Poly(ADP-ribose) polymerases (PARPs) are crucial nuclear proteins that play important roles in various cellular processes, including DNA repair, gene transcription, and cell death. Among the 17 identified PARP family members, PARP1 is the most abundant enzyme, with approximately 1–2 million molecules per cell, acting primarily as a DNA damage sensor. It has become a promising biological target for anticancer drug studies. Enhanced PARP expression is present in several types of tumors, such as melanomas, lung cancers, and breast tumors, correlating with low survival outcomes and resistance to treatment. PARP inhibitors, especially newly developed third-generation inhibitors currently undergoing Phase II clinical trials, have shown efficacy as anticancer agents both as single drugs and as sensitizers for chemo- and radiotherapy. This review explores the properties, characteristics, and challenges of PARP inhibitors, discussing their development from first-generation to third-generation compounds, more sustainable synthesis methods for discovery of new anti-cancer agents, their mechanisms of therapeutic action, and their potential for targeting additional biological targets beyond the catalytic active site of PARP proteins. Perspectives on green chemistry methods in the synthesis of new anticancer agents are also discussed.

Two distinct synthetic pathways are disclosed that lead to new gold–selenolato complexes, stabilized by N-heterocyclic carbenes (NHCs). The weak base route can provide facile access to phenylselenolate complexes of gold, using both NHC and phopshine ligands. In addition, the pathway based on the carbometallation of elemental selenium enables the construction of a more diverse library of products, based on substituted aryl-selenide fragments whose selenol congeners are not commercially available. Biological studies performed on human cancer cell lines (A-549, H-T29, and MCF-7) and mammal healthy cell lines (Vero-E6) reveal that a selection of these complexes exhibit cytotoxic activity and are selective towards cancerous cells. In vitro experiments confirmed that our lead candidate is indeed a TrxR inhibitor. Finally, this complex showed strong cytotoxic activity even in advanced biological models, including patient-derived 3D tumor organoids. Noteworthily, it remained effective in both colon cancer and HGSOC organoids, even in patients resistant to standard chemotherapy agents.

Sulfonylated 5-piperazine-substituted 1,3-oxazole-4-carbonitriles were synthesized and evaluated for in vitro anticancer activity. Cytotoxicity was assessed in hepatocellular (HepG2, Huh7), breast (MCF-7, MDA-MB-231), cervical (HeLa), melanoma (M21), and neuroblastoma (Kelly, SH-SY5Y) cell lines, with HEK293 cells used as a non-malignant control. Compounds 7a, 7b, and 8aa emerged as lead structures. Notably, compound 7b showed the highest activity in Kelly neuroblastoma cells (IC₅₀ = 1.3 µM) while exhibiting low cytotoxicity toward HEK293 cells (IC₅₀ > 10 µM), indicating an improved selectivity profile relative to doxorubicin. In silico molecular docking suggested favorable interactions of the lead compounds with several cancer-associated proteins, with the highest predicted affinity observed for Aurora A kinase, along with additional predicted interactions with cyclin-dependent kinases. Predicted ADMET properties of compounds 7a, 7b, and 8aa compared favorably with doxorubicin, although the lead compounds were not readily biodegradable under OECD 301D conditions. Overall, these findings identify oxazole-4-carbonitriles as promising anticancer candidates with a putative kinase-directed mechanism of action.

Neuroblastoma, a leading cause of pediatric cancer mortality, requires efficient and selective therapeutics. We synthesized and characterized a series of sulfonated 5-piperazine-containing 1,3-oxazole-4-carbonitrile derivatives via sulfonylation protocols and evaluated their in vitro cytotoxicity against human hepatocellular carcinoma (HepG2, Huh7), breast (MCF7, MDA-MB-231), cervical (HeLa), melanoma (M21), and two neuroblastoma (Kelly, SHSY5Y) cell lines, alongside non-malignant HEK293 cells. Three compounds (7a, 7b, and 8aa) demonstrated efficient and selective cytotoxicity toward MYCN-amplified (Kelly) and MYCN-non-amplified (SHSY5Y) neuroblastoma cells, with 7b being the most active (IC₅₀ = 1.9 µM in Kelly cells) and showing minimal toxicity in HEK293 (IC₅₀ > 10 µM). In Kelly cells, 7b matched doxorubicin while showing lower off-target toxicity and low-micromolar activity in solid tumors. The hit compounds were shown to be not readily biodegradable under OECD 301D test. In silico docking revealed high-affinity binding to the ATP-binding site of Aurora A kinase in the Aurora A/N-MYC complex (ΔG = –10.8 to –10.9 kcal/mol). Compound 7b exhibited broad cytotoxicity across all tested cancers (IC₅₀ = 1.5–4.0 µM). ADMET profiling of 7a, 7b, and 8aa indicated favorable pharmacokinetic and toxicity parameters compared with doxorubicin. These findings identify sulfonylated oxazole-4-carbonitriles as neuroblastoma therapeutics with potential use against proliferating malignancies.