from your amide inversion experiments demonstrated that a cyclohexane at the tail terminus does itself increase selectivity for SphK1, as shown during the variations in activity between compounds 1 and 23a. The terminal cyclohexyl derivative 9c was synthesized to assess saturation as in contrast towards the aromaticity of 9a, and the good functionality of 9c suggests a preference to the larger and more hydrophobic terminal cyclohexane. Incorporating additional steric bulk inside the adamantyl derivative 9e triggered a loss of exercise and selectivity, suggesting an alternative binding conformation for such a large substituent. Short and longer cyclohexyl containing tails, 9b and 9d respectively, each carried out even more poorly than 9c indicating which is was the optimum length. Regretably, compound 9c didn’t yield the substantial gains in potency or selectivity that were expected, but did grow water solubility to a CLogP 3. 61 versus a CLogP four. 00 for compound two. 54 This added polar character permitted us to reconsider the aryl deletion series, and compounds 19a and 19b were then synthesized.
Shown in Scheme six is the example synthesis of 19a, cyclohexylmethanol hop over to this site was coupled to 10 bromo one decene utilizing sodium hydride in DMF to kind ether 15a. The terminal olefin was converted on the primary alcohol 16a below hydroboration oxidation problems, and then displaced for the primary azide 17a by way of its mesylate. The azide 17a was diminished and ligated making use of Staudinger conditions55 to kind nitrile 18a, before being converted to amidine 19a. Compound 19a proved to become both far more potent, having a KI 110 nM, and 470 fold selective for SphK1 more than SphK2. The reduction in terminal ring dimension for the cyclopentyl 19b demonstrated the steric bulk within the 6 membered saturated ring of 19a was optimal for each potency and selectivity. Obtaining achieved the style and design of the compound two and a single half log orders selective for SphK1, our interest shifted to regardless of whether the bulkier tail layout had aided selectivity in an amide dependant method.
To check this partnership, the inverted amide derivatives of compounds 9c and 19a were synthesized. The synthesis from the aryl containing inverted amide is shown in Scheme 7, starting up from the exact same terminal alkene utilized in the synthesis of 9c, the reduction of 5c to its alkylborane and coupling under Suzuki conditions to 4 bromobenzaldehyde selleck chemicals gave the aryl aldehyde 20a. The aldehyde was then oxidized to benzoic acid 21a utilizing Pinnick oxidation circumstances. 56 The carboxylic acid was coupled to 1 amino one cyclopropanecarbonitrile through its acid chloride. Nitrile 22a was then converted to its amidine to kind the wanted 23a. The synthesis in the non aryl inverted amide analog 26 was relatively basic, beginning with the Williamson ether coupling of cyclohexylmethanol and 11 bromoundecenoic acid. The acid 24 was then coupled to one amino 1 cyclopropanecarbonitrile with PyBOP to form nitrile 25, and converted to your corresponding amidine 26. The results