrrolidino; stilbenyl = 1-(4-[(E)-2-phenylethyl]benzyl; thiomorph = thiomorpholino.