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[ 18 F]F-DOPA is widely used in PET diagnostics. Diseases diagnosed with this tracer are schizophrenia, Parkinson's disease, gliomas, neuroendocrine tumors, pheochromocytomas, and pancreatic adenocarcinoma. It should be noted that the [ 18 F]F-DOPA tracer has been known for over 30 years. However, the methods of radiosynthesis applied in the past did not allow its clinical use due to low efficiency and purity. Currently, in the market, one encounters different types of radiosynthesis using the fluorine 18 F isotope and variants of the same method. The synthesis and its modifications were carried out using a Raytest Synchrom R&D module. The synthesis consists of the following steps: (a) binding of the fluoride anion 18 F - on an anion exchange column; (b) elution with TBAHCO 3 - ; (c) nucleophilic fluorination to the ABX 1336 precursor; (d) purification of the intermediate product on the C18ec column; (e) Baeyer-Villiger oxidation; (f) hydrolysis; and (gfinal purification of the crude product on a semipreparative column. The nucleophilic synthesis of [ 18 F]F-DOPA was successfully performed in 120 min, using the ABX 1336 precursor on the Raytest SynChrom R&D module, with a radiochemical yield (RCY) of 15%, radiochemical purity (RCP) ≥ 97%, and enantiomeric purity (ee) ≥ 96%.

Despite the continuous development of medicine, there is still a lack of effective and fully safe protocols for the treatment of neoplastic diseases. The drug-drug conjugates approach seems to give a chance to obtain more efficient molecules. New alkoxy and metronidazole substituted porphyrins were synthesized. Novel porphyrins were purified by flash column chromatography and characterized using NMR, MS, UV-Vis and HPLC. The Nuclear Magnetic Resonance study was performed to annotate experimentally observed 1 H NMR and 13 C NMR signals of new compounds. The 2D NMR techniques such as 1 H- 1 H COSY (Correlation Spectroscopy), 1 H- 13 C HSQC (Heteronuclear Single Quantum Correlation) and 1H-13C HMBC (Heteronuclear Multiple Bond Correlation) were used for the structure elucidation of the new compounds. In the range of 250-450 nm of the absorption spectra, the Soret band was observed, whereas the Q band was noted in the range of 500-650 nm. Compounds revealed a fluorescence quantum yield in the range 0.03-0.12. Singlet oxygen generation quantum yields up to 0.54 were determined. Electrochemical properties has also been studied. It has been noticed electropolymerization of compound bearing 5-nitroimidazole substituents. The photodynamic activity of the studied porphyrins against A549 and HEK001/HPV16 cancer cells were examined. The most active against A549 and HEK 001/HPV16 was light-excited trioxanonylporphyrin with the values of IC 50 equal to 0.49 μM and 50 nM respectively., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The growing interest in anticancer hybrids in the last few years has resulted in a great number of reports on hybrid design, synthesis and bioevaluation. Many novel multi-target-directed drug candidates were synthesized, and their biological activities were evaluated. For the design of anticancer hybrid compounds, the molecules of stilbenes, aromatic quinones, and heterocycles (benzimidazole, imidazole, pyrimidine, pyridine, pyrazole, quinoline, quinazoline) were applied. A distinct group of hybrids comprises the molecules built with natural compounds: Resveratrol, curcumin, coumarin, and oleanolic acid. In this review, we present the studies on bioactive hybrid molecules of a well-known tubulin polymerization inhibitor, combretastatin A-4 and its analogs with other pharmacologically active entities. The mechanism of anticancer activity of selected hybrids is discussed considering the structure-activity relationship.

A series of novel combretastatin A-4 (CA-4) thio derivatives containing different molecular cores, namely α-phenylcinnamic acids (core 1), (Z)-stilbenes (core 2), 4,5-disubstituted oxazoles (core 3), and 4,5-disubstituted N-methylimidazoles (core 4), as cis-restricted analogues were designed and synthesized. They were selected with the use of a parallel virtual screening protocol including the generation of a virtual combinatorial library based on an elaborated synthesis protocol of CA-4 analogues. The selected compounds were evaluated for antiproliferative activity against a panel of six human cancer cell lines (A431, HeLa, MCF7, MDA-MB-231, A549 and SKOV) and two human non-cancer cell lines (HaCaT and CCD39Lu). Moreover, the effect of the test compounds on the inhibition of tubulin polymerization in vitro was estimated. In the series studied here, oxazole-bridged analogues exhibited the most potent antiproliferative activity. Compounds 23a, 23e, and 23i efficiently inhibited tubulin polymerization with IC 50 values of 0.86, 1.05, and 0.85 μM, respectively. Thio derivative 23i, when compared to its oxygen analogue 23j, showed a 5-fold higher inhibitory impact on tubulin polymerization. Compounds 23e and 23i, which showed both best cytotoxic and antitubulin activity, were further studied in terms of their effect on cell cycle distribution and proapoptotic activity. Compound 23e induced a statistically significant block of the cell cycle at the G2/M phase in A431, HaCaT, HeLa, MCF-7, MDA-MB-231, and SKOV-3 cells to an extent comparable to that observed in CA-4. In HeLa and SKOV-3 cells incubated with 23i, a concentration-dependent block of the G2/M phase was observed. The proapoptotic effect of 23e and 23i in A431, HaCaT, MCF-7, MDA-MB-231, and SKOV-3 was demonstrated with ELISA assay and double staining with Annexin V-FITC/PI. The results indicated that compound 23e and 23i may serve as novel lead compounds in research on more effective anticancer agents., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

For the first time combretastatins were isolated from African willow tree Combretum Caffrum. Subsequent studies have shown the impact of combretastatin A4 phosphate, a water-soluble prodrug, on endothelial cells in tumor vascular system. The same effect was not observed in the vascular system. This selectivity is associated with combretastatins mechanism of action: binding to colchicine domain of microtubules, which affects the cytoskeleton functionality of immature endothelial cells. At the same time, combretastatins directly induce cell death via apoptosis and/or mitotic catastrophe pathways. The combination of both elements makes combretastatin an anticancer compound of high efficiency. The cis-configuration is crucial for its biological activity. To date, many derivatives were synthesized. The attempts to resolve spontaneous isomerization to less active trans-stilbene derivative are still in progress. This issue seems to be overcome by incorporation of the ethene bridge with heterocyclic moiety in combretastatins structure. This modification retains the cis-configuration and prevents isomerization. Nevertheless, combretastatin A4 phosphate disodium is still the most potent compound of this group. The combination therapy, which is the most effective treatment, includes combretastatin A4 phosphate (CA4P) and conventional chemotherapeutics and/or radiotherapy. CA4P is relatively well tolerated giving adverse events of moderate severity, which includes: nausea, vomiting, headache, and tumor pain. The aforementioned effects subside on the day of drug administration or on the following day., (Copyright © 2016 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.)

Background: Resveratrol is a natural stilbene derivative whose chemopreventive activity has been well established. Our previous studies have shown that modification of the stilbene backbone with the methylthio group may influence selectivity and inhibitory potency toward P450 isozymes. The aim of this study was to further investigate the mechanism of their potential chemopreventive activity by evaluating the effect of two 4'-methylthio-trans-stilbene derivatives possessing one (3-M-4'-MTS; S2) and two (3,5-DM-4'-MTS; S5) additional methoxy groups on constitutive nuclear factor-κB (NF-κB) and activator protein-1 (AP-1) activation in immortalized human HaCaT keratinocytes., Methods: The synthesis of MTS was performed as described earlier. Translocation of NF-κB and AP-1 was evaluated by Western blot analysis. Binding of p65 (NF-κB) and c-Jun and c-Fos subunits (AP-1) to consensus oligonucleotide was assessed by ELISA. Real-time PCR and Western blot were used to evaluate COX-2 and iNOS expression., Results: We found differential modulation of signaling pathways depending on the stilbene structure after 24h of cells treatment. The S2 compound, in contrast to S5 and resveratrol, significantly reduced NF-κB activation by blocking the translocation of the p65 subunit to the nucleus, and decreasing IκB kinase activity. All compounds, but particularly S5, increased c-Jun binding to the AP-1 consensus sequence, while c-Fos binding was not affected., Conclusions: We conclude that methylthiostilbenes differently modulate constitutive signal transduction pathways in HaCaT cells. These observations should be taken into account in designing new stilbene derivatives with potential chemopreventive activity., (Copyright © 2014 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.)

Resveratrol is the most extensively studied stilbene derivative. We previously showed that methylthiostilbenes were more effective inhibitors of CYP1A1 and 1B1 activity than resveratrol. In this study, we investigated whether resveratrol and its methylthio-substituted derivatives, i.e. 3-M-4'-MTS (S2), 3,5-DM-4'-MTS (S5) and 3,4,5-TM-4'-MTS (S7) could activate Nrf2 signaling in the mouse epidermis and in human keratinocytes. Western blot analysis showed translocation of Nrf2 from the cytosol to the nucleus in both models. All of the tested stilbenes increased GST activity, but resveratrol was the most effective inducer. Moreover, only resveratrol increased the protein level of GSTP in the mouse epidermis. GSTM was enhanced in HaCaT cells after the treatment with derivatives S2 and S5. The same effect was observed for GSTP in the case of compound S2. Resveratrol and its derivatives reduced the NQO2 protein level in HaCaT cells. Thus, it is possible that increased expression of GSTP or GSTM and GST activity was linked with NQO2 inhibition in these cells. The results of this study indicate that resveratrol and its methylthioderivatives activate Nrf2 not only in the mouse epidermis, but also in human keratinocytes. Upregulating GST isozymes might be particularly important for deactivating chemical carcinogens, such as PAH.

Mammalian cytochrome P450 1A (CYP1A) are key phase I xenobiotic-metabolizing enzymes that play a distinctive role in metabolic activation or metabolic clearance of a variety of procarcinogens, drugs, and endogenous substances. Human CYP1A subfamily contains two members (hCYP1A1 and hCYP1A2), which are known to catalyze the oxidative activation of some environmental procarcinogens into carcinogenic species. Increasing evidence has demonstrated that CYP1A inhibitor therapies are promising strategies for cancer chemoprevention or overcoming CYP1A-associated drug toxicity and resistance. Herein, we reviewed recent advances in the discovery and characterization of hCYP1A inhibitors, from the discovery approaches to structural features and biomedical applications of hCYP1A inhibitors. The inhibition potentials, inhibition modes, and inhibition constants of all reported hCYP1A inhibitors are comprehensively summarized. Meanwhile, the structural features and structure-activity relationships of different classes of hCYP1A1 and hCYP1A2 inhibitors are analyzed and discussed in depth. Furthermore, the major challenges and future directions for this field are presented and highlighted. Collectively, the information and knowledge presented here will strongly facilitate the researchers to discover and develop more efficacious CYP1A inhibitors for specific purposes, such as chemo-preventive agents or as tool molecules in hCYP1A-related fundamental studies., (© 2023 Wiley Periodicals LLC.)

In the title compound, C(18)H(20)O(3)S, the rings are almost coplanar [inter-ring dihedral angle = 6.6 (2)°]. In the crystal, weak C-H⋯O hydrogen bonds between the meth-oxy groups connect adjacent mol-ecules, giving chains which extend along [001].

A series of trans-stilbene derivatives containing 4'-methylthio substituent were synthesized and evaluated for inhibitory activities on human recombinant cytochrome P450(s): CYP1A1, CYP1A2, and CYP1B1. CYP1A2-related metabolism of stilbene derivatives was estimated by using NADPH oxidation assay. Additionally, for CYP1A2 and CYP1B1 molecular docking analysis was carried out to provide information on enzyme-ligand interactions and putative site of metabolism. 3,4,5-Trimethoxy-4'-methylthio-trans-stilbene, an analogue of DMU-212 (3,4,5,4'-tetramethoxy-trans-stilbene) was an effective inhibitor of all CYP1 enzymes. On the other hand, 2,3,4-trimethoxy-4'-methylthio-trans-stilbene, appeared to be the most selective inhibitor of the isozymes CYP1A1 and CYP1B1, displaying extremely low affinity towards CYP1A2. Molecular modeling suggested that the most probable binding poses of the methylthiostilbene derivatives in CYP1A2 active sites are those with the methylthio substituent directed towards the heme iron. Products of CYP1A2-catalyzed oxidation of 2,4,5-trimethoxy-4'-methylthiostilbene and 3,4,5-trimethoxy-4'-methylthiostilbene were identified as monohydroxylated compounds. Other studied derivatives appeared to be poor substrates of CYP1A2. Structure-activity relationship analysis rendered better understanding of the mechanism of action of xenobiotic-metabolizing enzymes crucial at the early stage of carcinogenesis., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Porphyrazines possessing non-coordinating alkyl (propyl) and aralkyl (4-tert-butylphenyl) groups in the periphery were studied as optical sensors for a set of mono-, di- and trivalent cations. Investigated porphyrazines in the UV-Vis monitored titrations revealed significant responses towards aluminium and gallium cations, unlike other metal ions studied. Additionally, porphyrazine possessing 4-tert-butylphenyl peripheral substituents showed sensor property towards ruthenium cation and was chosen for further investigation. The presence of isosbestic points in absorption spectra for its titration with aluminium, gallium and ruthenium cations, accompanied by a linear Benesi-Hildebrand plot, proved complex formation. The continuous variation method was used to determine binding stoichiometry in 1:1 porphyrazine-metal ratio. X-Ray studies and density functional theory calculations were employed to investigate octa(4-tert-butylphenyl)porphyrazine structure. The results helped to explain the observed selectivity towards certain ions. Interaction between ion and porphyrazine meso nitrogen in a Lewis acid-Lewis base manner is proposed.

Pleomorphic rhabdomyosarcoma of the uterus is a rare malignant tumor. It is connected with postmenopausal abnormal vaginal bleeding and abdominal pain. We report a case of a 66-year-old postmenopausal woman diagnosed with abnormal vaginal bleeding and abdominal pain. Vaginal ultrasonography showed enlarged uterus, 82 mm x 64 mm in size. The patient underwent total abdominal hysterectomy and bilateral salpingo-oophorectomy with postoperative chemotherapy due to pleomorphic rhabdomyosarcoma of the uterus. The patient died 2.5 years after the surgery as a result of a rapid spread of the neoplastic process. The case of rhabdomyosarcoma, together with the review of the literature, is presented in the following work. We find that the rarity of this histological entity makes it particularly worthy of publication.

Resveratrol (3,5,4'-trihydroxy-trans-stilbene) is a natural stilbene derivative occurring in grapes, peanuts and red wine. Its chemopreventive action has been established in studies on animal models. Recently, numerous classes of compounds with stilbene backbone have been investigated for their biological activity concerning cancer prevention; e. g. resveratrol methyl ethers appeared to be specific and potent inhibitors of cytochromes P450 (CYP) family 1 involved in the activation of procarcinogens. Since the replacement of the 4'-hydroxyl with a thiomethyl group is supposed to reduce toxicity of stilbene derivatives, the purpose of this study was the synthesis and evaluation of a series of 4-thiomethyl-trans-stilbene derivatives differing in a number and position of additional methoxy groups. Their inhibitory potency toward human recombinant CYPs: CYP1A1, CYP1A2 and CYP1B1 have been studied and compared with the effect of resveratrol and its analogues. Among compounds tested, 2-methoxy-4'-thiomethyl-trans-stilbene and 3-methoxy-4'-thiomethyl-trans-stilbene demonstrated the most potent and selective inhibitory effect on CYP1A1 and CYP1B1 activities. The results of our study indicate that modification of stilbene derivatives with thiomethyl group may influence the selectivity and inhibitory potency of these compounds toward P450 isozymes. Thus, it should be considered in developing new chemopreventive agents based on their mechanism of action.

The aryl hydrocarbon receptor (AhR) is an environmentally sensitive transcription factor (TF) historically associated with carcinogenesis initiation via the activation of numerous carcinogens. Nowadays, the AhR has been attributed to multiple endogenous functions to maintain cellular homeostasis. Moreover, crosstalk, often reciprocal, has been found between the AhR and several other TFs, particularly estrogen receptors (ERs) and nuclear factor erythroid 2-related factor-2 (Nrf2). Adequate modulation of these signaling pathways seems to be an attractive strategy for cancer chemoprevention. Several naturally occurring and synthetically modified AhR or ER ligands and Nrf2 modulators have been described. Sulfur-containing derivatives of glucosinolates, such as indole-3-carbinol (I3C), and stilbene derivatives are particularly interesting in this context. I3C and its condensation product, 3,3′-diindolylmethane (DIM), are classic examples of blocking agents that increase drug-metabolizing enzyme activity through activation of the AhR. Still, they also affect multiple essential signaling pathways in preventing hormone-dependent cancer. Resveratrol is a competitive antagonist of several classic AhR ligands. Its analogs, with ortho-methoxy substituents, exert stronger antiproliferative and proapoptotic activity. In addition, they modulate AhR activity and estrogen metabolism. Their activity seems related to a number of methoxy groups introduced into the stilbene structure. This review summarizes the data on the chemopreventive potential of these classes of phytochemicals, in the context of AhR and its crosstalk modulation. [ABSTRACT FROM AUTHOR]

Porphyrazines (Pzs) are porphyrin derivatives that show potential application as photosensitizers for photodynamic therapy (PDT), but are still far less explored in the literature. In this work, we evaluate how the photophysics and phototoxicity of the octakis(trifluoromethylphenyl)porphyrazine (H2Pz) against tumor cells can be modulated by coordination with Mg(II), Zn(II), Cu(II) and Co(II) ions. Fluorescence and singlet oxygen quantum yields for the Pzs were measured in organic solvents and in soy phosphatidylcholine (PC) liposomes suspended in water. While H2Pz and the respective complexes with Cu(II) and Co(II) showed very low efficiency to fluoresce and to produce 1O2, the Mg(II) and Zn(II) complexes showed significantly higher quantum yields in organic solvents. The fluorescence of these two Pzs in the liposomes was sensitive to the fluidity of the membrane, showing potential use as viscosity markers. The cytotoxicity of the compounds was tested in HaCaT (normal) and A431 (tumor) cells using soy PC liposomes as drug carriers. Despite the low 1O2 quantum yields in water, the Mg(II) and Zn(II) complexes showed IC50 values against A431 cells in the nanomolar range when activated with low doses of red LED light. Their phototoxicity was ca. three times higher for the tumor cells compared to the normal ones, showing promising application as photosensitizers for PDT protocols. Considering that H2Pz and the respective Co(II) and Cu(II) complexes were practically non-phototoxic to the cells, we demonstrate the importance of the central metal ion in the modulation of the photodynamic activity of porphyrazines. [ABSTRACT FROM AUTHOR]

The compound studied is 1,2-dimethyl-4-nitro-5-morpholinoimidazole (1) in its anhydrous (1) and hydrated [(1).H(2)O] crystal forms. In spite of the strong electron-withdrawing effect of the nitro group, the unsubstituted N atom of the imidazole moiety retains its basic character and acts as an acceptor for intermolecular hydrogen bonds: either weak C-H....N bonds in (1) or strong O-H...N bonds, with the water molecules, in (1).H(2)O. The packing in (1) is determined by weak C-H.N and C-H.O hydrogen bonds, van der Waals interactions and the stacking of imidazole fragments. The crystal structure of (1).H(2)O is determined by strong O-H(water)...N3(imidazole) and O-H(water)...O(water) hydrogen bonds. This structure consists of a centrosymmetric 'matrix' of imidazole derivative molecules and locally noncentrosymmetric arrays of hydrogen-bonded water molecules. Each of these arrays is strictly homodromic, i.e. it runs only in one direction:.H-O....H-O....H-O.... or....O-H....O-H....O-H.... These homodromic domains are statistically distributed within the crystal.

Six new phenacylidene derivatives of 5-(4-nitrophenyl)furan were obtained by reacting 5-(nitrophenyl)furfural with 4 substituted acetophenones.

The presented studies aimed to evaluate the peripheral coordinating properties of a novel porphyrinoid family representative preceded by its synthesis for potential sensing purposes. Two synthetic pathways were employed to a obtain maleonitrile derivative, further used as a starting material in the cyclotetramerization reaction. In the first one, DAMN was used in sequential double-reductive alkylation with 2-thiophene-carboxyaldehyde and sodium borohydride. In the second, DAMN was used in a one-pot reaction with 2-thiophene-carboxyaldehyde in the presence of a 5-ethyl-2-methylpyridine borane complex in methanol and acetic acid. Following the Linstead approach, the cyclization reaction led to a novel symmetrical magnesium(II) octaaminoporphyrazine with methyl(2-thiophenylmethylene) substituents. The macrocycle's electrochemical properties were assessed by cyclic and differential pulse voltammetries revealing one reduction and two oxidation peak potentials. The additional spectroelectrochemical measurements showed formation of a cationic form of the macrocycle at an applied potential of 0.6 V. The coordinating properties due to the palladium ion of novel porphyrazines were measured with the use of titration combined with UV–vis spectrometry. The titration of Pd2+ revealed the good sensing activity of porphyrazine in the range of 0.1 to 5 palladium molar equivalents. In addition, Pd2+ ions coordination was also assessed by electrochemical studies, indicating the peak potential shift of 0.1 V in the presence of metal cations. DFT calculations showed the good agreement between theoretical and experimental data in the UV–vis and 1H NMR studies. [ABSTRACT FROM AUTHOR]

Inverse vulcanization exploits S8 to synthesize polysulfides. However, evolution of products and its mechanism during inverse vulcanization remains elusive. Herein, inverse vulcanization curves are obtained to describe the inverse vulcanization process in terms of three stages: induction, curing and over-cure. The typical curves exhibit a moduli increment before declining or plateauing, reflecting the process of polysulfide network formation and loosing depending on monomers. For aromatic alkenes, in the over-cure, the crosslinked polysulfide evolves significantly into a sparse network with accelerated relaxation, due to the degradation of alkenyl moieties into thiocarbonyls. The inverse vulcanization product of olefins degrades slowly with fluctuated relaxation time and modulus because of the generation of thiophene moieties, while the inverse vulcanization curve of dicyclopentadiene has a plateau following curing stage. Confirmed by calculations, the mechanisms reveal the alkenyl groups react spontaneously into thiocarbonyls or thiophenes via similar sulfur-substituted alkenyl intermediates but with different energy barriers. Inverse vulcanization exploits elemental sulfur to synthesize versatile polysulfides but the mechanism of inverse vulcanization remains elusive. Herein, the authors use inverse vulcanization curves to describe the three-stage structural evolution during the inverse vulcanization process. [ABSTRACT FROM AUTHOR]

Semaphorin 3A (SEMA3A), a nerve-repellent factor produced by keratinocytes, has an inhibitory effect on nerve extension to the epidermis. Epidermal innervation is involved in pruritus in inflammatory skin diseases such as atopic dermatitis (AD) and dry skin. We previously reported that tapinarof, a stilbene molecule, upregulates SEMA3A in human keratinocytes. We also showed that this mechanism is mediated via the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor, and the nuclear factor erythroid 2-related factor 2 (NRF2) axis. Since some stilbenes activate AHR and NRF2, we attempted to identify other stilbenes that upregulate SEMA3A. We analyzed normal human epidermal keratinocytes (NHEKs) treated with 11 types of stilbenes and examined SEMA3A expression. We found that resveratrol and pinostilbene, antioxidant polyphenols, upregulated SEMA3A and increased nuclear AHR and NRF2 expression. In addition, AHR knockdown by small interfering RNA (siRNA) transfection abolished the NRF2 nuclear expression. Furthermore, AHR and NRF2 knockdown by siRNA transfection abrogated resveratrol- and pinostilbene-induced SEMA3A upregulation. Finally, we confirmed that resveratrol and pinostilbene increased SEMA3A promoter activity through NRF2 binding using ChIP-qPCR analysis. These results suggest that resveratrol and pinostilbene upregulate SEMA3A via the AHR–NRF2 axis in human keratinocytes. [ABSTRACT FROM AUTHOR]

Irritable bowel syndrome (IBS) is a common gastrointestinal disorder affecting 9–23% of the world's population, with a higher prevalence among women. IBS is a complex disorder influenced by psychosocial, physiological, and genetic factors, exacerbated by stress. Research confirms that the most common subtype of IBS is IBS-C. Therefore, new therapies are being developed to speed up bowel movement and reduce constipation, with drugs such as linaclotide, plecanatide, lubiprostone, or tegaserod available to reduce IBS-C symptoms. In addition, patients' condition is improved by foods rich in fiber and low in FODMAP and the use of biotics. The topic is of great importance due to the growing number of patients suffering from IBS-C and its significant impact on quality of life. Current clinical trials of new therapeutic options are not too successful, and it seems that one of the plausible treatment options could be the multi-drug cocktail with some, or perhaps even all its ingredients emerging from drug re-purposing. Another important path that needs to be explored further in IBS-C patients is the adjustment of dietary habits and/or introduction of dietary or nutritional intervention. [ABSTRACT FROM AUTHOR]

Background: Accurate preoperative prediction of glioma is crucial for developing individualized treatment decisions and assessing prognosis. In this study, we aimed to establish and evaluate the value of integrated models by incorporating the intratumoral and peritumoral features from conventional MRI and clinical characteristics in the prediction of glioma grade. Methods: A total of 213 glioma patients from two centers were included in the retrospective analysis, among which, 132 patients were classified as the training cohort and internal validation set, and the remaining 81 patients were zoned as the independent external testing cohort. A total of 7728 features were extracted from MRI sequences and various volumes of interest (VOIs). After feature selection, 30 radiomic models depended on five sets of machine learning classifiers, different MRI sequences, and four different combinations of predictive feature sources, including features from the intratumoral region only, features from the peritumoral edema region only, features from the fusion area including intratumoral and peritumoral edema region (VOI-fusion), and features from the intratumoral region with the addition of features from peritumoral edema region (feature-fusion), were established to select the optimal model. A nomogram based on the clinical parameter and optimal radiomic model was constructed for predicting glioma grade in clinical practice. Results: The intratumoral radiomic models based on contrast-enhanced T1- weighted and T2-flair sequences outperformed those based on a single MRI sequence. Moreover, the internal validation and independent external test underscored that the XGBoost machine learning classifier, incorporating features extracted from VOI-fusion, showed superior predictive efficiency in differentiating between low-grade gliomas (LGG) and high-grade gliomas (HGG), with an AUC of 0.805 in the external test. The radiomic models of VOI-fusion yielded higher prediction efficiency than those of feature-fusion. Additionally, the developed nomogram presented an optimal predictive efficacy with an AUC of 0.825 in the testing cohort. Conclusion: This study systematically investigated the effect of intratumoral and peritumoral radiomics to predict glioma grading with conventional MRI. The optimal model was the XGBoost classifier coupled radiomic model based on VOI-fusion. The radiomic models that depended on VOI-fusion outperformed those that depended on feature-fusion, suggesting that peritumoral features should be rationally utilized in radiomic studies. [ABSTRACT FROM AUTHOR]

Cancer therapy, especially for tumors near sensitive areas, demands precise treatment. This review explores photodynamic therapy (PDT), a method leveraging photosensitizers (PS), specific wavelength light, and oxygen to target cancer effectively. Recent advancements affirm PDT's efficacy, utilizing ROS generation to induce cancer cell death. With a history spanning over decades, PDT's dynamic evolution has expanded its application across dermatology, oncology, and dentistry. This review aims to dissect PDT's principles, from its inception to contemporary medical applications, highlighting its role in modern cancer treatment strategies. [ABSTRACT FROM AUTHOR]

Stilbene derivatives (pterostilbene and resveratrol) and 4-methylumbelliferone occur naturally in plants. These compounds and coumarin-stilbene hybrids have a variety of biological activities. It was envisioned that the molecular hybridization strategy would produce new bioactive molecules. Thus, six new coumarin-stilbene hybrids (3a-b, 4a-b, and 5a-b) with different hydrocarbon chains as linkers were synthesized by the O-alkylation reaction and characterized using FTIR, 1H NMR, 13C NMR, DEPT-135, and HRMS (ESI+) spectral analysis. An MTT assay was used to test the synthesized hybrids against breast cancer (MCF-7 and T47D) and liver cancer (HepG2) cell lines. The results showed that the synthesis of coumarin-stilbene hybrids via the O-alkylation reaction requires the presence of KI in addition to K2CO3 as a base to complete the reaction. On the other hand, the synthesis of coumarin-pterostilbene hybrids (3a-b) via the O-alkylation reaction with DMF as a solvent and an excess of base (K2CO3) and catalyst (KI) improved the yield significantly (65.43 and 73.71%, respectively). The biological results exhibited that all hybrids showed moderate to weak anticancer activities, much lower than the medication (cisplatin). However, most compounds showed superior activities than parent compounds against three different human cell lines. Among them, compounds 4a and 4b exhibited the best cytotoxic activity against T47D and MCF-7, with IC50 values of 102.05 and 23.12 µM, respectively. Compound (3a) showed the most cytotoxic activity against HepG2, with an IC50 value of 80.09 µM. To conclude, due to the simplicity of synthesis, hybridization is a promising strategy for producing new hybrid compounds with hydrocarbon chains as linkers and improving biological activity compared with their parent compounds. [ABSTRACT FROM AUTHOR]

Background and aims: Epidemiological evidence suggests that the phenotype of glutathione S-transferase mu 1 (GSTM1), a hepatic high-expressed phase II detoxification enzyme, is closely associated with the incidence of alcohol-related liver disease (ALD). However, whether and how hepatic GSTM1 determines the development of ALD is largely unclear. This study was designed to elucidate the role and potential mechanism(s) of hepatic GSTM1 in the pathological process of ALD. Methods: GSTM1 was detected in the liver of various ALD mice models and cultured hepatocytes. Liver-specific GSTM1 or/and micro (miR)-743a-3p deficiency mice were generated by adenoassociated virus-8 delivered shRNA, respectively. The potential signal pathways involving in alcohol-regulated GSTM1 and GSTM1-associated ALD were explored via both genetic manipulation and pharmacological approaches. Results: GSTM1 was significantly upregulated in both chronic alcohol-induced mice liver and ethanol-exposed murine primary hepatocytes. Alcohol-reduced miR-743a-3p directly contributed to the upregulation of GSTM1, since liver specific silencing miR-743a-3p enhanced GSTM1 and miR-743a-3p loss protected alcohol-induced liver dysfunctions, which was significantly blocked by GSTM1 knockdown. GSTM1 loss robustly aggravated alcohol-induced hepatic steatosis, oxidative stress, inflammation, and early fibrotic-like changes, which was associated with the activation of apoptosis signal-regulating kinase 1 (ASK1), c-Jun N-terminal kinase (JNK), and p38. GSTM1 antagonized ASK1 phosphorylation and its downstream JNK/p38 signaling pathway upon chronic alcohol consumption via binding with ASK1. ASK1 blockage significantly rescued hepatic GSTM1 loss-enhanced disorders in alcohol-fed mice liver. Conclusions: Chronic alcohol consumption-induced upregulation of GSTM1 in the liver provides a feedback protection against hepatic steatosis and liver injury by counteracting ASK1 activation. Down-regulation of miR-743a-3p improves alcohol intake-induced hepatic steatosis and liver injury via direct targeting on GSTM1. The miR-743a-3p–GSTM1 axis functions as an innate protective pathway to defend the early stage of ALD. [ABSTRACT FROM AUTHOR]

The aim of this work is to create new modified dosage forms of amiodarone with triterpene glycosides in various stoichiometric ratios and to study their cytotoxicity on HeLa cells. Complexes of glycyrrhizic acid (GA) and the monoammonium salt of glycyrrhizic acid (MASGA) with amiodarone hydrochloride were obtained, characterized by certain physicochemical parameters, and studied by IR and UV spectroscopy. The supramolecular complexes were formed mainly through weak intermolecular interactions such as hydrogen bonding and ion-dipole, electrostatic, and dipole-dipole interactions. The quantitative content of GA and MASGA in the complexes was shown to affect the cytotoxicity of the drug. A modified form of amiodarone may be developed in future research and could become a promising antiarrhythmic drug. [ABSTRACT FROM AUTHOR]

Stilbenes are phytoalexins, and their biosynthesis can occur through a natural route (shikimate precursor) or an alternative route (in microorganism cultures). The latter is a metabolic engineering strategy to enhance production due to stilbenes recognized pharmacological and medicinal potential. It is believed that in the human body, these potential activities can be modulated by the regulation of the nuclear factor erythroid derived 2 (Nrf2), which increases the expression of antioxidant enzymes. Given this, our review aims to critically analyze evidence regarding E-stilbenes in human metabolism and the Nrf2 activation pathway, with an emphasis on inflammatory and oxidative stress aspects related to the pathophysiology of chronic and metabolic diseases. In this comprehensive literature review, it can be observed that despite the broad number of stilbenes, those most frequently explored in clinical trials and preclinical studies (in vitro and in vivo) were resveratrol, piceatannol, pterostilbene, polydatin, stilbestrol, and pinosylvin. In some cases, depending on the dose/concentration and chemical nature of the stilbene, it was possible to identify activation of the Nrf2 pathway. Furthermore, the use of some experimental models presented a challenge in comparing results. In view of the above, it can be suggested that E-stilbenes have a relationship with the Nrf2 pathway, whether directly or indirectly, through different biological pathways, and in different diseases or conditions that are mainly related to inflammation and oxidative stress. [ABSTRACT FROM AUTHOR]

Monoamine oxidase and xanthine oxidase inhibitors represent useful multi-target drugs for the prevention, attenuation, and treatment of oxidative damage and neurodegenerative disorders. Chimeric molecules, constituted by naturally derived compounds linked to drugs, represent lead compounds to be explored for the discovery of new synthetic drugs acting as enzyme inhibitors. We have previously reported that seven hydroxytyrosol-donepezil hybrid compounds play a protective role in an in vitro neuronal cell model of Alzheimer's disease. In this work, we analyzed the effects exerted by the hybrid compounds on the activity of monoamine oxidase A (MAO-A) and B (MAO-B), as well as on xanthine oxidase (XO), enzymes involved in both neurodegenerative disorders and oxidative stress. The results pointed to the identification, among the compounds tested, of selective inhibitors between the two classes of enzymes. While the 4-hydroxy-3-methoxyphenethyl 1-benzylpiperidine-4-carboxylate- (HT3) and the 4-hydroxyphenethyl 1-benzylpiperidine-4-carboxylate- donepezil derivatives (HT4) represented the best inhibitors of MAO-A, with a scarce effect on MAO-B, they were almost ineffective on XO. On the other hand, the 4,5-dihydroxy-2-nitrophenethyl 1-benzylpiperidine-4-carboxylate donepezil derivative (HT2), the least efficient MAO inhibitor, acted like the best XO inhibitor. Therefore, the differential enzymatic targets identified among the hybrid compounds synthesized enhance the possible applications of these polyphenol-donepezil hybrids in neurodegenerative disorders and oxidative stress. [ABSTRACT FROM AUTHOR]

This document is a summary of a special issue of the journal Pharmaceuticals titled "Molecular Imaging in Oncology: Radiopharmaceuticals for PET and SPECT 2022." The issue focuses on the development of novel radiopharmaceuticals for tumor imaging and therapy. Several articles in the issue discuss the development and evaluation of specific radiopharmaceuticals for prostate cancer, tumor immunotherapy, fibroblast activator protein (FAP)-targeted imaging, glucose-based imaging, and therapeutic radiopharmaceuticals. The articles highlight the potential of these radiopharmaceuticals for early diagnosis, monitoring therapeutic response, and guiding clinical treatments. The issue also includes a review of therapeutic methods and a study on dual-ligand gold nanoparticles. The authors acknowledge the challenges that lie ahead in the development of more effective tumor radiopharmaceuticals and express gratitude to the contributors. [Extracted from the article]

Cytochrome P450-1B1 is a majorly overexpressed drug-metabolizing enzyme in tumors and is responsible for inactivation and subsequent resistance to a variety of anti-cancer drugs, i.e., docetaxel, tamoxifen, and cisplatin. In the present study, a 3D quantitative structure–activity relationship (3D-QSAR) model has been constructed for the identification, design, and optimization of novel CYP1B1 inhibitors. The model has been built using a set of 148 selective CYP1B1 inhibitors. The developed model was evaluated based on certain statistical parameters including q2 and r2 which showed the acceptable predictive and descriptive capability of the generated model. The developed 3D-QSAR model assisted in understanding the key molecular fields which were firmly related to the selective CYP1B1 inhibition. A theoretic approach for the generation of new lead compounds with optimized CYP1B1 receptor affinity has been performed utilizing bioisosteric replacement analysis. These generated molecules were subjected to a developed 3D-QSAR model to predict the inhibitory activity potentials. Furthermore, these compounds were scrutinized through the activity atlas model, molecular docking, electrostatic complementarity, molecular dynamics, and waterswap analysis. The final hits might act as selective CYP1B1 inhibitors which could address the issue of resistance. This 3D-QSAR includes several chemically diverse selective CYP1B1 receptor ligands and well accounts for the individual ligand's inhibition affinities. These features of the developed 3D-QSAR model will ensure future prospective applications of the model to speed up the identification of new potent and selective CYP1B1 receptor ligands. [ABSTRACT FROM AUTHOR]

Lactate dehydrogenase (LDH) is a crucial enzyme involved in energy metabolism and present in various cells throughout the body. Its diverse physiological functions encompass glycolysis, and its abnormal activity is associated with numerous diseases. Targeting LDH has emerged as a vital approach in drug discovery, leading to the identification of LDH inhibitors among natural compounds, such as polyphenols, alkaloids, and terpenoids. These compounds demonstrate therapeutic potential against LDH-related diseases, including anti-cancer effects. However, challenges concerning limited bioavailability, poor solubility, and potential toxicity must be addressed. Combining natural compounds with LDH inhibitors has led to promising outcomes in preclinical studies. This review highlights the promise of natural compounds as LDH inhibitors for treating cancer, cardiovascular, and neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Inhibitory crosstalk between estrogen receptor alpha (ERα) and aryl hydrocarbon receptor (AHR) regulates 17β-estradiol (E2)-dependent breast cancer cell signaling. ERα and AHR are transcription factors activated by E2 and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), respectively. Dietary ligands resveratrol (RES) and 3,3′diindolylmethane (DIM) also activate ERα while only DIM activates AHR and RES represses it. DIM and RES are reported to have anti-cancer and anti-inflammatory properties. Studies with genome-wide targets and AHR- and ERα-regulated genes after DIM and RES are unknown. We used chromatin immunoprecipitation with high-throughput sequencing and transcriptomics to study ERα as well as AHR coregulation in MCF-7 human breast cancer cells treated with DIM, RES, E2, or TCDD alone or E2+TCDD for 1 and 6 h, respectively. ERα bound sites after being DIM enriched for the AHR motif but not after E2 or RES while AHR bound sites after being DIM and E2+TCDD enriched for the ERE motif but not after TCDD. More than 90% of the differentially expressed genes closest to an AHR binding site after DIM or E2+TCDD also had an ERα site, and 60% of the coregulated genes between DIM and E2+TCDD were common. Collectively, our data show that RES and DIM differentially regulate multiple transcriptomic targets via ERα and ERα/AHR coactivity, respectively, which need to be considered to properly interpret their cellular and biological responses. These novel data also suggest that, when both receptors are activated, ERα dominates with preferential recruitment of AHR to ERα target genes. [ABSTRACT FROM AUTHOR]

Photodynamic therapy facilitates the selective destruction of cancer tissue by utilizing a photosensitizer drug, the light near the absorbance wavelength of the drug, and oxygen. Methylene Blue, 5-aminolevulinic acid (the precursor of the photosensitizer, protoporphyrin IX), porphyrin, Foscan, Chlorin e6, and HPPH have been used successfully as photosensitizers in the treatment of oral verrucous hyperplasia, oral leukoplakia, oral lichen planus, and head and neck squamous cell carcinoma. "Theranostic" liposomes can deliver a contrast agent for magnetic resonance imaging and a photosensitizer for the image-guided photodynamic therapy of head and neck cancer. Liposomes incorporating photosensitizers can be targeted to cell surface markers overexpressed on cancer cells. Novel porphyrinoids have been developed in our laboratories that are highly effective as photosensitizers. Tribenzoporphyrazines encapsulated in cationic liposomes have produced IC50 values up to 50 times lower compared to the free photosensitizers. It is anticipated that targeting these drugs to cancer stem cells, using upconversion nanoparticles for the near-infrared irradiation of tumors to activate the photosensitizers, and overcoming tumor hypoxia will enhance the efficacy of photodynamic therapy of tumors accessible to light sources. [ABSTRACT FROM AUTHOR]

Combretastatin A4 phosphate (CA4P) is a potent vascular disrupting agent with good water solubility. However, it is only effective at high doses, which decreases clinical applicability. Herein, we designed stable CA4P polymeric nanoparticles (CA4P NPs) consisting of various cholesterol derivatives, and with a drug loading efficacy of 93%. The nanoparticles released CA4P in a sustained manner and achieved a 72% inhibition rate in the murine H22 liver tumor model, which was about 2.9-fold higher than that of free CA4P (24.6%). Furthermore, the carrier components of CA4P NPs were metabolized to arginine, cholesterol, ethanol and poly(ethylene glycol) in vivo; therefore, the CA4P NPs are safe and have significant potential for clinical translation. [ABSTRACT FROM AUTHOR]

Cytochromes CYP1A1, CYP1A2, and CYP1B1, the members of the cytochrome P450 family 1, catalyze the metabolism of endogenous compounds, drugs, and non-drug xenobiotics which include substances involved in the process of carcinogenesis, cancer chemoprevention, and therapy. In the present study, the interactions of three selected polymethoxy-trans-stilbenes, analogs of a bioactive polyphenol trans-resveratrol (3,5,4′-trihydroxy-trans-stilbene) with the binding sites of CYP1 isozymes were investigated with molecular dynamics (MD) simulations. The most pronounced structural changes in the CYP1 binding sites were observed in two substrate recognition sites (SRS): SRS2 (helix F) and SRS3 (helix G). MD simulations show that the number and position of water molecules occurring in CYP1 APO and in the structures complexed with ligands are diverse. The presence of water in binding sites results in the formation of water–protein, water–ligand, and bridging ligand–water–protein hydrogen bonds. Analysis of the solvent and substrate channels opening during the MD simulation showed significant differences between cytochromes in relation to the solvent channel and the substrate channels 2c, 2ac, and 2f. The results of this investigation lead to a deeper understanding of the molecular processes that occur in the CYP1 binding sites and may be useful for further molecular studies of CYP1 functions. [ABSTRACT FROM AUTHOR]

By reactions of di(4-halophenyl)maleindinitriles with magnesium and zinc(II) acetates in boiling ethylene glycol, Mg(II)-octa-(4-chlorophenyl)tetraazaporphyrin, Mg(II)-octa-(4-fluorophenyl)-tetraazaporphyrin, Zn(II)-octa-(4-chlorophenyl)tetraazaporphyrin, and Zn(II)-octa-(4-fluorophenyl)tetraazaporphyrins were synthesized. The cyclomerization of diphenylmaleinitrile with zinc acetate in ethylene glycol resulted in Zn(II)-Octaphenyltetraazaporphyrin. The corresponding Cu(II) and Mn(III)-octaphenyltetraazaporphyrins were synthesized in dimethylformamide using the metal exchange reaction of halogen-substituted magnesium complexes with copper(II) and manganese(II) chlorides. The obtained compounds were identified by electron absorption, IR, and 1H NMR spectroscopy, and mass spectrometry. The photochemical stability of the synthesized complexes was studied. [ABSTRACT FROM AUTHOR]

Resveratrol, a stilbene molecule belonging to the polyphenol family, is usually extracted from a great many natural plants. The technologies of preparation and extraction methods are developing rapidly. As resveratrol has many beneficial properties, it has been widely utilized in food and medicine industry. In terms of its structure, it is susceptible to degradation and can undergo chemical changes during food processing. Different studies have therefore given more attention to various aspects of resveratrol, including anti-aging, anti-oxidant, and anti-cancer activity. This review classifies the study of resveratrol, considers plant sources, synthesis, stability, common reactions, and food applications, and provides references to boost its food and medical utilization. © 2019 Society of Chemical Industry., (© 2019 Society of Chemical Industry.)

In recent years, fluorescent compounds that emit efficiently in the solid state have become particularly interesting, especially those that are easily prepared and inexpensive. Hence, exploring the photophysical properties of stilbene derivatives, supported by a detailed analysis of molecular packing obtained from single-crystal X-ray diffraction data, is a relevant area of research. A complete understanding of the interactions to determine the molecular packing in the crystal lattice and their effect on the material's physicochemical properties is essential to tune various properties effectively. In the present study, we examined a series of methoxy-trans-stilbene analogs with substitution pattern-dependent fluorescence lifetimes between 0.82 and 3.46 ns and a moderate-to-high fluorescence quantum yield of 0.07–0.69. The relationships between the solid-state fluorescence properties and the structure of studied compounds based on X-ray analysis were investigated. As a result, the QSPR model was developed using PLSR (Partial Least Squares Regression). Decomposition of the Hirshfeld surfaces (calculated based on the arrangement of molecules in the crystal lattice) revealed the various types of weak intermolecular interactions that occurred in the crystal lattice. The obtained data, in combination with global reactivity descriptors calculated using HOMO and LUMO energy values, were used as explanatory variables. The developed model was characterized by good validation metrics (RMSECAL = 0.017, RMSECV = 0.029, R2CAL = 0.989, and R2CV = 0.968) and indicated that the solid-state fluorescence quantum yield of methoxy-trans-stilbene derivatives was mainly dependent on weak intermolecular C...C contacts corresponding to π-π stacking and C...O/O...C interactions. To a lesser extent and inversely proportional, the fluorescence quantum yield was affected by the interactions of the type O...H/H...O and H...H and the electrophilicity of the molecule. [ABSTRACT FROM AUTHOR]

Introduction and aim. Photodynamic therapy with hypericin (HYP-PDT) is gaining importance as a potential treatment method for malignant neoplasms. The following study investigated whether HYP-PDT influences the secretion of certain factors of colon cancer cells in vitro. Material and methods. Two colon cancer cell lines were used in this experiment: SW480 and SW620. The cells were properly prepared and then treated with photodynamic therapy with hypericin at concentrations of 0.25 µM and 0.5 µM and irradiation at the doses of 1 J/cm², 5 J/cm² and 10 J/cm². After using HYP-PDT, changes in the concentrations of four factors: GM-CSF, MIF, VCAM-1 and ICAM-1 were analyzed in the test tubes. Results. In the case of SW480 cells: a notable decrease in GM-CSF, MIF, VCAM-1 and ICAM-1 secretion was noted after HYP-PDT. In the case of SW620 cells, after HYP-PDT: no effect on GM-CSF secretion was noted; it inhibited the secretion of VCAM-1 and MIF and increased the secretion of ICAM-1. Conclusion. Photodynamic therapy with hypericin shows immunomodulatory potential in an in vitro cell line experiments. This may indicate its possible ability to modify the course of malignant tumors and therefore requires further research. [ABSTRACT FROM AUTHOR]

The structural symmetry or asymmetry of organic compounds is one of the most fundamental characteristics. Z-geometrical isomers are promiscuous and kinetically preferred structures with a plethora of biological activities. A new series of hybrid molecules containing Schiff base and 3,4,5-trimethoxybenzamide moieties were synthesized from the starting material ethyl acrylate ester derivative (Z)-1 and structurally confirmed by elemental microanalysis, 1H-NMR, and 13C-NMR spectroscopic studies. The in vitro cytotoxic activity of the target hybrids was tested against the MCF-7 breast cancer line compared with colchicine as the reference compound. Most of the newly synthesized hybrids showed good growth inhibition activity against the MCF-7 cells compared to the reference substance. The results of the β-tubulin polymerization inhibition activity assay showed that the p-vanillin Schiff base 4g displayed good inhibition activity. In addition, p-vanillin Schiff base 4g exhibited antiproliferative activity over the MCF-7 cells by cellular cycle blockade at the G2/M phase and it is a potent apoptotic agent. qRT-PCR analysis showed that Schiff base 4g boosted the mRNA expression of the p53 and Bax levels while lowering the expression of the Bcl-2 level. [ABSTRACT FROM AUTHOR]