A number of new chiral bispidines containing monoterpenoid fragments have been obtained. The bispidines were studied as ligands for Ni-catalyzed addition of diethylzinc to chalcones. The conditions for chromatographic analysis by HPLC-UV were developed, in which the peaks of the enantiomers of all synthesized chiral products were separated, which made it possible to determine the enantiomeric excess of the resulting mixture. It was demonstrated that bispidine-monoterpenoid conjugates can be used as the ligands for diethylzinc addition to chalcone C=C double bond but not as inducers of chirality. Besides products of ethylation, formation of products of formal hydrogenation of the chalcone C=C double bond was observed in all cases. Note, that this formation of hydrogenation products in significant amounts in the presence of such catalytic systems was found for the first time. A tentative scheme explaining the formation of all products was proposed.

The modification of natural or semisynthetic triterpenoids with amines can be explored as a promising strategy for improving their pharmacological properties. Here, we report the design and synthesis of 11 novel amide derivatives of soloxolone methyl (SM), a cyano enone-bearing derivative of 18βH-glycyrrhetinic acid. Analysis of their bioactivities in vitro and in silico revealed their high toxicity against a panel of tumor cells (average IC₅₀^(24h) = 3.7 µM) and showed that the formation of amide moieties at the C-30 position of soloxolone did not enhance the cytotoxicity of derivatives toward tumor cells compared to SM, though it can impart an ability to pass across the blood–brain barrier. Further HPLC–MS/MS and mechanistic studies verified significant brain accumulation of hit compound 12 (soloxolone tryptamide) in a murine model and showed its high anti-glioblastoma potential. It was found that 12 induced ROS-dependent and autophagy-independent death of U87 and U118 glioblastoma cells via mitochondrial apoptosis and effectively blocked their clonogenicity, motility and capacity to form vessel-like structures. Further in vivo study demonstrated that intraperitoneal injection of 12 at a dosage of 20 mg/kg effectively inhibited the growth of U87 glioblastoma in a mouse xenograft model, reducing the proliferative potential of the tumor and leading to a depletion of collagen content and normalization of blood vessels in tumor tissue. The obtained results clearly demonstrate that 12 can be considered as a promising leading compound for drug development in glioblastoma treatment.

Multidrug resistance (MDR) remains a significant obstacle to effective cancer chemotherapy, primarily due to overexpression of P-glycoprotein (P-gp), which reduces intracellular accumulation of cytotoxic drugs. This study evaluated the pharmacological potential of the glycyrrhetinic acid derivative soloxolone N-3-(dimethylamino)propylamide (Sol-DMAP) as a biocompatible P-gp inhibitor with hepatoprotective properties. Using a murine model of P-gp-overexpressing RLS40 lymphosarcoma, we demonstrated that Sol-DMAP significantly enhanced the antitumor efficacy of doxorubicin (DOX) by increasing its intratumoral concentration 4.7-fold without enhancing systemic toxicity. Independently, Sol-DMAP exhibited direct antitumor activity, reducing tumor growth in vivo and inducing apoptosis and G1-phase arrest in RLS40 cells in vitro. In addition, Sol-DMAP mitigated DOX-induced hepatic injury by reducing necrotic and dystrophic changes in liver tissue and restoring heme oxygenase 1 (Hmox1) expression. Further studies in HepG2 cells confirmed that Sol-DMAP activated the NRF2-dependent antioxidant response, upregulating HMOX1, GCLC, GCLM, and NQO1 genes. Molecular docking revealed that Sol-DMAP can disrupt the KEAP1-NRF2 interaction, likely leading to NRF2 activation. Collectively, these findings demonstrate that Sol-DMAP effectively reverses P-gp-mediated MDR while protecting the liver from oxidative stress, highlighting its potential as a multifunctional scaffold for the development of safer and more effective chemotherapeutic adjuvants.

Topotecan is widely used against various malignancies inhibiting topoisomerase 1 (TOP1). It traps TOP1 in the cleavage complex bound to the DNA, which potentially may be repaired by a tyrosyl‑DNA phosphodiesterase 1 (TDP1). The usnic acid derivative OL9‑116, that inhibits TDP1, increases the antitumor efficacy of topotecan and is a promising adjunct for combination therapy. However, its safety and the optimal administration schedules when used with topotecan remain uncharacterized. We demonstrated that OL9‑116 has no genotoxic and epigenetic effects using Ames and CBMN tests, as well as HeLa trichostatin A‑inducible cells with an epigenetically repressed GFP gene. Intraperitoneal administration was found to provide higher bioavailability than intragastric administration. We showed on the RShM‑5 cervical cancer model that repeated topotecan administration in a clinically relevant low single‑dose regimen was more effective than a single injection, and addition of topotecan at the Tmax of OL9-116 enhanced tumor growth inhibition. In the Lewis lung carcinoma model, the OL9‑116–topotecan combination reduced primary tumor mass and lung metastases, enhancing both antitumor and antimetastatic effects. Monitoring of hematological parameters, liver, and spleen indices revealed no clinically significant systemic toxicity. Moreover, peripheral blood parameters improved with the OL9‑116–topotecan combination compared with topotecan monotherapy. Collectively, these findings support OL9‑116 as a promising safe TDP1 inhibitor for combination with topotecan.

Topotecan inhibits topoisomerase 1 (TOP1) by trapping the enzyme in a DNA-cleavage complex, which can be repaired by tyrosyl-DNA phosphodiesterase 1 (TDP1). The usnic acid derivative OL9-116 inhibits TDP1 and thereby enhances the antitumor activity of topotecan, making it a promising combination partner. However, the safety and optimal administration schedule of OL9-116 with topotecan have not been characterized. We demonstrated that OL9-116 has no genotoxic or epigenetic effects using Ames and CBMN assays, as well as HeLa trichostatin A-inducible cells with an epigenetically repressed GFP gene. Intraperitoneal administration was found to provide higher bioavailability than intragastric administration. We showed on the RShM-5 cervical cancer model that repeated topotecan administration in a clinically relevant low single-dose regimen was more effective than a single injection, and addition of topotecan at the T_max of OL9-116 enhanced tumor growth inhibition. In the Lewis lung carcinoma model, the OL9-116–topotecan combination reduced primary tumor mass and lung metastases, enhancing both antitumor and antimetastatic effects. Monitoring of hematological parameters, liver, and spleen indices revealed no clinically significant toxicity. Moreover, peripheral blood parameters improved with the OL9-116–topotecan combination compared with topotecan monotherapy. Collectively, these findings support OL9-116 as a promising safe TDP1 inhibitor for combination with topotecan.