Synthesis, structure–activity relationship and biological evaluation of 2,4,5-trisubstituted pyrimidine CDK inhibitors as potential anti-tumour agents

CDK9: A key player in cancer and other diseases

“…Cisplatin) . Moreover, in vitro models of Colon Cancer and Multiple intestinal neoplasia (Min) show an antiproliferative response to novel CDK inhibitors, suggesting a potential chemopreventive role …”

Fluorine‐Containing sp3‐Enriched Building Blocks for the Multigram Synthesis of Fluorinated Pyrazoles and Pyrimidines with (Hetero)aliphatic Substituents

“…[26,31] In turn, synthesis of 10 can be performed by electrophilic fluorination of silyl enolates 6 (Scheme 7). [17][18][19][20][21][22][23] We have found that fluorination of silyl enolates 6 a-d pre-formed from the corresponding ketones 5 a-d with SelectFluor® in acetonitrile proceeded smoothly, and the products 10 a-d were obtained in 20-82 % yield on up to 70 g scale. Modest yield of azetidine-containing compound 10 d can be addressed to limited stability of this product at r.t.…”

“…Compounds of this type can be useful building blocks for the synthesis of 5-fluoropyrimidines like 2 (Scheme 2B). Again, this approach was more or less well-studied for the fluorinated enaminones with aromatic and heteroaromatic substituents; [17][18][19][20][21][22][23] only a few simplest representatives of their aliphatic counterparts have been known to date. [24,25] In principle, building blocks of type 4 can also provide access to 4fluorinated pyrazoles.…”

Structure-based design of highly selective 2,4,5-trisubstituted pyrimidine CDK9 inhibitors as anti-cancer agents

“…We have previously reported 2,4,5-trisubstituted pyrimidine compounds as potent CDK9 inhibitors but selectivity for CDK9 over CDK2 remained a challenge. [30,31] We elected to rationally design inhibitors with improved selectivity for CDK9 by taking advantage of the structural differences between CDK2 and CDK9. By comparing the amino acid residues that form the active site of CDK2 and CDK9, we hoped to identify non-conserved regions that could be targeted with suitably designed compounds.…”