New 5-Hydroxycoumarin-Based Tyrosyl-DNA Phosphodiesterase I Inhibitors Sensitize Tumor Cell Line to Topotecan.

Tyrosyl-DNA-phosphodiesterase 1 (TDP1) is an important enzyme in the DNA repair system. The ability of the enzyme to repair DNA damage induced by a topoisomerase 1 poison such as the anticancer drug topotecan makes TDP1 a promising target for complex antitumor therapy. In this work, a set of new 5-hydroxycoumarin derivatives containing monoterpene moieties was synthesized.

New Inhibitors of Respiratory Syncytial Virus (RSV) Replication Based on Monoterpene-Substituted Arylcoumarins.

Respiratory syncytial virus (RSV) causes annual epidemics of respiratory infection. Usually harmless to adults, the RSV infection can be dangerous to children under 3 years of age and elderly people over 65 years of age, often causing serious problems, even death. At present, there are no vaccines and specific chemotherapeutic agents for the treatment of this disease, so the search for low-molecular weight compounds to combat RSV is a challenge.

Biotransformation of (-)-Isopulegol by .

The ability of actinobacteria of the genus to biotransform the monoterpenoid (-)-isopulegol has been established for the first time. . strain IEGM 1362 was selected as a bacterium capable of metabolizing (-)-isopulegol to form new, previously unknown, 10-hydroxy () and 10-carboxy () derivatives, which may presumably have antitumor activity and act as respiratory stimulants and cancer prevention agents.

Adamantane-Monoterpenoid Conjugates Linked via Heterocyclic Linkers Enhance the Cytotoxic Effect of Topotecan.

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 - and - showed activity against TDP1 at a low micromolar range with IC ~5-6 μM, whereas camphor-containing compounds and were ineffective.

Monoterpene-Containing Substituted Coumarins as Inhibitors of Respiratory Syncytial Virus (RSV) Replication.

Respiratory syncytial virus (RSV) is a critical cause of infant mortality. However, there are no vaccines and adequate drugs for its treatment. We showed, for the first time, that O-linked coumarin-monoterpene conjugates are effective RSV inhibitors.

Novel Tdp1 Inhibitors Based on Adamantane Connected with Monoterpene Moieties via Heterocyclic Fragments.

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 IC values in the 0.

New chemical agents based on adamantane-monoterpene conjugates against orthopoxvirus infections.

Currently, the spectrum of agents against orthopoxviruses, in particular smallpox, is very narrow. Despite the fact that smallpox is well controlled, there is, for many reasons, a real threat of epidemics associated with this or a similar virus. In order to search for new low molecular weight orthopoxvirus inhibitors, a series of amides combining adamantane and monoterpene moieties were synthesized using 1- and 2-adamantanecarboxylic acids as well as myrtenic, citronellic and camphorsulfonic acids as acid components.

Influenza antiviral activity of F- and OH-containing isopulegol-derived octahydro-2H-chromenes.

We synthesized fluoro- and hydroxy-containing octahydro-2H-chromenes by the Prins reaction starting from a monoterpenoid (-)-isopulegol and a wide range of aromatic aldehydes in the presence of the BF∙EtO/HO system acting as both an acid catalyst and a fluorine source. Activity of the produced compounds against the influenza A/Puerto Rico/8/34 (H1N1) virus was studied. The highest activity was demonstrated by fluoro- (11i) and hydroxy-containing (10i) derivatives of 2,4,6-trimethoxybenzaldehyde.

New type of anti-influenza agents based on benzo[d][1,3]dithiol core.

We synthesized a series of amides with a benzo[d][1,3]dithiol core. The chemical library of compounds was tested for their cytotoxicity and inhibiting activity against influenza virus A/California/07/09 (H1N1)pdm09 in MDCK cells. For each compound, values of CC, IC and selectivity index (SI) were determined.

Promising New Inhibitors of Tyrosyl-DNA Phosphodiesterase I (Tdp 1) Combining 4-Arylcoumarin and Monoterpenoid Moieties as Components of Complex Antitumor Therapy.

Tyrosyl-DNA phosphodiesterase 1 (Tdp1) is an important DNA repair enzyme in humans, and a current and promising inhibition target for the development of new chemosensitizing agents due to its ability to remove DNA damage caused by topoisomerase 1 (Top1) poisons such as topotecan and irinotecan. Herein, we report our work on the synthesis and characterization of new Tdp1 inhibitors that combine the arylcoumarin (neoflavonoid) and monoterpenoid moieties. Our results showed that they are potent Tdp1 inhibitors with IC values in the submicromolar range.

Antimicrobial Activity of Substituted Benzopentathiepin-6-amines.

A number of substituted benzopentathiepin-6-amines and their analogues without a polysulfur ring were synthesized and evaluated in vitro for antimicrobial activity against a panel of reference bacterial and fungal strains. Trifluoroacetamide 14 demonstrated high antibacterial activity against Staphylococcus aureus (MRSA strain) with a MIC of 4 μg/mL, which was four-fold higher than the activity of a reference drug amoxicillin. This compound was also most active against the Candida albicans fungus (MIC of 1 μg ml), whereas amide 17 containing a morpholine substituent was most active against the Cryptococcus neoformans fungus (MIC of 2 μg ml).

Novel Inhibitors of DNA Repair Enzyme TDP1 Combining Monoterpenoid and Adamantane Fragments.

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.

Highly potent activity of isopulegol-derived substituted octahydro-2H-chromen-4-ols against influenza A and B viruses.

A set of (-)-isopulegol derived octahydro-2H-chromen-4-ols was synthesized and evaluated in vitro for antiviral activity against panel of reference influenza virus strains differing in subtype, origin (human or avian) and drug resistance. Compound (4R)-11a produced via one-pot synthesis by interaction between (-)-isopulegol and acetone was found to exhibit an outstanding activity against a number of H1N1 and H2N2 influenza virus strains with selectivity index more than 1500. (4R)-11a was shown to be most potent at early stages of viral cycle.

Aminoadamantanes containing monoterpene-derived fragments as potent tyrosyl-DNA phosphodiesterase 1 inhibitors.

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 IC values of 6 and 3.

Anti-influenza activity of monoterpene-containing substituted coumarins.

Compounds simultaneously carrying the monoterpene and coumarin moieties have been tested for cytotoxicity and inhibition of activity against influenza virus A/California/07/09 (H1N1)pdm09. The structure of substituents in the coumarin framework, as well as the structure and the absolute configuration of the monoterpenoid moiety, are shown to significantly influence the anti-influenza activity and cytotoxicity of the compounds under study. The compounds with a bicyclic pinane framework exhibit the highest selectivity indices (the ratios between the cytotoxicity and the active dose).

Anti-influenza activity of monoterpene-derived substituted hexahydro-2H-chromenes.

The antiviral activity of 4-hydroxy-hexahydro-2H-chromenes and 4-fluorine-hexahydro-2H-chromenes with an aromatic substituent, synthesized from monoterpene (-)-verbenone, was studied for the first time. Five of 11 (45 per cent) of 4-hydroxy-hexahydro-2H-chromene-type compounds have been found to exhibit antiviral activity against influenza A virus of subtype H1N1pdm09. Although a portion of active compounds among 4-fluorine-containing series was fewer, just compound 5i that contains a fluorine substituent exhibited more potent anti-influenza activity along with low cytotoxicity.

A practical way to synthesize chiral fluoro-containing polyhydro-2H-chromenes from monoterpenoids.

Conditions enabling the single-step preparative synthesis of chiral 4-fluoropolyhydro-2H-chromenes in good yields through a reaction between monoterpenoid alcohols with para-menthane skeleton and aldehydes were developed for the first time. The BF3·Et2O/H2O system is used both as a catalyst and as a fluorine source. The reaction can involve aliphatic aldehydes as well as aromatic aldehydes containing various acceptor and donor substituents.

Compounds Combining Aminoadamantane and Monoterpene Moieties: Cytotoxicity and Mutagenic Effects.

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 short way to chiral compounds with hexahydrofluoreno[9,1-bc]furan framework: synthesis and cytotoxic activity.

A simple and efficient method for synthesizing chiral heterocyclic compounds with the hexahydrofluoreno[9,1-bc]furan framework via interaction between trans-4-hydroxymethyl-2-carene and aromatic aldehydes containing methoxy and hydroxyl moieties in the presence of montmorillonite clay was found. One of the synthesized compounds exhibited a high cytotoxic activity against lymphoblastoid cell line MT-4 (CTD50 0.9μM), which was higher than that of the comparative drug Doxorubicin.

Camphor-based symmetric diimines as inhibitors of influenza virus reproduction.

Influenza is a continuing world-wide public health problem that causes significant morbidity and mortality during seasonal epidemics and sporadic pandemics. The purpose of the study was synthesis and investigation of antiviral activity of camphor-based symmetric diimines and diamines. A set of C2-symmetric nitrogen-containing camphor derivatives have been synthesized.

Antiparkinsonian activity of some 9-N-, O-, S- and C-derivatives of 3-methyl-6-(prop-1-en-2-yl)cyclohex-3-ene-1,2-diol.

Earlier it was found, that (1R,2R,6S)-3-methyl-6-(prop-1-en-2-yl)cyclohex-3-ene-1,2-diol (1) possess high antiparkinsonian activity. The N-, O-, S- and C-derivatives at the C-9 position of diol 1 were synthesized in this work. The antiparkinsonian activity of these compounds was studied in MPTP mice models.