Extending the alkyl group from ethyl to pentyl as in compound t restored some Bcl exercise but had no effect on Bcl xL . Substitution of your naphthyl ring having a chloride from the position gave a slight improvement in both Bcl and Bcl xL exercise as when compared with unsubstituted naphthyl j. An X ray crystal structure of compound r complexed to Bcl xL demonstrated that these pyrazole based mostly inhibitors bind from the conserved hydrophobic groove normally occupied by pro apoptotic loved ones this kind of as Bim . As intended, the THIQ moia ety resides while in the I pocket and interacts with Phe, Tyr, and Phe via a mixture of p stacking and edge encounter interactions. The pyrazole C butyl group extends into the L pocket. The reduction in potency in shortening this butyl group to a methyl as in a can now be rationalized because the methyl group is simply not long ample to fill this hydrophobic room in most cases occupied by the amino acid side chain of leucine.
The pyrazole N phenyl ring points for the I pocket and biaryls such as j probably extend into this area. The alcohol at C with the pyrazole ring can make a hydrogen bond with Leu. Eventually, the acyl sulfonamide types many essential interactions with the Bcl xL protein. One example is, the acyl sulfonamide carbonyl accepts a hydrogen bond in the Tyr Tyrphostin 23 hydroxyl group. The trimethylsilylethyl group tasks into a rather huge hydrophobic pocket defined by Ala, Phe, Arg, Val, and Tyr. Ordinarily occupied by Phe of Bim, its clear that groups like naphthyl can be nicely accomodated in such an environment. Next, we applied lessons realized through the pyrazole series to your design and style of aminopyrimidine based antagonists . The mother or father compound in this series, pyrimidine a, gave modest potency against Bcl and Bcl xL .
Addition of a halide to the naphthyl ring gave around five fold improvement in Bcl exercise, but had small effect on Bcl xL. Likewise, replacement on the naphthyl Oligomycin A ring by indoline to provide d had a similar impact. As just before, addition of amino or hydroxy methyl groups at the THIQ position gave enhanced effects . A significant discovery came from your observation that substitution within the pyrimidine ring at C with chloro or methyl groups led to improvement in potency . Finally, substitute from the dibutylamino group for the pyrimidine ring with dipropylamino was optimum since the ethyl and pentyl analogs showed diminished action . Compounds from this series are expected to bind Bcl and Bcl xL analogously to pyrazole r.
Molecular modeling suggests the dipropylamine simultaneously fills both the I and L pockets which explains why the length in the alkyl chain is so vital. Optimized acylsulfonamide, THIQ, and pyrimidine substituents have been combined to offer pyrimidines j and k. These compounds demonstrated potent dual Bcl Bcl xL exercise with better than fold improvement in exercise compared to the parent compound a.