Platinum-based drugs are widely used in chemotherapy for various types of cancer and are considered crucial. Tetravalent platinum (Pt(IV)) compounds have gained significant attention and have been extensively researched among these drugs. Traditionally, Pt(IV) compounds are reduced to divalent platinum (Pt(II)) after entering cells, causing DNA lesions and exhibiting their anti-tumor effect. However, the available evidence indicates that some Pt(IV) derivatives may differ from the traditional mechanism and exert their anti-tumor effect through their overall structure. This review primarily focuses on the existing literature regarding targeted Pt(II) and Pt(IV) compounds, with a specific emphasis on their in vivo mode of action and the properties of reduction release in multifunctional Pt(IV) compounds. This review provides a comprehensive summary of the design and synthesis strategies employed for Pt(II) derivatives that selectively target various enzymes (glucose receptor, folate, telomerase, etc.) or substances (mitochondria, oleic acid, etc.). Furthermore, it thoroughly examines and summarizes the rational design, anti-tumor mechanism of action, and reductive release capacity of novel multifunctional Pt(IV) compounds, such as those targeting p53-MDM2, COX-2, lipid metabolism, dual drugs, and drug delivery systems. Finally, this review aims to provide theoretical support for the rational design and development of new targeted Pt(IV) compounds.

Therapeutic resistance remains a major obstacle to durable cancer control, with functional reprogramming of the DNA damage response (DDR) network playing a central role. The poly(ADP-ribose) polymerase (PARP) family, particularly PARP1 and PARP2, is crucial for maintaining genomic integrity. By exploiting synthetic lethality, PARP inhibitors (PARPi) selectively target tumors with homologous recombination deficiency (HRD) and are integral to precision therapy in ovarian, breast, and prostate cancers. However, over 40% of patients with BRCA1/2 alterations develop resistance, and patient eligibility remains limited by the low prevalence of HRD mutations. In this review, we summarize the molecular mechanisms of PARPi action, resistance pathways, and emerging combination strategies. PARPi resistance arises through HR restoration (e.g., BRCA1/2 reversion mutations), replication fork protection, RAD51-mediated strand invasion, and metabolic reprogramming. Combination therapies, integrating PARPi with histone deacetylase inhibitors, cyclin-dependent kinase inhibitors, immune checkpoint blockade, or radiation, enhance efficacy by converging on DNA repair pathways and the tumor immune microenvironment. A deeper understanding of coordinated DDR regulation and rationally designed combination regimens will be essential for overcoming PARPi resistance and advancing adaptive, precision-based therapeutic strategies.

Erectile dysfunction (ED) remains a global health burden, yet the clinical utility of tadalafil is constrained by its poor aqueous solubility, cross-inhibition of homologous PDE isoforms, and an efficacy ceiling that cannot be overcome by dose adjustment alone. Herein, a series of diketopiperazine-based tadalafil analogues were designed and synthesized by decorating the amide nitrogen with flexible carbon chains and polar fragments (glycine, taurine, cysteine, and succinic/glutaric anhydride spacers), and by replacing the 3,4-methylenedioxybenzyl motif with substituted aromatic aldehydes. All target compounds were characterized by ¹H/¹³C NMR and HR-MS and evaluated for cytotoxicity against rat aortic smooth muscle cells, calculated Log P and aqueous solubility, NO release, and phosphodiesterase type-5A (PDE5A) inhibitory activity, followed by 100 ns molecular dynamics (MD) simulations and MM/PBSA calculations on the leading analogue. Compound 18, bearing a p-methoxyphenyl group and an N-methyl amide, markedly enhanced NO release relative to tadalafil, reduced residual PDE5A activity to 38.69 ± 1.98% at 10 μM, and exhibited negligible cytotoxicity with a predicted logP of 1.53. Docking into PDE5 (PDB: 1XOZ) and MD analysis revealed a stable binding pose anchored by hydrogen bonds to Gln817 and Tyr612, reinforced by π–π stacking with Phe820 and extensive hydrophobic contacts with Leu765, Ile768, Val782, and Met816 (ΔG_bind = −9.13 ± 3.30 kcal/mol), with van der Waals contributions dominating (−41.78 ± 4.60 kcal/mol). Collectively, compound 18 emerges as a promising next-generation tadalafil-derived PDE5 inhibitor lead, and the resulting SAR picture outlines a hydrophobic-anchor-dominated optimization strategy for this scaffold.