Publication details
Dihydropyrrolo[1,2-b]pyrazoles: Synthesis of new potential inhibitors of transforming growth factor-β type I receptor (ALK5)
| Title in English | Dihydropyrrolo[1,2-b]pyrazoles: Synthesis of new potential inhibitors of transforming growth factor-ß type I receptor (ALK5) |
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| Authors | |
| Year of publication | 2015 |
| MU Faculty or unit | |
| Citation | |
| Description | During the last two decades, compounds with dihydropyrrolo[1,2-b]pyrazole (DPP) core showed promising biological activity. Sawyer published series of papers dealing with this field of organic chemistry.[1-5] These DPP derivatives are inhibitors of transforming growth factor b type I (also known as ALK5) of kinase receptor domain. TGF-b plays an important role in many pathological states including inflammation, fibrosis, cancer, asthma and cardiovascular diseases.[6-11] In my talk I will present our recent work aimed at synthesis of some analogues of these compounds with DPP core bearing 2-pyridyl, 2-(6-methylpyridyl), 4-pyridyl, 4-quinolinyl or 2-cyanophenyl moiety at position 2. Homoallenyl aldehyde (with H, alkyl or amine substitution at position 3), synthesized according to our improved procedure,[12] is a key intermediate for the creation of DPP core. Various palladium catalyzed coupling reactions (Suzuki, Sonogashira, Heck, direct arylation and C-H activation) are shown in the following schemes. Conditions for substitution of position 4 were discovered and they will be discuss as well. Based on some docking studies a series of compounds was selected for biological screening. In few cases, these tests shown a selective activity as inhibitors of ALK5 kinase (the best compound around 100 nM) and for some other derivatives lower activity in inhibition of CDK2/E was also observed. Biological testing of some recently prepared compounds is ongoing and it will be also discuss in my talk. |