Novel hybrid isoindole-1,3(2H)-dione compounds containing a 1H-tetrazole moiety: Synthesis, biological evaluation, and molecular docking studies.

In this study, novel hybrid isoindole-1,3(2H)-dione compounds (10 and 11) carrying a 1H-tetrazole moiety were synthesized, characterized and their inhibitory properties against xanthine oxidase (XO) and carbonic anhydrase isoenzymes (hCA I and hCA II) were investigated. Allopurinol for XO and acetazolamide for carbonic anhydrase isoenzymes were used as positive standards in inhibition studies. In addition, compounds 8 and 9, which were obtained in the intermediate step, were also investigated for their inhibition effects against the three enzymes. According to the enzyme inhibition results, hybrid isoindole-1,3(2H)-dione derivatives 10 and 11 showed significant inhibitory effects against all three enzymes. Surprisingly, compound 8, containing a SCN functional group, exhibited a greater inhibitory effect than the other compounds against hCA I and hCA II. The IC50 values of compound 8 against hCA I and hCA II were found to be 3.698 ± 0.079 and 3.147 ± 0.083 µM, respectively. Compound 8 (IC50 = 4.261 ± 0.034 µM) showed higher activity than allopurinol (IC50 = 4.678 ± 0.029 µM) and the other compounds against XO, as well. These results clearly show the effect of the SCN group on the inhibition. In addition, in silico molecular docking studies were performed to understand the molecular interactions between each compound and enzymes, and the results were evaluated.

Synthesis and biological evaluation of new chloro/acetoxy substituted isoindole analogues as new tyrosine kinase inhibitors.

We have developed a versatile synthetic approach for the synthesis of new isoindole derivatives via the cleavage of ethers from tricyclic imide skeleton compounds. An exo-cycloadduct prepared from the Diels-Alder reaction of furan and maleic anhydride furnished imide derivatives. The epoxide ring was opened with Ac2O or Ac2O/AcCl in the presence of a catalytic amount of H2SO4 in order to yield new isoindole derivatives 8a-d and 9a-d. The anticancer activity of these compounds was evaluated against the HeLa cell lines. The synthesized compounds showed inhibitory effects on the viability of HeLa cells and the degree of cytotoxicity was increased with the level of bigger branched isoindole derivatives. To better understand the acting mechanism of these molecules, western blot analysis was performed with using mTOR and its downstream substrates. In addition, human mTOR and ribozomal S6 kinase ß1 (RS6Kß1) have been investigated with molecular modelling studies as possible targets for compound series 8 and 9.

Evaluation of isoindole derivatives: Antioxidant potential and cytotoxicity in the HT-29 colon cancer cells.

Norcantharimides have an isoindole skeleton structure, and some isoindoline derivatives have positive effects on inflammatory pathologies, including cancers. The present study aims to evaluate the antioxidant and cytotoxic potential of four synthesized isoindoline derivatives (NCTD1-4). HT-29 cells exposed to 10, 50, 100, and 200 µM doses of each derivative were incubated for 24 and 48 h, respectively. The cytotoxicity of the new derivatives was analyzed using the cell growth inhibition assay and the cell membrane damage test. In vitro antioxidant activity studies showed that the derivatives have free radical-scavenging effects in a dose-dependent manner. NCTD3 and NCTD4 apparently have antioxidant effects when compared with the control group treated with dimethyl sulfoxide. Furthermore, NCTD4 inhibited the growth of the HT-29 cells due to membrane damage and exhibited a dose-dependent cytotoxic effect on colon adenocarcinoma cells. The findings suggest that NDTD4 has the highest potential for colon cancer treatment and may be interpreted as a candidate anticancer agent.

An anomalous addition of chlorosulfonyl isocyanate to a carbonyl group: the synthesis of ((3aS,7aR,E)-2-ethyl-3-oxo-2,3,3a,4,7,7a-hexahydro-1H-isoindol-1-ylidene)sulfamoyl chloride.

In this study, we developed a new addition reaction of chlorosulfonyl isocyanate (CSI), starting from 2-ethyl-3a,4,7,7a-tetrahydro-1H-isoindole-1,3(2H)-dione. The addition reaction of CSI with 2-ethyl-3a,4,7,7a-tetrahydro-1H-isoindole-1,3(2H)-dione resulted in the formation of ylidenesulfamoyl chloride, whose exact configuration was determined by X-ray crystal analysis. We explain the mechanism of product formation supported by theoretical calculations.

Investigation of Solvent Effects on Photophysical Properties of New Aminophthalimide Derivatives-Based on Methanesulfonate.

Novel aminophthalimide derivatives were synthesized starting from (3aR,7aS)-2-(2-hydroxypropyl)-3a,4,7,7a-tetrahydro-1H-isoindole-1,3(2H)-dione (9) , and solvent effects on the photo-physical properties of these newly synthesized aminophthalimide derivatives (compounds 14 and 15) were investigated using UV-Vis absorption spectroscopy, steady-state and time-resolved fluorescence measurements. Both absorption and fluorescence spectra exhibited bathochromic shift with the increased polarity of the solvents for both molecules. Solute-solvent interactions were analyzed using the Lippert-Mataga and Bakhshiev polarity functions, and Kamlet-Taft and Catalan multiple linear regression approaches. The results revealed that these two molecules experienced specific interactions. Furthermore, photo-physical parameters were calculated for both molecules in all of the solvents, such as the fluorescence quantum yield, fluorescence lifetime, radiative (kr) and non-radiative (knr) rate constant values. It was observed that the fluorescence quantum yield values decreased linearly with increasing solvent polarity. This study proved the new dyes including isopropyl methanesulfonate group displayed different behavior from previous studies of aminophthalimide derivatives in water. It was recommended that these new dyes having interesting properties by changing solvent can be used various applications such as environmentally sensitive fluorescent probes, labels in biology, laser industry.

Brighten up the Rainbow: Ecology-Based Group Work for LGBTQ+ People.

This research was carried out as a pretest-posttest experimental study in order to evaluate the effect of ecology-based group work on 18 LGBTQ+ people living in different districts of Istanbul. The study group of the research carried out between July 2022 and August 2022 consists of 18 LGBTQ+ people, between the ages of 19-22. Study participants were randomly selected for each group and assigned to the experimental and control groups. In addition to the Personal Information Form, the Flourishing Scale, the Nature Relatedness Scale, and the Depression Stress and Anxiety Scale (DASS21) were applied to the study group as pretest-posttest. Socializing, hiking, gardening, and human-animal interaction activities were held in the group work sessions consisting of 6 sessions on Saturdays at 13.00. In addition to all these activities, some documentaries on ecology were also suggested for the participants to watch, to be discussed in different sessions. The collected data were analyzed in the SPSS 22.0 package program. At the end of the group work, it was observed that there was a significant difference in the total scores of the Flourishing Scale, the Nature Relatedness Scale, and Depression Stress and Anxiety Scale (DASS21) of LGBTQ+ people in the experimental group.

Unusual Rearrangements in Cyclohex-3-ene-1-carboxamide Derivatives: Pathway to Bicyclic Lactones.

The synthesis of new bicyclic lactone derivatives was carried out starting from 2-methyl/phenyl-3a,4,7,7a-tetrahydro-1H-isoindole-1,3(2H)-dione. 6-(Hydroxymethyl)-N-methyl/phenylcyclohex-3-ene-1-carboxamide derivatives were obtained from the reduction of tetrahydro-1H-isoindole-1,3(2H)-diones with NaBH4. Bromination and epoxidation reactions of both compounds were examined, and the structures of the resulting products were determined by spectroscopic methods. Substituted bicyclic lactone compounds, which are interesting rearrangement products in both bromination and epoxidation reactions, were obtained. In particular, hydroxymethyl (-CH2OH) and amide (-CONHR) groups attached to the cyclohexene ring in the bromination and epoxidation reactions were found to be effective in product formation. As a result, a new and applicable method was developed for the synthesis of bicyclic lactone derivatives.

Effects of the COVID-19 Pandemic on LGBTQ+'s Sexual Behaviors in Turkey: "Everything about Sex Had Become A Black Box".

The COVID-19 pandemic has forced changes in the behavior patterns of many population groups due to restrictive measures all over the world. In this study, qualitative research method based on a phenomenological approach was used to determine the changes in the sexual behavior of a group of LGBTQ+ people living in Turkey. The COVID-19 pandemic has culminated in changes in the sexual life of LGBTQ+s. It has been determined that feelings such as the need of emotional support, loneliness, devaluation and helplessness were experienced, and quarantine and curfew restrictions were effective on sexuality and sexual behaviors. In addition, it has been determined that LGBTQ+s have changed in the standards of determining partners during the pandemic process. The use of sex toys has increased, the sensitivity toward self-care and hygiene rules has increased, the tendency to have sexual fantasies has changed, the sexual behavior of people in their social environment has changed, and the disruptions in health services have posed negative effects. It is recommended to carry out studies focusing on the sexual behavior of LGBTQ+s and to develop counseling services regarding the sexual behaviors of LGBTQ+s and the situations that occur in their sexual lives.

Synthesis, cytotoxicity, and antibacterial studies of 2,4,5,6-substituted hexahydro-1H-isoindole-1,3(2H)-dione.

In this study, synthesis of novel isoindole-1,3-dione analogues bearig halo, hydroxy, and acetoxy groups at the position 4,5,6 of the bicyclic imide ring was performed to examine their potential anticancer effects against some cell lines. A multistep chemical pathway was used to synthesize the derivatives. The cytotoxic effect of trisubstituted isoindole derivatives were evaluated by determining cellular viability using the MTT assay against A549, PC-3, HeLa, Caco-2, and MCF-7 cell lines. The C-2 selective ring-opening products were obtained from the ring-opening reaction of 5-alkyl/aryl-2-hydroxyhexahydro-4H-oxireno[2,3-e]isoindole-4,6(5H)-diones with nucleophiles such as chloride (Cl- ) and bromide (Br- ) ions. In addition, the ring-opening products halodiols were converted to their related acetates. The anticancer activity of synthesized isoindole-1,3-dione derivatives was investigated against HeLa, A549, MCF-7, PC3, and Caco-2 cells in vitro and resulted in varies cytotoxic effect depend on the group attached to the isoindole molecule. Furthermore, the evaluation of the antimicrobial action of trisubstituted isoindole derivatives against Gram-positive (Staphylococcus aureus) and Gram-negative (Escherichia coli) bacteria was assessed and found out selective inhibition of the both bacterial growth via different trisubstituted isoindole derivatives. The results of this work encourage further research on the potential utilization of trisubstituted isoindole derivatives as cytotoxic and antimicrobial agents.

Evaluation of In Vivo Biological Activity Profiles of Isoindole-1,3-dione Derivatives: Cytotoxicity, Toxicology, and Histopathology Studies.

The anticancer activity of N-benzylisoindole-1,3-dione derivatives was evaluated against adenocarcinoma (A549-Luc). First, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide activity assay studies of two isoindole-1,3-dione derivatives were performed against A549 cell lines. Both compounds showed inhibitory effects on the viability of A549 cells. Then, we explored the potential of these compounds as active ingredients by in vivo studies. Nude mice were given A549-luc lung cancer cells, and tumor growth was induced with a xenograft model. Then, nude mice were divided into three groups: the control group, compound 3 group, and compound 4 group. After application of each compound to the mice, tumor sizes, their survival, and weight were determined for 60 days. Furthermore, toxicological studies were performed to examine the effects of the drugs in mice. In addition to toxicological studies, histopathological analyses of organs taken from mice were performed, and the results were evaluated. The obtained results showed that both N-benzylisoindole derivatives are potential anticancer agents.

Synthesis of a new class of aminocyclitol analogues with the conduramine D-2 configuration.

A new class of aminocyclitol derivatives with the bicyclo[4.2.0]octane skeleton was synthesized starting from cyclooctatetraene. Photooxygenation of trans-7,8-diacetoxy- and cis-7,8-dichlorobicyclo[4.2.0]octa-2,4-diene afforded the bicyclic endoperoxides. Reduction of the latter with thiourea followed by a Pd(0) catalyzed ionization/cyclization reaction gave the corresponding oxazolidinone derivatives. Oxidation of the double bond with KMnO4 or OsO4 followed by acetylation gave the acetate derivatives, the exact configuration of which was determined by spectroscopic methods. Hydrolysis of the oxazolidinone rings and removal of the acetate groups furnished the desired aminocyclitols.

The Synthesis, Anticancer Activity, Structure-Activity Relationships and Molecular Modelling Studies of Novel Isoindole-1,3(2H)-dione Compounds Containing Different Functional Groups.

BACKGROUND: Isoindole-1,3(2H)-dione derivatives are known to have cytotoxic effects on many cancer cells. The anticancer activity of these compounds varies depending on the substituents attached to them. Therefore, the effect of substituents is very important when determining the anticancer activities of molecules. We have recently reported an example of the substituent effect. According to that work, the anticancer activity against HeLa, C6, and A549 cancer cell lines of isoindole- 1,3(2H)-dione compounds containing tert-butyldiphenylsilyl ether, azido, and hydroxyl groups was examined by our group. It was found that an isoindole-1,3(2H)-dione compound containing both tert-butyldiphenylsilyl ether group and azido groups showed higher anticancer activity than 5-fluorouracil and another isoindole-1,3(2H)- dione compound containing both azido and hydroxyl groups. After we discovered that tert-butyldiphenylsilyl ether group in the skeletal structure of isoindole-1,3(2H)-dione exhibits anticancer activity against HeLa, C6, and A549 cancer cell lines, we wanted to examine the anticancer activities of different silyl ether groups, i.e., OTMS, -OTBDPS, and -OTBDMS groups, and also -OH and -Br groups, by comparing them with each other according to the structure-activity relationship. METHODS: All of the synthesized compounds were characterized by 1H and 13C NMR spectra, IR spectroscopy, and mass spectra measurements. The IC50 values of these compounds were calculated for all cancer cell lines and compared with each other and cisplatin, which is a platinum-containing chemotherapeutic drug. Molecular modelling studies were carried out using the MOE software package. RESULTS: It was found that compounds 13 and 16, containing both silyl ether (-OTBDMS) and -Br groups, showed higher anticancer activity than cisplatin against both Caco-2 and MCF-7 cell lines. Compounds 20 and 23 showed anticancer activity in MCF-7 cells and compounds 8, 9, 20, and 23 in Caco-2 cells. While compounds 20 and 23 have only a silyl ether (-OTMS) group, compounds 8 and 9 have only a -OH group. Molecular modelling studies indicated that compounds 8 and 13, as well as their analogs, may bind to the active site of hRS6KB1 (pdb: 4l3j), compound 11 may bind to the active site of human mTOR (pdb: 4jt5) and additionally, compounds 10-17 are expected to be both mutagenic and reactive according to the mutagenicity and reactivity calculations. CONCLUSION: According to these results, the anticancer activities of isoindole-1,3(2H)-dione compounds (8 - 23) vary depending on the groups they contain and these groups affect each other's activities. Silyl ethers (-OTBDMS and -OTMS) and -OH and -Br groups in the skeletal structure of isoindole-1,3(2H)-dione can be regarded as anticancer agents. In this sense, compounds 13 and 16, containing both silyl ether (-OTBDMS) and - Br groups, may be regarded as alternative chemotherapeutic drugs. This work may lead to the synthesis of new isoindole-1,3(2H)-dione compounds containing different silyl ether groups and studies evaluating their anticancer activities or other biological properties.

Evaluation of Cytotoxic Potentials of Some Isoindole-1, 3-Dione Derivatives on HeLa, C6 and A549 Cancer Cell Lines.

BACKGROUND: Norcantharimides are known as norcantharidine derivatives and contain an isoindole skeleton structure. Isoindole derivatives have positive effect on inflammatory pathologies including cancers. OBJECTIVE: Considering this information, firstly, isoindole derivatives containing different functional groups 4-13 have been synthesized from 2-alkyl/aryl-3a, 4,7,7a-tetrahydro-1H-isoindole-1, 3(2H)-dione. METHODS: For the synthesis of all compounds, 2-alkyl/aryl-3a, 4,7,7a-tetrahydro-1H-isoindole- 1,3(2H)-dione was used as the starting compound. The syntheses were based on two main reactions: Ene-reaction of singlet oxygen and epoxidation. Secondly, their anticancer activities were evaluated against HeLa, C6 and A549 cancer cell lines by the BrdU assay. RESULTS: Anticancer activities of synthesized compounds (4-13) and 5-FU (5-Florouracil) against HeLa, C6 and A549 cells were investigated at four concentrations (100, 50, 25 and 5 µM). IC50 values of compounds 4-13 were calculated for all cancer cell lines. The investigated compounds showed anticancer activity against the cancer cell lines depending on doses. Compound 7 containing azide and silyl ether exhibited higher inhibitory activity than the other compounds and 5-FU against A549 cancer cell lines (IC50 =19.41± 0.01 µM). Compounds 9 and 11 were determined to exhibit cell-selective activity against HeLa cancer cell lines. Compound 11 had higher activity than the positive control at 100 µM concentrations against C6 cancer cell lines. CONCLUSION: According to the results observed, isoindole derivatives 7, 9, and 11 might be good potential anticancer agents for the treatment of cervical and glioma cancer due to their antiproliferative properties, having less cytotoxic effects on healthy cells. In addition, compound 7 could be used in in vivo studies of all three-cancer cell lines (C6, HeLa, and A549).

rac-3,4-trans-Dichloro-1,2,3,4-tetra-hydro-2-naphthyl acetate.

The title compound, C(12)H(12)Cl(2)O(2), has a bicyclic skeleton containing cyclo-hexene and benzene fragments. The cyclo-hexene ring adopts a half-chair conformation with displacements of two atoms out of the least-squares plane of 0.311 (2) and -0.336 (2) Å. The Cl atoms are trans-positioned.

An intramolecular substitution of hydroperoxy-endoperoxide to a bis-endoperoxide.

[reaction: see text] A new and stereospecific synthesis for bis-endoperoxide has been developed starting from tetrahydronaphthalene. Photooxygenation of tetrahydronaphthalene resulted in the formation of hydroperoxy-endoperoxide. The bromination reaction of hydroperoxy-endoperoxide gave bis-endoperoxide, whose exact configuration has been determined by X-ray analysis. The lowest-energy conformer of bis-endoperoxide is the boat-chair form.

Stereospecific synthesis of a new class of compounds: bis-homoconduritol-A, -D, and -F.

Bis-homoconduritol derivatives with conduritol-A, -D, and -F structures have been synthesized starting from cyclooctatetraene. The photooxygenation of trans-7,8-dibromo- and cis-7,8-dichlorobicyclo[4.2.0]octa-2,4-dienes afforded the bicyclic endoperoxides. Reduction of the endoperoxides with thiourea followed by acetylation gave the corresponding diacetates. The KMnO(4) oxidation and epoxidation of the diacetates followed by acetylation gave the tetraacetates. Removal of the halides either with zinc-dust or Na-anthracene followed by the ammonolysis of tetraacetates afforded the bis-homoconduritol derivatives in high yield.

(1SR,2SR,3SR,4RS,5RS,6RS,7SR,8RS)-7,8-Dichlorobicyclo[4.2.0]octa-2,3,4,5-tetrayl tetraacetate.

In the title compound, C(16)H(20)Cl(2)O(8), the bicyclic system contains a central non-planar cyclohexane ring which is fused to a cyclobutane moiety. The cyclohexane ring has a chair conformation and the whole system adopts a syn conformation. The structure provides information on the stereochemical course of the chlorination, photo-oxidation and hydroxylation steps of the reaction.