1383717-80-3

Upstream product

• 23504-03-2 2,4-dihydroxy-1-isopropylbenzene 
• 1155371-78-0 2-(2,4-bis(benzyloxy)phenyl)propan-2-ol 
• 22877-01-6 2,4-bis(benzyloxy)acetophenone 
• 89-84-9 2',4'-dihydroxy-4-acetophenone 
• 100-39-0 benzyl bromide 
• 1383717-79-0 (((4-isopropyl-6-nitro-1,3-phenylene)bis(oxy))bis(methylene))dibenzene 
• 1155371-80-4 (((4-isopropyl-1,3-phenylene)bis(oxy))bis(methylene))dibenzene 

Downstream Products

• 1383717-48-3 1-(2,4-dihydroxy-5-isopropyl-phenyl)-5-(4-morpholin-4-yl-phenylamino)-1H-[1,2,3]triazole-4-carboxylic acid ethylamide 
• 1383717-81-4 1,5-bis-benzyloxy-2-isopropyl-4-azido-benzene 
• 1383717-82-5 1-[2,4-bis(benzyloxy)cumenyl]-5-[p-(hydroxymethyl)phenyl]-1H-1,2,3-triazole 
• 1383717-83-6 4-{4-[3-(2,4-bis-benzyloxy-5-isopropyl-phenyl)-3H-[1,2,3]triazol-4-yl]-benzyl}-morpholine 
• 1383717-88-1 methyl 1-[2,4-bis(benzyloxy)cumenyl]-5-[p-(tert-butyldimethylsilyloxymethyl)phenyl]-1H-1,2,3-triazole-4-carboxylate 
• 1383717-89-2 methyl 1-[2,4-bis(benzyloxy)cumenyl]-5-[p-(hydroxymethyl)-phenyl]-1H-1,2,3-triazole-4-carboxylate 
• 1383717-90-5 1-(2,4-bis-benzyloxy-5-isopropyl-phenyl)-5-(4-methanesulfonyloxy-methyl-phenyl)-1H-[1,2,3]triazole-4-carboxylic acid methyl ester 
• 1383717-91-6 methyl 1-[2,4-bis(benzyloxy)cumenyl]-5-[p-(morpholin-4-ylmethyl)phenyl]-1H-1,2,3-triazole-4-carboxylate 
• 1383718-25-9 1-(2,4-bis-benzyloxy-5-isopropyl-phenyl)-5-(4-morpholin-4-ylmethyl-phenyl)-1H-[1,2,3]triazole-4-carboxylic acid ethylamide 
• 1383717-28-9 1-(2,4-dihydroxy-5-isopropylphenyl)-5-(4-morpholin-4-ylmethylphenyl)-1H-[1,2,3]triazole-4-carboxylic acid ethylamide 
• 1383718-03-3 methyl 1-[2,4-bis(benzyloxy)cumenyl]-5-[p-(bromomethyl)-phenyl]-1H-1,2,3-triazole-4-carboxylate 
• 1383718-04-4 1-(2,4-bis-benzyloxy-5-isopropyl-phenyl)-5-{4-[(2-diethylamino-ethylamino)-methyl]-phenyl}-1H-[1,2,3]triazole-4-carboxylic acid methyl ester 
• 1383718-07-7 [3-(2,4-bis-benzyloxy-5-isopropyl-phenyl)-3H-[1,2,3]triazol-4-yl]-(4-morpholin-4-yl-phenyl)-carbamic acid tert-butyl ester 
• 1383718-08-8 [3-(2,4-dihydroxy-5-isopropyl-phenyl)-3H-[1,2,3]triazol-4-yl]-(4-morpholin-4-yl-phenyl)-carbamic acid t-butyl ester 

Relevant academic research and scientific papers

Design and Synthesis of Hsp90 Inhibitors with B-Raf and PDHK1 Multi-Target Activity

The design of multi-target ligands has become an innovative approach for the identification of effective therapeutic treatments against complex diseases, such as cancer. Recent studies have demonstrated that the combined inhibition of Hsp90 and B-Raf provides synergistic effects against several types of cancers. Moreover, it has been reported that PDHK1, which presents an ATP-binding pocket similar to that of Hsp90, plays an important role in tumor initiation, maintenance and progression, participating also to the senescence process induced by B-Raf oncogenic proteins. Based on these premises, the simultaneous inhibition of these targets may provide several benefits for the treatment of cancer. In this work, we set up a design strategy including the assembly and integration of molecular fragments known to be important for binding to the Hsp90, PDHK1 and B-Raf targets, aided by molecular docking for the selection of a set of compounds potentially able to exert Hsp90-B-Raf-PDHK1 multi-target activities. The designed compounds were synthesized and experimentally validated in vitro. According to the in vitro assays, compounds 4 a, 4 d and 4 e potently inhibited Hsp90 and moderately inhibited the PDHK1 kinase. Finally, molecular dynamics simulations were performed to provide further insights into the structural basis of their multi-target activity.

HEAT SHOCK PROTEIN 90 INHIBITORS

Substituted aromatic compounds of formula (I) shown below: (formula I) The definition of each variable in formula (I) appears in the Specification. Also disclosed is a pharmaceutical composition containing one of the substituted aromatic compounds. Further disclosed is a method of using one of these compounds for treating a medical condition associated with HSP90.

Synthesis and evaluation of new Hsp90 inhibitors based on a 1,4,5-trisubstituted 1,2,3-triazole scaffold

Ruthenium catalyzed 1,3-cycloaddition (click chemistry) of an azido moiety installed on dihydroxycumene scaffold with differently substituted aryl propiolates gave a new family of 1,4,5-trisubstituted triazole carboxylic acid derivatives that showed high affinity toward Hsp90 associated with cell proliferation inhibition, both in nanomolar range. The 1,5 arrangement of the resorcinol, the aryl moieties, and the presence of an alkyl (secondary) amide in position 4 of the triazole ring were essential to get high activity. Docking simulations suggested that the triazoles penetrate the Hsp90 ATP binding site. Some 1,4,5-trisubstituted triazole carboxamides induced dramatic depletion of the examined client proteins and a very strong increase in the expression levels of the chaperone Hsp70. In vitro metabolic stability and in vivo preliminary studies on selected compounds have shown promising results comparable to the potent Hsp90 inhibitor NVP-AUY922. One of them, (compound 18, SST0287CL1) was selected for further investigation as the most promising drug candidate.

ARYL TRIAZOLE COMPOUNDS WITH ANTITUMOURAL ACTIVITY

The present invention relates to aryl triazole derivatives of Formula I having antitumoural activity through, as one possible biological target, the molecular chaperone heat shock protein 90 (Hsp90) inhibition. The invention includes the use of such compounds in medicine, in relation to cancer disease as well as other diseases where an inhibition of Hsp90 is responsive, and the pharmaceutical composition containing such compounds.