Synthesis, DFT calculations, and anti-proliferative evaluation of pyrimidine and selenadiazolopyrimidine derivatives as dual Topoisomerase II and HSP90 inhibitors

Abstract

Novel series of aminopyrimidines bearing a biologically active cyclohexenone 3a–f and oxo-selaneylidene moiety 4 , besides selenadiazolopyrimidines ( 5a–e and 7 ), were synthesised using 5,6-diaminouracils as starting materials. Compound 3a exhibited strong anti-proliferative activity against three cell lines: HepG-2 (IC 50 14.31 ± 0.83 µM), A-549 (IC 50 30.74 ± 0.76 µM), and MCF-7 (IC 50 27.14 ± 1.91 µM). Also, it was four times more selectively cytotoxic against WI-38 cell lines than doxorubicin. Furthermore, Topoisomerase II (IC 50 4.48 ± 0.65 µM) and HSP90 (IC 50 1.78 ± 0.11 µM) were both strongly inhibited in vitro by 3a . The cell cycle was halted at the G1-S phase, and total apoptotic cells were 65 times more than control Hep-G2 cells. Besides, it increased caspase-3 gene expression, triggering mitochondrial cell death. Molecular docking study indicated that it could bind to Topoisomerase II and HSP90 binding sites in an inhibitory mode. Its geometric properties were investigated using the density functional theory (DFT). Furthermore, compound 3a demonstrated in silico good oral bioavailability.

Design and synthesis of new spirooxindole candidates and their selenium nanoparticles as potential dual Topo I/II inhibitors, DNA intercalators, and apoptotic inducers

“…The spirooxindoles were synthesised by refluxing isatin with two equivalents of 6-aminouracil derivatives 44 , 46 , 65 , 66 as a follow-up to our work on the uracil moiety. Bazgir and coworkers 67 refluxed 6-aminouracils with different isatin derivatives in ethanol and p -TSA to get spiro[pyrimido[4,5- b ]quinoline-5,5′-pyrrolo[2,3- d ]pyrimidine]pentaones.…”

Novel Aminopyrimidine-2,4-diones, 2-Thiopyrimidine-4-ones, and 6-Arylpteridines as Dual-Target Inhibitors of BRD4/PLK1: Design, Synthesis, Cytotoxicity, and Computational Studies

“…Then, pteridine compounds 9 and 10 , which have important applications in both medicine and biotechnology, were synthesized using a simple and efficient method, as displayed in Scheme 3 . The starting materials used, 5,6-diaminouracils/thiouracils 3a – d , were constructed using our previously reported procedures [ 44 , 45 , 46 ], which involved the nitrosation of 6-aminouracil 1a – d in a stirred solution of sodium nitrite in glacial acetic acid at room temperature, yielding 2a – d . Finally, ammonium sulfide was used as a reducing agent to reduce the latter compounds, which provided our target backbone.…”

“…Using a six-dose MTT colorimetric assay [ 44 , 66 ], all new synthetic compounds were tested for cytotoxicity against three cancer cell lines: MDA-MB-231 breast cancer cells, HT-29 colorectal adenocarcinoma cells, and U-937 renal cancer cells. Additionally, the normal Vero cell line was used to test the most potent compounds 4 , 6a , 6b , and 7 .…”

“…Overall, all of the rule principles that could indicate drug-likeness for the investigated compounds 4, 6a, 6b, 7, and 9 possessed excellent values, which suggests that those substances might fulfill the cell membrane permeability and bioavailability requirements. Using a six-dose MTT colorimetric assay [44,66], all new synthetic compounds were tested for cytotoxicity against three cancer cell lines: MDA-MB-231 breast cancer cells, HT-29 colorectal adenocarcinoma cells, and U-937 renal cancer cells. Additionally, the normal Vero cell line was used to test the most potent compounds 4, 6a, 6b, and 7.…”