Synthesis, Biological Evaluation and in Silico Studies of Novel Urea/Thiourea Derivatives of Lenalidomide.

Publisher: Wiley Country of Publication: United States NLM ID: 9717231 Publication Model: Print Cited Medium: Internet ISSN: 1099-0461 (Electronic) Linking ISSN: 10956670 NLM ISO Abbreviation: J Biochem Mol Toxicol Subsets: MEDLINE

Original Publication: New York, NY : Wiley, c1998-

Urea*/chemistry ; Urea*/pharmacology ; Urea*/analogs & derivatives ; Thiourea*/pharmacology ; Thiourea*/chemistry ; Thiourea*/analogs & derivatives ; Thiourea*/chemical synthesis ; Molecular Docking Simulation* ; Antineoplastic Agents*/pharmacology ; Antineoplastic Agents*/chemical synthesis ; Antineoplastic Agents*/chemistry ; Lenalidomide*/pharmacology ; Lenalidomide*/chemistry ; Lenalidomide*/chemical synthesis; Humans ; Cell Line, Tumor ; Histone Deacetylase 1/antagonists & inhibitors ; Histone Deacetylase 1/metabolism ; Histone Deacetylase 1/chemistry ; Human Umbilical Vein Endothelial Cells/drug effects ; Apoptosis/drug effects ; Histone Deacetylase Inhibitors/pharmacology ; Histone Deacetylase Inhibitors/chemical synthesis ; Histone Deacetylase Inhibitors/chemistry

Designing new compounds from existing chemotherapeutic drugs to enhance inhibitory effects on tumor cells while overcoming multidrug resistance is one of the important strategies for new drug discovery in medicinal chemistry. A new series of urea and thiourea derivatives based on Lenalidomide as potential anticancer agents have been designed and synthesized. In vitro anticancer activity assay against Caki cancer cells and HUVEC endothelial cells revealed that 1-(4-methylphenyl)-3-[2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl]urea (11) exhibited the highest anticancer activity and selectivity in the series with IC 50 values of 9.88 and 179.03 µM, respectively. Among the compounds, 11 showed significant HDAC1 inhibiton of 68.02 ± 2.44% at 10 µM concentration. TGF-β, Bax, Bcl-2 protein levels and scratch assay were analyzed in Caki cells. As a result, compound 11 induced apoptosis in Caki cells. In this study, it has been demonstrated that compound 11 can be a lead compound for further detailed investigation in renal cancer treatment. Through molecular docking studies, it was determined that the most active compound, 11, forms stable interactions with key residues in the enzyme's active site, particularly engaging in hydrogen bonds with GLY149 and coordinating with the zinc ion in the HDAC1 active site. These interactions are crucial for the observed inhibitory activity. Molecular dynamics simulation revealed the binding event of the most active compound with class I histone deacetylase and the stability of the complex in a biological environment.
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Keywords: Caki; HDAC; Lenalidomide; thiourea; urea

8W8T17847W (Urea)
GYV9AM2QAG (Thiourea)
0 (Antineoplastic Agents)
F0P408N6V4 (Lenalidomide)
EC 3.5.1.98 (Histone Deacetylase 1)
EC 3.5.1.98 (HDAC1 protein, human)
0 (Histone Deacetylase Inhibitors)

Date Created: 20241202 Date Completed: 20241202 Latest Revision: 20241202

20241204

10.1002/jbt.70079

39620426