Design,synthesis and activity evaluation of the derivatives of verubulin through drug splicing
Objective The pyrrole[2,3-d]thiazole-5-formamide group of MP-HJ-1c(3)was introduced into the 2 position of the quinazoline ring of verubulin(1)to find new structural type of microtubule aggregation inhibitor.Methods The crystal structures 6BR1 and 5YZ3 of the derivative 2 of 1 and 3 with tubulin were superimposed,then the target compounds 4a and 4b were designed by linking the 2 position of quinazoline ring of 1 and the pyrrole[2,3-d]thiazole-5-formamide group of 3 with methylene group or 1,2-ethylidene group,respectively,and molecular docking was performed.4a and 4b were synthesized by 4 steps of reaction including amide condensation,intramolecular cyclization,nucleophilic substitution and amide condensations with total yields of 7.9%and 11.3%,respectively.Their structures were confirmed by 1H-NMR,13C-NMR and HR-ESI-MS.The inhibitory activities of 4a and 4b against A549(human lung cancer)tumor cell line and tubulin polymerization were evaluated.Results Molecular docking results showed that the binding energy of 4a with 5YZ3 was-27.93 kcal·mol-1,and the structural parts derived from 1 and 3 basically main-tained their interaction with tubulin.The GI50 value of 4a and 4b against A549 were(0.15±0.03)μmol·L-1 and(9.91±1.04)μmol·L-1.Only 4a showed poor microtubule aggregation inhibitory activity with IC50 values of(67.1±11.1)μmol·L-1.Conclusion The target compound 4a exhibited a certain inhibitory activity on tumor cell proliferation and microtubule aggregation in vitro,and could be used as a lead compound for further structure-activity relationship study on the N-methyl-4-methyl benzene ring.4b showed no obvious mi-crotubule aggregation inhibition activity in vitro,which was consistent with the result that pyrrole and[2,3-d]thiazole-5-formamide group could not effectively interact with tubulin due to the excessive length of the linkage chain in molecular docking.
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