Synthesis and characterization of bis-amide SSE1917 as a microtubule-stabilizing anticancer agent.

Microtubule dynamics are critical for spindle assembly and chromosome segregation during cell division. Pharmacological inhibition of microtubule dynamics in cells causes prolonged mitotic arrest, resulting in apoptosis, an approach extensively employed in treating different types of cancers. The present study reports the synthesis of thirty-two novel bis-amides (SSE1901-SSE1932) and the evaluation of their antiproliferative activities. N-(1-oxo-3-phenyl-1-(phenylamino)propan-2-yl)benzamide (SSE1917) exhibited the most potent activity with GI50 values of 0.331 ± 0.01 µM in HCT116 colorectal and 0.48 ± 0.27 µM in BT-549 breast cancer cells. SSE1917 stabilized microtubules in biochemical and cellular assays, bound to taxol site in docking studies, and caused aberrant mitosis and G2/M arrest in cells. Prolonged treatment of cells with the compound increased p53 expression and triggered apoptotic cell death. Furthermore, SSE1917 suppressed the growth of both mouse and patient-derived human colon cancer organoids, highlighting its potential therapeutic value as an anticancer agent.

Discovery and prospects of new heterocyclic Isatin-hydrazide derivative with a novel role as estrogen receptor α degrader in breast cancer cells.

Introduction: Isatin, a heterocycle scaffold, is the backbone of many anticancer drugs and has previously been reported to engage multiple cellular targets and mechanisms, including angiogenesis, cell cycle, checkpoint pathways and multiple kinases. Here, we report that a novel isatin derivative, 5i, degrades estrogen receptor alpha (ERα) in estrogen-dependent breast cancer cells. This effect of the isatin nucleus has not been previously reported. Tamoxifen and fulvestrant represent standard therapy options in estrogen-mediated disease but have their own limitations. Isatin-based triple angiokinase inhibitor BIBF1120 (Nintedanib) and multikinase inhibitor Sunitinib (Sutent) have been approved by the FDA. Methods: Keeping this in view, we synthesized a series of N'-(1-benzyl-2-oxo-1, 2-dihydro-3H-indol-3-ylidene) hydrazide derivatives and evaluated them in vitro for antiproliferative activities in MCF-7 (ER+) cell line. We further investigated the effect of the most potent compound (5i) on the Erα through Western Blot Analysis. We used in silico pharmacokinetics prediction tools, particularly pkCSM tool, to assess the activity profiles of the compounds. Results and discussion: Compound 5i showed the best antiproliferative activity (IC50 value; 9.29 ± 0.97 µM) in these cells. Furthermore, 5i downregulated ERα protein levels in a dose-dependent manner in MCF-7. A multifaceted analysis of physicochemical properties through Data Warrior software revealed some prominent drug-like features of the synthesized compounds. The docking studies predicted the binding of ligands (compounds) with the target protein (ERα). Finally, molecular dynamics (MD) simulations indicated stable behavior of the protein-ligand complex between ERα and its ligand 5i. Overall, these results suggest that the new isatin derivative 5i holds promise as a new ERα degrader.

Retrograde Ureteral Stents Versus Percutaneous Nephrostomy in the Management of Malignant Ureteral Obstruction: A Systematic Review and Meta-analysis.

OBJECTIVE: To evaluate outcomes in cancer patients with ureteral obstruction by comparison of retrograde stenting and percutaneous nephrostomy techniques. METHODS: Systematic review of all studies up to October 2023. Studies were identified from all major databases including MEDLINE, Cochrane, and EMBASE. All comparative studies between retrograde stenting and percutaneous nephrostomy were searched; studies with paediatric populations were excluded. Primary outcomes were procedure and intervention failure rates; secondary outcomes were infection, blockage, displacement, and unplanned exchange rates along with procedure time and length of stay. RESULTS: Eighteen studies with 1228 patients contributed to the summative outcome. Percutaneous nephrostomy was statistically superior to retrograde stenting for procedure failure rate (P <.00001) and intervention failure rate (P =.0004). Retrograde stenting was statistically superior to percutaneous nephrostomy for displacement rates (P = .003), procedure time (P <.00001), and length of stay (P <.00001). Retrograde stenting showed no difference to percutaneous nephrostomy for infection rates (P = .94), blockage rates (P = .93), unplanned exchange rates (P = .48), CONCLUSION: There is no absolute superiority for retrograde stenting or percutaneous nephrostomy for malignant ureteral obstruction. Both techniques have their advantages and disadvantages, with some comparable outcomes; patients are key when selecting the best technique. Larger studies are required to assess the outcomes of both techniques.