A Novel Series of Highly Potent 2,6,9-Trisubstituted Purine Cyclin-Dependent Kinase Inhibitors

Abstract

The inhibition of overactive CDKs during cancer remains an important strategy in cancer drug development. We synthesized and screened a novel series of 2-substituted-6-biarylmethylamino-9-cyclopentylpurine derivatives for improved CDK inhibitory activity and antiproliferative effects. One of the most potent compounds, 6b, exhibited strong cytotoxicity in the human melanoma cell line G361 that correlated with robust CDK1 and CDK2 inhibition and caspase activation. In silico modeling of 6b in the active site of CDK2 revealed a high interaction energy, which we believe is due to the 6-heterobiarylmethylamino substitution of the purine moiety.

Semisynthetic Esters of 17-Hydroxycativic Acid with <i>in Vitro</i> Cytotoxic Activity against Leukemia Cell Lines

“…Such changes are generally considered indicative of ongoing apoptosis, and have been observed in cells treated with a wide range of unrelated cytotoxic compounds. 19,[26][27][28][29] Although 2c and 4b are structurally similar to previously studied labdanes, it is possible that they might induce cell death by a different mechanism. For the most part, the direct targets of labdane diterpenoids have not yet been identified.…”

“…Fifty percent growth inhibition (GI 50 ) values, i.e., the compound concentrations required to reduce the number of viable cells by 50% relative to an untreated control, were determined from dose-response curves as described previously. 19) Cell Cycle Analysis THP-1 and U937 cells were treated with compounds 2c and 4b at different concentrations for 24 h and then fixed with ice-cold 70% ethanol. Cells were washed with phosphate buffered saline (PBS), stained with propidium iodide and then analyzed by flow cytometry using a 488 nm laser (FACSVerse, BD) as described previously.…”

“…The fluorescence of the product was measured after 4 h of incubation using a Fluoroskan Ascent microplate reader (Labsystems) at 346/442 nm (ex/em) as described earlier. 19) Immunoblotting For direct immunoblotting, total cellular protein lysates were prepared by harvesting cells in hot Laemmli electrophoresis sample buffer. Proteins were then separated by sodium dodecyl sulfate (SDS)-polyacrylamide gel electrophoresis on a 10% gel, and transferred onto a nitrocellulose membrane.…”

Novel fluorinated benzimidazole-based scaffolds and their anticancer activity in vitro

“…Lysates were then incubated for 3 h with 100 µM Ac-DEVD-AMC as a substrate of caspases 3 and 7 in the assay buffer (25 mM PIPES, 2 mM EGTA, 2 mM MgCl 2 , 5 mM DTT, pH 7.3). The fluorescence of the product was measured using a Fluoroskan Ascent microplate reader (Labsystems) at 355/460 nm (excitation/emission) as described previously [39,40]. …”

Effects of BP-14, a novel cyclin-dependent kinase inhibitor, on anaplastic thyroid cancer cells

“…Since CDKs and endogenous CDKIs are frequently deregulated in cancer cells, these have been considered as valid drug targets. A large number of synthetic CDKIs have been tested as anti-proliferative agents in cancer therapy, including roscovitine, one of the first CDKIs produced (12). Inhibitors of the kinase components of oncogenic pathways are also being currently explored as antiproliferative agents in several human neoplasms, including thyroid cancer (13).…”