Inhibition of gene expression has been achieved by targeting the open complex formed during transcription initiation with short, pentameric, modified oligonucleotides.[1] This approach is an alternative to double-stranded (ds) DNA targeting by using triplex-forming oligonucleotides, in which longer probes (> 10 nucleotides) are required for high-affinity binding and specificity.[2] A local opening of the dsDNA by RNA polymerase at the start of transcription is the key to the sequence-selective[a] Dr.
A new set of pyrazolo[3,4-d]pyrimidine and pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine scaffolds (4–13) as well as the thioglycoside derivatives (14, 15) were designed, and synthesized as novel CDK2 targeting compounds.
Cyclin-dependent kinase inhibition is considered a promising target for cancer treatment for its crucial role in cell cycle regulation. Pyrazolo pyrimidine derivatives were well established for their antitumor activity via CDK2 inhibition. In this research, new series of pyrazolopyrimidine derivatives (
4–15
) was designed and synthesised as novel CDK2 inhibitors. The anti-proliferative activities against MCF-7, HCT-116, and HepG-2 were used to evaluate their anticancer activity as novel CDK2 inhibitors. Most of the compounds showed superior cytotoxic activity against MCF-7 and HCT-116 compared to Sorafenib. Only compounds
8
,
14
, and
15
showed potent activity against HepG-2. The CDK2/cyclin A2 enzyme inhibitory activity was tested for all synthesised compounds. Compound
15
showed the most significant inhibitory activity with IC
50
0.061 ± 0.003 µM. It exerted remarkable alteration in Pre G1 and S phase cell cycle progression and caused apoptosis in HCT cells. In addition, the normal cell line cytotoxicity for compound
15
was assigned revealing low cytotoxic results in normal cells rather than cancer cells. Molecular docking was achieved on the designed compounds and confirmed the two essential hydrogen binding with Leu83 in CDK2 active site.
In silico
ADMET studies and drug-likeness showed proper pharmacokinetic properties which helped in structure requirements prediction for the observed antitumor activity.
6-Benzyl-5-phenyluracil (4) and 5,6-dibenzyluracil (9) were synthesised from diphenyl acetone (1) and ethyl 3-oxo-4-phenylbutyrate (6), respectively. The uracils were alkylated to afford the 1-alkoxymethyluracils 5, 10 and 11. Furthermore, S-alkylated dihydroalkoxybenzyloxopyrimidine (S-DABO) analogues were prepared by alkylating 5,6-dibenzyl-2-thiouracil (8) on sulfur to yield compounds 12a-f. All compounds were tested for their inhibition of HIV-1 reverse transcriptase, and moderate activity was found for 6-benzyl-1-(ethoxymethyl)-5-phenyluracil (5).
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