Evaluation of design,synthesis and biological activities novel macrocyclic Bcl-2 inhibitors
Objective To solve the drug resistance problem caused by Bcl-2 mutations,to design and synthesize a series of novel Bcl-2 inhibitors,and evaluate their inhibitory activities against Bcl-2 and the two mutations of G101V and D103Y to determine the preliminary conformational relationship.Methods A series of novel Bcl-2 inhibitors were synthesized by macrocyclization design and structurally confirmed by 1H NMR and ESI-MS.The inhibitory activities of the compounds on kinases and tumor cells were determined with time-resolved fluorescence resonance energy transfer technique(TR-FRET)and MTS.Results One positive compound and nine novel macrocyclic Bcl-2 inhibitors were synthesized.Compounds 28c,28d,28e,and 28f possessed strong kinase inhibitory activity against Bcl-2,G101V and D103Y mutations.Conclusion Some compounds(28c,28e,28g and 28i)in the synthesized novel macrocyclic Bcl-2 inhibitors have certain inhibitory activities on the proliferation of tumor cells.
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