Discovery of novel tacrine derivatives as potent antiproliferative agents with CDKs inhibitory property

Novel tacrine derivatives as potential CDK9 inhibitors with low cholinesterase inhibitory properties: design, synthesis, and biological evaluation

“…The results showed that most of them possessed low micromolar to nanomolar antiproliferative activity against A549 and HCT116 cells. Some meaningful SARs could be observed: (i) the antiproliferative activities of compounds containing the S configuration are more potent than those of compounds containing the R configuration (compound 5r vs. compound 5q , compound 5t vs compound 5s ), which was consistent with our previously reported results; 25 (ii) the replacement of the 5-membered ring of tacrine core has no significant effect on the cytotoxic activity (compound 5s vs compound 5q , compound 5t vs compound 5r ); and (iii) the antiproliferative activity of the compound bearing 4-pyridine at the 7-position of tacrine is stronger than that of the 3-pyridine moiety (compound 5r vs compound 5p ).…”

“…In this study, we aim to discover novel tacrine derivatives with good CDK9 potency, improved selectivity over CDK2, and low ChE inhibition. Due to the previously discovered compounds containing the ( S )-pyrrolidin-3-amine group at the 9-position of tacrine exhibiting strong antiproliferative activity, 25 we performed the enzymatic activity assay of CDK2 and CDK9 on representative compounds ZLWT-26 and ZLWT-39 . As shown in Table 1, compound ZLWT-26 bearing pyrrolidine and compound ZLWT-39 bearing ( S )-pyrrolidin-3-ol were found to exhibit weaker CDK2 and CDK9 inhibition than compound ZLWT-37 (IC 50 = 2.232 nM), this indicated that the ( S )-pyrrolidin-3-amine group at the 9-position plays a vital role in the antiproliferative activity and CDK9 inhibitory activity.…”

“…To a solution of 7a–7c (1 equiv.) and N -(4-(4,4,5,5-tretramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)cyclopropanecarboxamide 25 (1.2 equiv.) in dioxane/water (4 : 1) were added Cs 2 CO 3 (3 equiv.)…”

“…Previously, our group identified a series of tacrine derivatives as potential antiproliferative agents with low ChE inhibition. 25 Among these, the most promising compound ZLWT-37 (Fig. 1) possessed potent CDK9 (IC 50 = 0.002 μM) inhibitory activity and low AChE and BuChE inhibition with IC 50 values of 10.478 and 8.761 μM, respectively.…”

Discovery of novel and potent tacrine derivatives as CDK2 inhibitors

“…The synthesis of intermediates 3 were carried out according to our previous method. 11,21 A tacrine nucleus boronic acid ester was prepared via a Miyaura reaction. Intermediates 3a and 3b (10 mM, 4.4 g) and (BPIN) 2 (12 mM, 4 g), KOAc (40 mM) were added to 100 mL dry 1,4-dioxane, and a catalytic amount of PdCl 2 (PPh 3 ) 2 (0.05 mol%) was added, washed twice with N 2 , and kept overnight at 100 °C under an inert atmosphere.…”