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1.
J Chem Phys ; 160(21)2024 Jun 07.
Article in English | MEDLINE | ID: mdl-38828806

ABSTRACT

Solid solutions of ZryTi1-yS2 (y = 0.1, 0.2) compositions have been synthesized. The electrochemical introduction of lithium is carried out by the galvanostatic intermittent titration technique. An isothermal section of the phase diagram of the LixZryTi1-yS2 system at room temperature has been constructed. The limiting solubility of lithium in solid solutions decreases with an increasing amount of titanium substituted for zirconium. It was noted that at low lithium concentrations (x < 1), there is no change in the E(x) dependence when titanium is replaced by zirconium. This may indicate the formation of separate TiS2 and ZrS2 layers.

2.
Cancers (Basel) ; 15(20)2023 Oct 14.
Article in English | MEDLINE | ID: mdl-37894352

ABSTRACT

Multidrug resistance is the dominant obstacle to effective chemotherapy for malignant neoplasms. It is well known that neoplastic cells use a wide range of adaptive mechanisms to form and maintain resistance against antitumor agents, which makes it urgent to identify promising therapies to solve this problem. Hydroxamic acids are biologically active compounds and in recent years have been actively considered to be potentially promising drugs of various pharmacological applications. In this paper, we synthesized a number of hydroxamic acids containing a p-substituted cinnamic acid core and bearing bicyclic pinane fragments, including derivatives of (-)-myrtenol, (+)-myrtenol and (-)-nopol, as a Cap-group. Among the synthesized compounds, the most promising hydroxamic acid was identified, containing a fragment of (-)-nopol in the Cap group 18c. This compound synergizes with cisplatin to increase its anticancer effect and overcomes cisplatin resistance, which may be associated with the inhibition of histone deacetylase 1 and glycolytic function. Taken together, our results demonstrate that the use of hydroxamic acids with a bicyclic pinane backbone can be considered to be an effective approach to the eradication of tumor cells and overcoming drug resistance in the treatment of malignant neoplasms.

3.
Molecules ; 27(17)2022 Aug 25.
Article in English | MEDLINE | ID: mdl-36080227

ABSTRACT

Alzheimer's disease (AD) is a neurodegenerative disease associated with memory impairment and other central nervous system (CNS) symptoms. Two myrtenal-adamantane conjugates (MACs) showed excellent CNS potential against Alzheimer's models. Adamantane is a common pharmacophore for drug design, and myrtenal (M) demonstrated neuroprotective effects in our previous studies. The aim of this study is to evaluate the MACs' neuroprotective properties in dementia. METHODS: Scopolamine (Scop) was applied intraperitoneally in Wistar rats for 11 days, simultaneously with MACs or M as a referent, respectively. Brain acetylcholine esterase (AChE) activity, noradrenaline and serotonin levels, and oxidative brain status determination followed behavioral tests on memory abilities. Molecular descriptors and docking analyses for AChE activity center affinity were performed. RESULTS: M derivatives have favorable physicochemical parameters to enter the CNS. Both MACs restored memory damaged by Scop, showing significant AChE-inhibitory activity in the cortex, in contrast to M, supported by the modeling analysis. Moderate antioxidant properties were manifested by glutathione elevation and catalase activity modulation. MACs also altered noradrenaline and serotonin content in the hippocampus. CONCLUSION: For the first time, neuroprotective properties of two MACs in a rat dementia model were observed. They were stronger than the natural M effects, which makes the substances promising candidates for AD treatment.


Subject(s)
Adamantane , Alzheimer Disease , Neurodegenerative Diseases , Neuroprotective Agents , Acetylcholinesterase/metabolism , Adamantane/pharmacology , Alzheimer Disease/drug therapy , Animals , Antioxidants/pharmacology , Antioxidants/therapeutic use , Bicyclic Monoterpenes , Maze Learning , Neurodegenerative Diseases/drug therapy , Neuroprotective Agents/pharmacology , Neuroprotective Agents/therapeutic use , Norepinephrine , Oxidative Stress , Rats , Rats, Wistar , Scopolamine/pharmacology , Serotonin/metabolism
4.
Molecules ; 27(11)2022 May 24.
Article in English | MEDLINE | ID: mdl-35684313

ABSTRACT

Inhibiting tyrosyl-DNA phosphodiesterase 1 (TDP1) is a promising strategy for increasing the effectiveness of existing antitumor therapy since it can remove the DNA lesions caused by anticancer drugs, which form covalent complexes with topoisomerase 1 (TOP1). Here, new adamantane-monoterpene conjugates with a 1,2,4-triazole or 1,3,4-thiadiazole linker core were synthesized, where (+)-and (-)-campholenic and (+)-camphor derivatives were used as monoterpene fragments. The campholenic derivatives 14a-14b and 15a-b showed activity against TDP1 at a low micromolar range with IC50 ~5-6 µM, whereas camphor-containing compounds 16 and 17 were ineffective. Surprisingly, all the compounds synthesized demonstrated a clear synergy with topotecan, a TOP1 poison, regardless of their ability to inhibit TDP1. These findings imply that different pathways of enhancing topotecan toxicity other than the inhibition of TDP1 can be realized.


Subject(s)
Adamantane , Antineoplastic Agents , Adamantane/pharmacology , Antineoplastic Agents/pharmacology , Camphor , Monoterpenes/pharmacology , Phosphodiesterase Inhibitors/pharmacology , Phosphoric Diester Hydrolases/metabolism , Topotecan/pharmacology
5.
Viruses ; 15(1)2022 12 21.
Article in English | MEDLINE | ID: mdl-36680072

ABSTRACT

Despite the fact that the variola virus is considered eradicated, the search for new small molecules with activity against orthopoxviruses remains an important task, especially in the context of recent outbreaks of monkeypox. As a result of this work, a number of amides of benzoic acids containing an adamantane fragment were obtained. Most of the compounds demonstrated activity against vaccinia virus, with a selectivity index SI = 18,214 for the leader compound 18a. The obtained derivatives also demonstrated activity against murine pox (250 ≤ SI ≤ 6071) and cowpox (125 ≤ SI ≤ 3036). A correlation was obtained between the IC50 meanings and the binding energy to the assumed biological target, the p37 viral protein with R2 = 0.60.


Subject(s)
Communicable Diseases , Orthopoxvirus , Variola virus , Mice , Animals , Amides/pharmacology , Vaccinia virus , Virus Replication
6.
Molecules ; 26(24)2021 Dec 13.
Article in English | MEDLINE | ID: mdl-34946622

ABSTRACT

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.

7.
Molecules ; 26(11)2021 May 24.
Article in English | MEDLINE | ID: mdl-34073771

ABSTRACT

Tyrosyl-DNA phosphodiesterase 1 (Tdp1) is a promising target for anticancer therapy due to its ability to counter the effects topoisomerase 1 (Top1) poison, such as topotecan, thus, decreasing their efficacy. Compounds containing adamantane and monoterpenoid residues connected via 1,2,4-triazole or 1,3,4-thiadiazole linkers were synthesized and tested against Tdp1. All the derivatives exhibited inhibition at low micromolar or nanomolar concentrations with the most potent inhibitors having IC50 values in the 0.35-0.57 µM range. The cytotoxicity was determined in the HeLa, HCT-116 and SW837 cancer cell lines; moderate CC50 (µM) values were seen from the mid-teens to no effect at 100 µM. Furthermore, citral derivative 20c, α-pinene-derived compounds 20f, 20g and 25c, and the citronellic acid derivative 25b were found to have a sensitizing effect in conjunction with topotecan in the HeLa cervical cancer and colon adenocarcinoma HCT-116 cell lines. The ligands are predicted to bind in the catalytic pocket of Tdp1 and have favorable physicochemical properties for further development as a potential adjunct therapy with Top1 poisons.


Subject(s)
Adamantane/pharmacology , Monoterpenes/chemistry , Phosphoric Diester Hydrolases/drug effects , Adamantane/chemistry , Carbon-13 Magnetic Resonance Spectroscopy , Cell Line, Tumor , Humans , Ligands , Mass Spectrometry , Proton Magnetic Resonance Spectroscopy , Structure-Activity Relationship
8.
Anticancer Agents Med Chem ; 19(4): 463-472, 2019.
Article in English | MEDLINE | ID: mdl-30523770

ABSTRACT

BACKGROUND AND OBJECTIVE: The DNA repair enzyme tyrosyl-DNA-phosphodiesterase 1 (TDP1) is a current inhibition target to improve the efficacy of cancer chemotherapy. Previous studies showed that compounds combining adamantane and monoterpenoid fragments are active against TDP1 enzyme. This investigation is focused on the synthesis of monoterpenoid derived esters of 1-adamantane carboxylic acid as TDP1 inhibitors. METHODS: New esters were synthesized by the interaction between 1-adamantane carboxylic acid chloride and monoterpenoid alcohols. The esters were tested against TDP1 and its binding to the enzyme was modeling. RESULTS: 13 Novel ester-based TDP1 inhibitors were synthesized with yields of 21-94%; of these, nine esters had not been previously described. A number of the esters were found to inhibit TDP1, with IC50 values ranging from 0.86-4.08 µM. Molecular modelling against the TDP1 crystal structure showed a good fit of the active esters in the catalytic pocket, explaining their potency. A non-toxic dose of ester, containing a 3,7- dimethyloctanol fragment, was found to enhance the cytotoxic effect of topotecan, a clinically used anti-cancer drug, against the human lung adenocarcinoma cell line A549. CONCLUSION: The esters synthesized were found to be active against TDP1 in the lower micromolar concentration range, with these findings being corroborated by molecular modeling. Simultaneous action of the ester synthesized from 3,7-dimethyloctanol-1 and topotecan revealed a synergistic effect.


Subject(s)
Adamantane/analysis , DNA Repair , Monoterpenes/analysis , Phosphodiesterase Inhibitors/pharmacology , Phosphoric Diester Hydrolases/drug effects , Catalytic Domain , Cell Line, Tumor , Drug Screening Assays, Antitumor , Humans , Models, Molecular , Phosphodiesterase Inhibitors/chemistry , Phosphoric Diester Hydrolases/chemistry , Phosphoric Diester Hydrolases/metabolism , Spectrum Analysis/methods
9.
Bioorg Chem ; 76: 392-399, 2018 02.
Article in English | MEDLINE | ID: mdl-29248742

ABSTRACT

The ability of a number of nitrogen-containing compounds that simultaneously carry the adamantane and monoterpene moieties to inhibit Tdp1, an important enzyme of the DNA repair system, is studied. Inhibition of this enzyme has the potential to overcome chemotherapeutic resistance of some tumor types. Compound (+)-3c synthesized from 1-aminoadamantane and (+)-myrtenal, and compound 4a produced from 2-aminoadamantane and citronellal were found to be most potent as they inhibited Tdp1 with IC50 values of 6 and 3.5 µM, respectively. These compounds proved to have low cytotoxicity in colon HCT-116 and lung A-549 human tumor cell lines (CC50 > 50 µM). It was demonstrated that compound 4a at 10 µM enhanced cytotoxicity of topotecan, a topoisomerase 1 poison in clinical use, against HCT-116 more than fivefold and to a lesser extent of 1.5 increase in potency for A-549.


Subject(s)
Adamantane/analogs & derivatives , Adamantane/pharmacology , Antineoplastic Agents/pharmacology , Monoterpenes/pharmacology , Phosphodiesterase Inhibitors/pharmacology , Phosphoric Diester Hydrolases/metabolism , Adamantane/chemical synthesis , Adamantane/chemistry , Amines/chemical synthesis , Amines/chemistry , Amines/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Binding Sites , Drug Screening Assays, Antitumor , Drug Synergism , HCT116 Cells , Humans , Molecular Docking Simulation , Monoterpenes/chemical synthesis , Monoterpenes/chemistry , Phosphodiesterase Inhibitors/chemical synthesis , Phosphodiesterase Inhibitors/chemistry , Phosphoric Diester Hydrolases/chemistry , Stereoisomerism , Topotecan/pharmacology
10.
Bioorg Med Chem Lett ; 27(19): 4531-4535, 2017 10 01.
Article in English | MEDLINE | ID: mdl-28886889

ABSTRACT

The antiviral activity of several diaza-adamantanes containing monoterpenoid moieties against a rimantadine-resistant strain of the influenza A/Puerto Rico/8/34 (H1N1) virus was studied. Hetero-adamantanes containing monoterpene moieties at the aminal position of the heterocycle were found to exhibit lower activity compared to compounds with a diaza-adamantane fragment and a monoterpene moiety linked via an amino group at the 6-position of the hetero-adamantane ring. The highest selectivity index (a ratio of the 50% cytotoxic concentration to the 50% inhibitory concentration) out of 30 was observed for compound 8d, which contains a citronellal monoterpenoid moiety. Diaza-adamantane 8d was superior to its adamantane-containing analog 5 both in its anti-influenza activity and selectivity. Furthermore, 8d has more balanced physicochemical properties than 5, making the former a more promising drug candidate. Modelling these compounds against an influenza virus M2 ion channel predicted plausible binding modes to both the wild-type and the mutant (S31N).


Subject(s)
Adamantane/pharmacology , Antiviral Agents/pharmacology , Aza Compounds/pharmacology , Influenza A Virus, H1N1 Subtype/drug effects , Monoterpenes/pharmacology , Adamantane/chemistry , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Aza Compounds/chemistry , Dose-Response Relationship, Drug , Microbial Sensitivity Tests , Molecular Structure , Monoterpenes/chemistry , Structure-Activity Relationship
11.
Med Chem ; 13(8): 773-779, 2017.
Article in English | MEDLINE | ID: mdl-28545384

ABSTRACT

BACKGROUND: It was found earlier that compounds combining diazaadamantane and monoterpene moieties possessed promising analgesic activity along with low acute toxicity and the lack of ulcerogenic activity. OBJECTIVE: In this paper, new structural analogues of the most active compounds were synthesized and evaluated for their analgesic activity. METHODS: Their structures were confirmed by various analytical methods, such as 1H and 13C NMR, HRMS. All of them were evaluated for analgesic activity at a dose of 20 mg/kg or less using acetic acid-induced writhing test and hot plate test. RESULTS: Some compounds showed analgesic activity in acetic acid-induced writhing test. One of the synthesized compounds demonstrated high analgesic activity in both tests with 46% effect in acetic acid-induced writhing test and 89% effect in hot plate test. Both structural fragments of this compound did not possess any analgesic effect at a dose of 20 mg/kg. CONCLUSION: Structure-activity relationships indicated that the most active compound combines fragments of (-)-myrtenal and 6-amino-5,7-dimethyl-1,3-diazaadamantane. Both parts of the molecule are important for demonstrating analgesic activity.


Subject(s)
Adamantane/pharmacology , Amines/pharmacology , Analgesics/pharmacology , Monoterpenes/pharmacology , Pain/drug therapy , Acetic Acid , Adamantane/administration & dosage , Adamantane/chemistry , Administration, Oral , Amines/administration & dosage , Amines/chemistry , Analgesics/administration & dosage , Analgesics/chemistry , Animals , Dose-Response Relationship, Drug , Mice , Molecular Structure , Monoterpenes/administration & dosage , Monoterpenes/chemistry , Pain/chemically induced , Pain Measurement , Structure-Activity Relationship
12.
Med Chem ; 11(7): 629-35, 2015.
Article in English | MEDLINE | ID: mdl-25981517

ABSTRACT

A series of secondary amines combining monoterpenoid and aminoadamantane moieties have been synthesized. Their cytotoxic activity against human cancer cells CEM-13, MT-4, and U-937 has been studied for the first time. Most of the obtained compounds exhibited a significant cytotoxic activity with the median cytotoxic dose (CTD50) ranging from 6 to 84 µM. The most promising results were obtained for compound 2b which was synthesized from 1-aminoadamantane and (-)-myrtenal and revealed a high activity against all tumor lines used (CTD50 = 12 ÷ 21 µM) along with low toxicity with respect to MDCK cells (CTD50 = 1500 µM). The synthesized amines do not exert the genotoxic effect on cells of the biosensor strain based on recombinant E. coli cells bearing the pRAC-gfp plasmid.


Subject(s)
Adamantane/chemistry , Adamantane/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Monoterpenes/chemistry , Mutagens/chemistry , Mutagens/pharmacology , Animals , Cell Line, Tumor , Dogs , Humans , Madin Darby Canine Kidney Cells
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