Nariman Faridovich Salakhutdinov

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.

The monoterpene-derived 1,4-oxazepan-3-one, (5aS,8R,9aR)-5,5,8-trimethyloctahydrobenzo[f][1,4]oxazepin-3(2H)-one, was synthesized from the corresponding (−)-isopulegol-based chloroacetamide by intramolecular cyclization in acetonitrile. The product was isolated in 70% yield as colorless crystals. Its structure was established by one- and two-dimensional NMR spectroscopy and high-resolution mass spectrometry and was confirmed by single-crystal X-ray diffraction analysis. The transformation provides concise access to a fused bicyclic 1,4-oxazepan-3-one bearing a stereochemically defined para-menthane scaffold.

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.

Background/Objectives: Tryptophol and tyrosol are prominent secondary metabolites with diverse biological activities. Acetylation has been proposed as a strategy to modify the physicochemical properties of these compounds. Despite the proven neuroprotective and adaptogenic activity of tyrosol, in vivo studies, particularly concerning the anxiolytic effects of its acetylated forms, are currently limited. Materials and Methods: This study aimed to compare the behavioral effects of tryptophol, tryptophol acetate, and tyrosol acetate in mice using the chloral hydrate sleep model, the Open Field Test (OFT), and the Forced Swim Test (FST). Results: In the chloral hydrate sleep model, both tryptophol acetate and tyrosol acetate (100 mg/kg, i.g.) significantly prolonged sleep duration without affecting sleep latency, whereas none of the tested compounds induced sleep after single administration (100 mg/kg, i.p.). In the OFT, tyrosol acetate (100 mg/kg, i.g.) significantly increased exploratory activity, as reflected by increased time spent in the central zone and number/duration of verticalizations, indicating an anxiolytic-like behavioral profile. In the FST, tyrosol acetate (100 mg/kg, i.g.) significantly reduced immobility time, suggesting an effect on behavioral responses to acute inescapable stress. Conclusions: Overall, the tested compounds exhibited distinct behavioral profiles, with tyrosol acetate producing the most consistent behavioral effects across the experimental models. These findings suggest that acetylation modifies the neuropharmacological properties of naturally occurring aromatic alcohols and support further investigation of tyrosol acetate, including studies of its mechanisms of action and evaluation in additional anxiety-specific behavioral models.

Cridanimod (acridoneacetic acid), the active ingredient of the immunomodulatory drug Cycloferon^®, has a well-characterized antiviral profile, but an unexplored analgesic potential. Bornane monoterpenes, notably (+)-camphor and (−)-fenchone, are established scaffolds for analgesic drug design. We therefore synthesized thirteen cridanimod–monoterpene conjugates—seven amides, three acylhydrazones, and three esters—by EDCI/DMAP-mediated coupling or CDI/DBU-promoted esterification, and evaluated them in mice at an oral dose of 10.0 mg/kg in the acetic acid writhing and hot plate tests, with diclofenac sodium (10.0 mg/kg) as the reference. Acridoneacetic acid and Cycloferon^® were themselves inactive in both assays. By contrast, six of the thirteen conjugates were significantly active (p < 0.05) in at least one test, with distinct leads in each: amide 19 matched diclofenac in the writhing test (−63.7% vs. −64.4%), whereas acylhydrazone 23 exceeded diclofenac in the hot plate test (+43.9% vs. +25.7%). The divergent profiles suggest that different structural subclasses engage peripheral and central antinociceptive mechanisms. Conjugation thus converts an analgesically inactive immunomodulator into a substance yielding analgesics that match or exceed a standard NSAID at the same oral dose, providing a promising starting point for the development of new pain-relieving agents.

Tyrosyl-DNA phosphodiesterase 1 (TDP1) represents a compelling pharmacological target for the development of agents designed to circumvent tumor resistance to topoisomerase 1 (TOP1) inhibitors, a major class of clinically relevant antineoplastic drugs. This paper describes the design and synthesis of novel hybrid TDP1 inhibitors combining coumarin and monoterpene moieties via rigid isoxazole and 1,2,3-triazole heterocyclic linkers. The synthesis was accomplished via [3 + 2] cycloaddition of nitrile oxides to alkynes and copper-catalyzed click chemistry. Biological tests have demonstrated the crucial role of linker nature in the activity of the compounds. Isoxazole-linked conjugates showed strong inhibitory effects on TDP1, with IC₅₀ values in the submicromolar to low micromolar range (0.8–3.2 μM). Overall, these values slightly surpassed those of the triazole-linked analogues, whose IC₅₀ values ranged from 1.1 to 23.3 μM. At noncytotoxic doses, compounds 26e and 16b enhanced the sensitivity of human cervical cancer (HeLa) cells to the antitumor agent topotecan, a TOP1 inhibitor, thereby supporting the promise of this structural class as components of combination chemotherapy.

Cridanimod (acridoneacetic acid), the active ingredient of the immunomodulatory drug Cycloferon®, has a well-characterized antiviral profile, but an unexplored analgesic potential. Bornane monoterpenes, notably (+)-camphor and (−)-fenchone, are established scaffolds for analgesic drug design. We therefore synthesized thirteen cridanimod–monoterpene conjugates — seven amides, three acylhydrazones, and three esters — by EDC/DMAP-mediated coupling or CDI/DBU-promoted esterification, and evaluated them in mice at an oral dose of 10.0 mg/kg in the acetic acid writhing and hot plate tests, with diclofenac sodium (10.0 mg/kg) as the reference. Acridoneacetic acid and Cycloferon® were themselves inactive in both assays. By contrast, six of the thirteen conjugates were significantly active (p < 0.05) in at least one test, with distinct leads in each: amide 19 matched diclofenac in the writhing test (−63.7% vs −64.4%), whereas acylhydrazone 23 exceeded diclofenac in the hot plate test (+43.9% vs +25.7%). The divergent profiles suggest that different structural subclasses engage peripheral and central antinociceptive mechanisms. Conjugation thus converts an analgesically inactive immunomodulator into a substance yielding analgesics that match or exceed a standard NSAID at the same oral dose, providing a promising starting point for the development of new pain-relieving agents.

Background: Avian influenza is a critical zoonotic infection threatening both the poultry industry and global public health. While traditional intramuscular vaccines elicit systemic immunity, they often fail to provide robust local protection at mucosal surfaces. There is thus significant interest in the development of mucosal avian influenza vaccines administered via the intranasal route. However, in humans, this approach is significantly hampered by the availability of safe and effective adjuvants. Methods: This study investigated the immunogenicity of a modified recombinant influenza A/H5 hemagglutinin (rHA/H5-modif) formulated with Novochizol, a novel chitosan-derived delivery system, administered intranasally to laboratory animals. Results: Our results demonstrate that mucosal immunization with the rHA/H5-modif/Novochizol complex induces potent humoral (IgG and IgA) and cell-mediated immune responses. Crucially, the formulation provided 100% survival in mice following a lethal challenge with highly pathogenic avian influenza A/H5. Conclusions: These findings position the rHA/H5-modif/Novochizol complex as a promising candidate for next-generation mucosal vaccines, in particular against highly pathogenic avian influenza A/H5 subtype.

Tyrosyl-DNA phosphodiesterase 1 (TDP1) is a key enzyme for the repair of stalled topoi-somerase 1 (TOP1)-DNA complexes. We have previously developed a TDP1 inhibitor, compound OL9-116, which is capable of enhancing the action of the anticancer drug topotecan (TPC), a TOP1 poison, in vitro and in vivo. In this study, the inhibition mode of OL9-116 (uncompetitive) was investigated. We have shown that N-terminal domain of TDP1, which is important for the cell function of TDP1 but is not involved in catalysis directly, reduced the inhibitory potency of OL9-116 probably by influencing the conformation of the enzyme. OL9-116 did not reduce cell viability and did not affect mitochondrial membrane potential. OL9-116 enhanced the cytotoxic/antiproliferative effect of TPC on the panel of tumor cells. This effect was not observed on nontumor cells or TDP1-deficient cells. OL9-116 and TPC had different effects on TDP1 and TOP1 gene expression detected by PCR depending on the cell type and the presence of functional TDP1. The direct relation between the effects of the compounds on the gene expression and cell survival was not found. The obtained data indicated a synergistic effect of OL9-116 and TPC, which appeared to be mediated by TDP1 inhibition rather than by an effect on TDP1 gene expression.