Diversity-oriented synthesis of pyrazolo[4,3-b]indoles by gold-catalysed three-component annulation: application to the development of a new class of CK2 inhibitors

Zengye Hou, Shinya Oishi, Yamato Suzuki, Tatsuhide Kure, Isao Nakanishi, Akira Hirasawa, Gozoh Tsujimoto, Hiroaki Ohno, Nobutaka Fujii
2013 Organic and biomolecular chemistry  
Pyrazolo[4, indole derivatives have been designed as novel CK2 inhibitor compounds based on the binding mode analysis of a previously reported phenylpyrazole-type CK2 inhibitor. A series of pyrazolo [4,3-b]indoles and related dihydropyrazolo [4,3-b]indoles were efficiently prepared from simple starting materials using a gold-catalysed three-component annulation reaction as a key step. Several of the newly synthesized compounds displayed high levels of inhibitory activity, indicating that the
more » ... azolo[4,3-b]indole core represents a promising scaffold for the development of potent CK2 inhibitors. the NH and N positions on the pyrazole ring had be swapped around, could give rise to unfavourable electrostatic repulsions with the CK2α (Figure 2 ). Based on this structural information, it was envisaged that the inhibitory activity of the lead compound 3a could be improved by controlling the tautomerization process and pushing it towards the favoured structure. With this in mind, we designed and synthesized a series of benzo[g]indazole derivatives 4 ( Figure 1 ) 9 as novel CK2 inhibitor compounds. The compounds themselves could be regarded as a conformationally restricted analogue of the phenylpyrazole 3. It was anticipated that restricting the rotatable bond in this way would provide the preferred planar conformation and lead to a reduction in the entropic loss encountered during the binding to CK2α. Furthermore, it was envisaged that the desired tautomer of 2 the pyrazole moiety would be formed preferentially because of the presence of the fused benzene ring (Figure 3). 10 Indeed, the synthesized benzo[g]indazole derivatives 4a [IC50 = 0.040 µM (CK2α) and 0.042 µM (CK2α')] and 4b [IC50 = 0.089 µM (CK2α) and 0.067 µM (CK2α')] exhibited higher levels of inhibitory activity towards CK2 than the phenylpyrazole 3a [IC50 = 0.14 µM (CK2α) and 0.063 µM (CK2α')] (Figure 1). In the present work, we have designed and synthesized a series of pyrazolo[4,3-b]indole derivatives 5 (Figure 3) as a new class of CK2 inhibitor compounds in which the phenylpyrazole moiety was bridged with a nitrogen atom. Based on the same discussion provided for the development of the benzo[g]indazole-type inhibitors 4, enhanced levels of inhibitory activity were also expected for the pyrazolo[4,3-b]indoles 5. Several methods have been described in the literature for the synthesis of pyrazoloindoles according to linear synthetic strategies. 11 To the best of our knowledge, however, there have been no reports describing the synthesis of pyrazoloindoles based on multiple component reactions (MCRs). 12 MCRs provide a divergent approach to functionalised pyrazoloindoles from simple starting materials. We have recently developed a novel gold-catalysed three-component annulation reaction of alkynes, hydrazines and aldehydes/ketones for the direct synthesis of polysubstituted dihydropyrazoles (Scheme 1). 13 The mechanism of this reaction involves the formation of the propargyl hydrazine intermediate via the Mannich-type coupling of alkynes with N,N'-disubstituted hydrazines and aldehydes/ketones, followed by intramolecular hydroamination. It was envisaged that the pyrazolo[4,3-b]indole-type inhibitor compounds 5 could be efficiently synthesized using this gold-catalysed three-component annulation reaction. Herein, we report our synthetic studies towards the pyrazolo[4,3-b]indole derivatives 5 and their subsequent evaluation as CK2 inhibitors. Results and discussion Our initial efforts were focused on designing a strategy for the construction of pyrazolo [4,3b]indole scaffold via a diversity-oriented synthetic route (Scheme 2). The multi-substituted Tetrahedron, 2007, 63, 10320-10329. 15. The reaction with 5 mol% of IPrAuNTf2 prepared from IPrAuCl and AgNTf2 proceeded smoothly to afford the dihydropyrazole 9a in slightly lower yield (65%). As we previously reported, 13 the use of silver salts alone is nonreactive for the three-component annulation. These results supported that the in situ generated active gold(I) species (IPrAuOTf or IPrAuNTf2) is the real catalyst. 16. The 3-chloroaniline moiety of CX-4945, which locates at the similar position with that of R 1 or R 2 in pyrazolo[4,3-b]indoles 5, has been suggested to fit well within a small hydrophobic region of CK2, see: ref 5g and 5h.
doi:10.1039/c3ob40223a pmid:23535832 fatcat:cygoq752a5harpb37fb6z4wbia