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In the wake of health disasters associated with the chronic use of cyclooxygenase-2 (COX-2) inhibitor drugs, it has been widely proposed that modulation of downstream prostanoid synthases or receptors might provide more specificity than simply shutting down the entire COX cascade for anti-inflammatory benefits. The pathogenic actions of COX-2 have long been thought attributable to the prostaglandin E2 (PGE(2)) signaling through its Gα(s)-coupled EP2 receptor subtype; however, the truly selective EP2 antagonists did not emerge until 2011. These small molecules provide game-changing tools to better understand the EP2 receptor in inflammation-associated conditions. Their applications in preclinical models also reshape our knowledge of PGE(2)/EP2 signaling as a node of inflammation in health and disease. As we celebrate the 10-year anniversary of this breakthrough, the exploration of their potential as drug candidates for next-generation anti-inflammatory therapies has just begun. The first decade of EP2 antagonists passes, while their future looks brighter than ever.

Objective Prenatal metabolomics profiles, providing measures of in utero nutritional and environmental exposures, may improve the prediction of childhood outcomes. We aimed to identify prenatal plasma metabolites associated with early childhood body mass index (BMI) trajectories and overweight/obesity risk in offspring. Methods This study included 450 African American mother-child pairs from the Conditions Affecting Neurocognitive Development and Learning in Early Childhood Study. An untargeted metabolomics analysis was performed on the mothers' plasma samples collected during the second trimester. The children's BMI-z-score trajectories from birth to age 4 [rising-high- (9.8%), moderate- (68.2%), and low-BMI (22.0%)] and overweight/obesity status at age 4 were the main outcomes. The least absolute shrinkage and selection operator (LASSO) was used to select the prenatal metabolites associated with childhood outcomes. Results The mothers were 24.5 years old on average at recruitment, 76.4% having education less than 12 years and 80.0% with Medicaid or Medicare. In LASSO, seven and five prenatal metabolites were associated with the BMI-z-score trajectories and overweight/obese at age 4, respectively. These metabolites are mainly from/relevant to the pathways of steroid biosynthesis, amino acid metabolism, vitamin B complex, and xenobiotics metabolism (e.g., caffeine and nicotine). The odds ratios (95% CI) associated with a one SD increase in the prenatal metabolite risk scores (MRSs) constructed from the LASSO-selected metabolites were 2.97 (1.95-4.54) and 2.03 (1.54-2.67) for children being in the rising-high-BMI trajectory group and overweight/obesity at age 4, respectively. The MRSs significantly improved the risk prediction for childhood outcomes beyond traditional prenatal risk factors. The increase (95% CI) in the area under the receiver operating characteristic curves were 0.10 (0.03-0.18) and 0.07 (0.02-0.12) for the rising-high-BMI trajectory (P = 0.005) and overweight/obesity at age 4 (P = 0.007), respectively. Conclusions Prenatal metabolomics profiles advanced prediction of early childhood growth trajectories and obesity risk in offspring.

Primary effusion lymphoma (PEL) is an aggressive malignancy with poor prognosis even under chemotherapy. Kaposi sarcoma–associated herpesvirus (KSHV), one of the human oncogenic viruses, is the principal causative agent. Currently, there is no specific treatment for PEL; therefore, developing new therapies is of great importance. Sphingolipid metabolism plays an important role in determining the fate of tumor cells. Our previous studies have demonstrated that there is a correlation between sphingolipid metabolism and KSHV+ tumor cell survival. To further develop sphingolipid metabolism-targeted therapy, after screening a series of newly synthesized ceramide analogs, here, we have identified compounds with effective anti-PEL activity. These compounds induce significant PEL apoptosis, cell-cycle arrest, and intracellular ceramide production through regulation of ceramide synthesizing or ceramide metabolizing enzymes and dramatically suppress tumor progression without visible toxicity in vivo. These new compounds also increase viral lytic gene expression in PEL cells. Our comparative transcriptomic analysis revealed their mechanisms of action for inducing PEL cell death and identified a subset of novel cellular genes, including AURKA and CDCA3, controlled by sphingolipid metabolism, and required for PEL survival with functional validation. These data provide the framework for the development of promising sphingolipid-based therapies against this virus-associated malignancy.

We aimed to validate two metabolites, aspartic acid and glutamic acid, which were associated with sarcopenia-related traits, muscle mass and strength, in our previous untargeted metabolomics study and to identify novel metabolites from five metabolic pathways involving these two metabolites. We included a discovery cohort of 136 white women aged 20-40 years (used for the previous untargeted metabolomics analysis) and a validation cohort of 174 subjects aged ≥ 60 years, including men and women of white and black. A targeted LC-MS assay successfully detected 12 important metabolites from these pathways. Aspartic acid was associated with muscle mass and strength in the discovery cohort, but not in the validation cohort. However, glutamic acid was associated with these sarcopenia traits in both cohorts. Additionally, N-acetyl-L-aspartic acid and carnosine were the newly identified metabolites that were associated with muscle strength in the discovery and validation cohorts, respectively. We did not observe any significant sex and race differences in the associations of these metabolites with sarcopenia traits in the validation cohort. Our findings indicated that glutamic acid might be consistently associated with sarcopenia-related traits across age, sex, and race. They also suggested that age-specific metabolites and metabolic pathways might be involved in muscle regulation.

Background Many studies have found that ruthenium complexes possess unique biochemical characteristics and inhibit tumor growth or metastasis. Results Here, we report the novel dual-targeting ruthenium candidate 2b, which has both antitumor and antimetastatic properties and targets tumor sites through the enhanced permeability and retention (EPR) effect and transferrin/transferrin receptor (TF/TFR) interaction. The candidate 2b is composed of ruthenium-complexed carboline acid and four chloride ions. In vitro, 2b triggered DNA cleavage and thus blocked cell cycle progression and induced apoptosis via the PARP/ATM pathway. In vivo,2b inhibited not only Lewis lung cancer (LLC) tumor growth but also lung metastasis. We detected apoptosis and decreased CD31 expression in tumor tissues, and ruthenium accumulated in the primary tumor tissue of C57BL/6 mice implanted with LLC cells. Conclusions Thus, we conclude that 2b targets tumors, inhibits tumor growth and prevents lung metastasis.

AIM: To evaluate the anti-cancer and anti-tumor activities of ceramide analog 315 in nude mice. METHODS: Nude mice (n=10) were injected bilaterally with 5×10(6) MDA-MB-231 cells on each side. Tumors were allowed to form for two weeks. The mice were then divided into two groups (n=5 in each group). The control group mice were injected with 25 μL of DMSO (dimethyl sulfoxde) and the treatment group mice were injected with 10 mg/kg of analog 315 (in DMSO, 25 μL volume) every day for a period of 3 weeks. Animal weights and tumors were measured every week for 3 weeks. RESULTS: At the end of the experimental period, control animals had retained excess fluid, and showed larger tumor sizes compared to the treated group (2.95 g vs. 1.67 g). A 45% reduction in tumor size and 80% decrease in tumor volume were observed in the treatment group. There was a significant increase in the weights of liver (10%) and spleen (19%) between the control and treated animals. Hematoxylin and Eosin (H&E) staining of MDA-MB-231 tumor sections revealed more acellular necrotic regions in tumors from the treatment groups compared to the ones from the control group. Ki67, a proliferation marker was higher in number in control tumor section (71.8 ±12.8) compared to the treatment tumor section (37.4±10.4), (P

PURPOSE: Selective estrogen receptor degrader (SERD) has proven clinically effective in treating advanced or metastatic breast cancer since the approval of fulvestrant by FDA in 2002. Recent expansion of indications as a first line monotherapy and as combination therapy with CDK4/6 inhibitors further extends its clinical utility as an efficacious breast cancer endocrine regimen. However, the poor pharmacokinetic properties of fulvestrant and its injection-only administration route has driven continued efforts to develop orally bioavailability SERD that could potentially improve clinical response to SERD treatment. GLL398, a boron-modified GW5638 analog, showed superior oral bioavailability while retaining both antiestrogenic activity and ER degrading efficacy at a potency level comparable to the more active metabolite of GW5638, GW7604. METHOD: Here we used molecular modeling, ER (Y537S) binding assay, MCF-7 Xenograft tumor and patient derived xenograft (PDX) tumor model to conduct further studies on the pharmacology and metabolism of GLL398. RESULTS: Consistent with GLL398’s robust activities in breast cancer cells that are either tamoxifen resistant or express constitutively active, mutant ESR1 (Y537S), it was found to bind the mutant ER(Y537S) at a high affinity. Molecular modeling of the binding mode of GLL398 to ER also found its molecular interactions consistent with the experimentally determined high binding affinity towards WT ER and ER(Y537S). To test the in vivo efficacy of GLL398, mice bearing MCF-7 derived xenograft breast tumors and patient derived xenograft tumors harboring ER(Y537S) were treated with GLL398 which potently inhibited tumor growth in mice. CONCLUSIONS: This study demonstrates GLL398 is an oral SERD that has therapeutic efficacy in clinically relevant breast tumor models.

Cytochrome P450 enzymes (CYPs) are important phase I enzymes involved in the metabolism of endogenous and xenobiotic compounds mainly through mono-oxygenation reactions into more polar and easier to excrete species. In addition to their role in detoxification, they play important roles in the biosynthesis of endogenous compounds and the bioactivation of xenobiotics. Coumarins, phytochemicals abundant in food and commonly used in fragrances and cosmetics, have been shown to interact with P450 enzymes as substrates and/or inhibitors. In this review, these interactions and their significance in pharmacology and toxicology are discussed in detail.

Mycobacterium tuberculosis lipid metabolism pathways facilitate access to carbon and energy sources during infection. M. tuberculosis gene Rv1075c was annotated as a conserved hypothetical protein. We identified that Rv1075c amino acid sequence shares similarities with other bacterial lipase/esterases and we demonstrated that it has esterase activity, with preference for short-chain fatty acids, particularly acetate, with highest activity at 45°C, pH 9. Site-direct mutagenesis revealed its activity triad as Ser80, Asp244, and His247. We further determined that rRv1075c hydrolyzed triacetin and tributyrin, and it was mainly distributed in cell wall and membrane. Its expression was induced at pH 4.5, mimicking the acidic phagosome of macrophages. Mutation of Rv1075c led to reduced bacterial growth in THP-1 cells and human peripheral blood mononuclear cell-derived macrophages, and attenuated M. tuberculosis infection in mice. Our data suggest that Rv1075c is involved in ester and fatty acid metabolism inside host cells.

Background: The Wnt signaling pathway involves secreted glycoproteins that bind to the Frizzled family receptors to activate intracellular signal transduction events that regulate cell proliferation, apoptosis, cell migration and many critical aspects of developmental biology. Discussion: Aberrant Wnt signaling underlies a wide range of pathologies in humans including tumor initiation, tumor growth, cell senescence, cell death, differentiation and metastasis. The inhibition of Wnt signaling offers a novel approach for anticancer therapeutics. Conclusion: Focusing on recent developments, we reviewed the small-molecule inhibitors targeting various components of Wnt signaling pathways and the progress from the discovery of lead compounds to highly potent inhibitors with significant therapeutic potential.

Cytochrome P450's (CYP's) constitute a diverse group of over 500 monooxygenase hemoproteins, catalyzing transformations that involve xenobiotic metabolism, steroidogenesis and other metabolic processes. Over-production of the steroid hormone cortisol is implicated in the progression of diseases such as diabetes, heart failure and hypertension, stroke, Cushing's syndrome, obesity and renal failure, among others. The biosynthesis of cortisol involves a cascade of cholesterol metabolizing reactions regulated through three major CYP proteins: 17α–hydroxylase-C17/20-lyase (CYP17), 21-hydroxylase (CYP21), and 11β-hydroxylase (CYP11B1). Excess activities of these enzymes are linked to the progression of malignancies including prostate, breast, ovarian, and uterine cancers. A series of novel functionalized dioxane analogs have been developed and recently patented as CYP17, CYP21, and CYP11B1 inhibitors, which lead to the modulation of cortisol production as a method for treating, delaying, slowing, and inhibiting the implicated diseases. The findings disclosed in this patent have been analyzed and compared with the literature data on inhibitors of CYP17, CYP21, and CYP11B1. The compiled data provide insight into the novel functionality of the compounds described in the patent. In this regard, an objective opinion on the effectiveness and novel biochemistry of these compounds in comparison to current CYP inhibitors used in the treatment of cortisol-related diseases is presented in this paper.

1. The polycyclic hydrocarbons (PAHs), pyrene, 1-hydroxypyrene, 1-nitropyrene and 1-acetylpyrene, were found to induce Type I binding spectra with human cytochrome P450 (P450) 2A13 and were converted to various mono- and di-oxygenated products by this enzyme. 2. Pyrene was first oxidized by P450 2A13 to 1-hydroxypyrene which was further oxidized to di-oxygenated products, i.e. 1,8- and 1,6-dihydroxypyrene. Of five other human P450s examined, P450 1B1 catalyzed pyrene oxidation to 1-hydroxypyrene at a similar rate to P450 2A13 but was less efficient in forming dihydroxypyrenes. P450 2A6, a related human P450 enzyme, which did not show any spectral changes with these four PAHs, showed lower activities in oxidation of these compounds than P450 2A13. 3. 1-Nitropyrene and 1-acetylpyrene were also found to be efficiently oxidized by P450 2A13 to several oxygenated products, based on mass spectrometry analysis. 4. Molecular docking analysis supported preferred orientations of pyrene and its derivatives in the active site of P450 2A13, with lower interaction energies (U values) than observed for P450 2A6 and that several amino acid residues (including Ala-301, Asn-297 and Ala-117) play important roles in directing the orientation of these PAHs in the P450 2A13 active site. In addition, Phe-231 and Gly-329 were found to interact with pyrene to orient this compound in the active site of P450 1B1. 5. These results suggest that P450 2A13 is one of the important enzymes that oxidizes these PAH compounds and may determine how these chemicals are detoxicated and bioactivated in humans.

With the widespread use of O-alkoxyresorufin dealkylation assays since the 1990s, thousands of inhibitors of cytochrome P450 family 1 enzymes (P450s 1A1, 1A2, and 1B1) have been identified and studied. Generally, planar polycyclic molecules such as polycyclic aromatic hydrocarbons, stilbenoids, and flavonoids are considered to potentially be effective inhibitors of these enzymes, however, the details of the structure-activity relationships and selectivity of these inhibitors are still ambiguous. In this review, we thoroughly discuss the selectivity of many representative P450 family 1 inhibitors reported in the past 20 years through a meta-analysis.

Ceramide serves as a central mediator in sphingolipid metabolism and signaling pathways, regulating many fundamental cellular responses. It is referred to as a ‘tumor suppressor lipid’, since it powerfully potentiates signaling events that drive apoptosis, cell cycle arrest, and autophagic responses. In the typical cancer cell, ceramide levels and signaling are usually suppressed by overexpression of ceramide-metabolizing enzymes or downregulation of ceramide-generating enzymes. However, chemotherapeutic drugs as well as radiotherapy increase intracellular ceramide levels, while exogenously treating cancer cells with short-chain ceramides leads to anticancer effects. All evidence currently points to the fact that the upregulation of ceramide levels is a promising anticancer strategy. In this review, we exhibit many anticancer ceramide analogs as downstream receptor agonists and ceramide-metabolizing enzyme inhibitors.

Selective inhibition of P450 enzymes is the key to block the conversion of environmental procarcinogens to their carcinogenic metabolites in both animals and humans. To discover highly potent and selective inhibitors of P450s 1A1, 1A2, and 1B1, as well as to investigate active site cavities of these enzymes, 14 novel flavone derivatives were prepared as chemical probes. Fluorimetric enzyme inhibition assays were used to determine the inhibitory activities of these probes towards P450s 1A1, 1A2, 1B1, 2A6, and 2B1. A highly selective P450 1B1 inhibitor, 5-hydroxy-4′-propargyloxyflavone (5H4′FPE) was discovered. Some tested compounds also showed selectivity between P450s 1A1 and 1A2. Alpha-naphthoflavone-like and 5-hydroxyflavone derivatives preferentially inhibited P450 1A2, while beta-naphthoflavone-like flavone derivatives showed selective inhibition of P450 1A1. On the basis of structural analysis, the active site cavity models of P450 enzymes 1A1 and 1A2 were generated, demonstrating a planar long strip cavity and a planar triangular cavity, respectively.

Background: Members of the cytochrome P450 1A family metabolize many procarcinogens such as polycyclicaromatic hydrocarbons and heterocyclic amines. Inactivation of these enzymes is a prerequisite for cancer prevention and treatment in certain cases. Mechanism-based inhibition (time and co-factor dependent) is an effective method for the inactivation of these enzymes. Our recent study on emodin analogs revealed an anthraquinone with ortho-methylarylamine moiety that exhibited timedependent inhibition of P450 enzymes 1A1 and 1A2. Methods: To determine whether the amino group or the methyl group or both were responsible for the time-dependent inhibition of these enzymes, a set of eleven compounds containing the orthomethylarylamine moiety were identified through a database search, and studied for the inhibition of the P450 enzymes 1A1, 1A2, 2A6 and 2B1. Our earlier studies on carbazole derivatives provided us with highly selective P450 1A2 inhibitors. Glycine scanning studies were performed on the docked proteinligand complexes of compounds 1-20 in order to understand the contribution of different protein residues towards the ligand binding. Results: Four compounds were found to cause selective time-dependent inhibition of P450 1A1 with KI values ranging from 0.24 to 8.25 mM. These compounds exhibited only direct inhibition of P450 1A2. Molecular modeling studies of these molecules indicated that the shapes of the molecules, their binding modes, and the methyl substituent in close proximity (4.5-5.7 A) to the heme-Fe all contributed to their selective time-dependent inhibition activity on P450 1A1. Glycine scanning studies for P450 1A1 indicated that ligand interaction with Phe123 was the strongest binding contributor and similar studies for P450 1A2 indicated that ligand interactions with the phenylalanine residues 226 and 260 were the largest binding contributors. Conclusion: Four compounds have been identified that exhibit selective time-dependent inhibition of P450 1A1. Modeling studies have indicated that the proximity of the aromatic methyl group to the heme-Fe could be the main contributor for time-dependent inhibition. Future studies will focus on the confirmation of the involvement of the aromatic methyl group in enzyme inactivation.

The cytochrome P450 (CYP) superfamily of heme enzymes play an important role in the metabolism of a large number of endogenous and exogenous compounds, including most of the drugs currently on the market. Inhibitors of CYP enzymes have important roles in the treatment of several disease conditions such as numerous cancers and fungal infections in addition to their critical role in drug-drug interactions. Structure activity relationships (SAR), and three-dimensional quantitative structure activity relationships (3D-QSAR) represent important tools in understanding the interactions of the inhibitors with the active sites of the CYP enzymes. A comprehensive account of the QSAR studies on the major human CYPs 1A1, 1A2, 1B1, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1, 3A4 and a few other CYPs are detailed in this review which will provide us with an insight into the individual/common characteristics of the active sites of these enzymes and the enzyme-inhibitor interactions.

To discover new selective mechanism-based P450 inhibitors, eight 7-ethynylcoumarin derivatives were prepared through a facile two-step synthetic route. Cytochrome P450 activity assays indicated that introduction of functional groups in the backbone of coumarin could enhance the inhibition activities toward P450s 1A1 and 1A2, providing good selectivity against P450s 2A6 and 2B1. The most potent product 7-ethynyl-3,4,8-trimethylcoumarin (7ETMC) showed IC(50) values of 0.46 μM and 0.50 μM for P450s 1A1 and 1A2 in the first six minutes, respectively, and did not show any inhibition activity for P450s 2A6 and 2B1 even at the dose of 50 μM. All of the inhibitors except 7-ethynyl-3-methyl-4-phenylcoumarin (7E3M4PC) showed mechanism-based inhibition of P450s 1A1 and 1A2. In order to explain this mechanistic difference in inhibitory activities, X-ray crystallography data were used to study the difference in conformation between 7E3M4PC and the other compounds studied. Docking simulations indicated that the binding orientations and affinities resulted in different behaviors of the inhibitors on P450 1A2. Specifically, 7E3M4PC with its two-plane structure fits into the P450 1A2's active site cavity with an orientation leading to no reactive binding, causing it to act as a competitive inhibitor.

In silico docking studies and quantitative structure-activity relationship analysis of a number of in-house cytochrome P450 inhibitors have revealed important structural characteristics that are required for a molecule to function as a good inhibitor of P450 enzymes 1A1, 1A2, 2B1, and/or 2A6. These insights were incorporated into the design of pharmacophores used for a 2D search of the Chinese medicine database. Emodin, a natural anthraquinone isolated from Rheum emodi and known to be metabolized by cytochrome P450 enzymes, was one of the hits and was used as the lead compound. Emodin was found to inhibit P450s 1A1, 1A2, and 2B1 with IC(50) values of 12.25, 3.73, and 14.89 μM, respectively. On the basis of the emodin molecular structure, further similarity searches of the PubChem and ZINC chemical databases were conducted resulting in the identification of 12 emodin analogues for testing against P450s 1A1-, 1A2-, 2B1-, and 2A6-dependent activities. 1-Amino-4-chloro-2-methylanthracene-9,10-dione (compound 1) showed the best inhibition potency for P450 1A1 with an IC(50) value of 0.40 μM. 1-Amino-4-chloro-2-methylanthracene-9,10-dione (compound 1) and 1-amino-4-hydroxyanthracene-9,10-dione (compound 2) both inhibited P450 1A2 with the same IC(50) value of 0.53 μM. In addition, compound 1 acted as a mechanism-based inhibitor of cytochrome P450s 1A1 and 1A2 with K(I) and K(inactivation) values of 5.38 μM and 1.57 min(-1) for P450 1A1 and 0.50 μM and 0.08 min(-1) for P450 1A2. 2,6-Di-tert-butyl-5-hydroxynaphthalene-1,4-dione (compound 8) directly inhibited P450 2B1 with good selectivity and inhibition potency (IC(50) = 5.66 μM). Docking studies using the 3D structures of the enzymes were carried out on all of the compounds. The binding modes of these compounds revealed the structural characteristics responsible for their potency and selectivity. Compound 1, which is structurally similar to compound 2 with the presence of an amino group at position 1, showed a difference in the mechanism of inhibition toward P450s 1A1 and 1A2. The mechanism-based inhibition seen for compound 1 may be attributed to the presence of the methyl group at the 2-position, in close proximity to the amino group. Compound 2, which is otherwise similar, lacks that methyl moiety and did not show mechanism-based inhibition.

Resistance to endocrine and chemotherapies remains the primary cause of breast cancer treatment failure. We have synthesized four novel D: -erythro N-octanoyl sphingosine analogs and catalogued their activity in drug-sensitive (MCF-7), endocrine-resistant (MDA-MB-231) and chemoresistant (MCF-7TN-R) breast cancer cells.3-(4,5-Dimethylthiazol-2-Yl)-2,5-diphenyltetrazolium bromide (MTT) assay was used to determine cell viability; colony assay was performed to determine effects on clonogenic survival and (1)H NMR, (13)C NMR, HPLC spectra and elemental analytical data analyses were used to determine analog identity and purity.All four analogs inhibited both viability and clonogenic survival, with analog C exhibiting a log-fold improvement in anti-survival activity compared to the parent compound.With resistance to current breast cancer chemotherapies on the rise, the development of novel therapeutic targets is of growing importance. Our results show that lipid analogs have therapeutic potential in treating chemo- and endocrine-resistant breast cancer.

Resistance to chemotherapy and endocrine therapy is a major cause of breast cancer treatment failure. We have synthesized six novel analogues using C8-ceramide as the lead analogue and studied their effect on hormone therapy resistant (MDA-MB-231) and chemoresistant (MCF-7TN-R) breast cancer cells. Pharmacologic intervention using these ceramide analogues inhibited clonogenic survival and induced apoptosis, with one analogue being more effective than C8-ceramide. Our results show ceramide-based therapy has therapeutic potential in treating drug resistant breast cancer.

In humans, cytochrome P450 1A2 is the major enzyme metabolizing environmental arylamines or heterocyclic amines into carcinogens. Since evidence shows that planar triangle-shaped molecules are capable of selectively inhibiting P450 1A2, 16 triangular flavone, and coumarin derivatives were designed and synthesized for these studies. Among these compounds, 7,8-furanoflavone time-dependently inhibits P450 1A2 with a K(I) value of 0.44 μM. With a 5 min preincubation in the presence of NADPH, 0.01 μM 7,8-furanoflavone completely inactivates P450 1A2 but does not influence the activities of P450s 1A1 and 1B1. Another target compound, 7,8-pyrano-4-trifluoromethylcoumarin, is found to be a competitive inhibitor, showing high selectivity for the inhibition of P450 1A2 with a K(i) of 0.39 μM, 155- and 52-fold lower than its K(i) values against P450s 1A1 and 1B1, respectively. In yeast AhR activation assays, 7,8-pyrano-4-trifluoromethylcoumarin does not activate aryl hydrocarbon receptor when the concentration is lower than 1 μM, suggesting that this compound would not up-regulate AhR-caused P450 enzyme expression. In-cell P450 1A2 inhibition assays show that 7,8-pyrano-4-trifluoromethylcoumarin decreases the MROD activity in HepG2 cells at concentrations higher than 1 μM. Thus, using 7,8-pyrano-4-trifluoromethylcoumarin, a selective and specific P450 1A2 action suppression could be achieved, indicating the potential for the development of P450 1A2-targeting cancer preventive agents.

The cytochrome P450 (CYP) family 1A enzymes, CYP1A1 and CYP1A2, are two of the most important enzymes implicated in the metabolism of endogenous and exogenous compounds through oxidation. These enzymes are also known to metabolize environmental procarcinogens into carcinogenic species, leading to the advent of several types of cancer. The development of selective inhibitors for these P450 enzymes, mitigating procarcinogenic oxidative effects, has been the focus of many studies in recent years. CYP1A1 is mainly found in extrahepatic tissues while CYP1A2 is the major CYP enzyme in human liver. Many molecules have been found to be metabolized by both of these enzymes, with varying rates and/or positions of oxidation. A complete understanding of the factors that govern the specificity and potency for the two CYP 1A enzymes is critical to the development of effective inhibitors. Computational molecular modeling tools have been used by several research groups to decipher the specificity and potency factors of the CYP1A1 and CYP1A2 substrates. In this review, we perform a thorough analysis of the computational studies that are ligand-based and protein-ligand complex-based to catalog the various factors that govern the specificity/potency toward these two enzymes.

Multidrug-resistance is a major cause of cancer chemotherapy failure in clinical treatment. Evidence shows that multidrug-resistant cancer cells are as sensitive as corresponding regular cancer cells under the exposure to anticancer ceramide analogs. In this work we designed five new ceramide analogs with different backbones, in order to test the hypothesis that extending the conjugated system in ceramide analogs would lead to an increase of their anticancer activity and selectivity towards resistant cancer cells. The analogs with the 3-ketone-4,6-diene backbone show the highest apoptosis-inducing efficacy. The most potent compound, analog 406, possesses higher pro-apoptotic activity in chemo-resistant cell lines MCF-7TN-R and NCI/ADR-RES than the corresponding chemo-sensitive cell lines MCF-7 and OVCAR-8, respectively. However, this compound shows the same potency in inhibiting the growth of another pair of chemo-sensitive and chemo-resistant cancer cells, MCF-7 and MCF-7/Dox. Mechanism investigations indicate that analog 406 can induce apoptosis in chemo-resistant cancer cells through the mitochondrial pathway. Cellular glucosylceramide synthase assay shows that analog 406 does not interrupt glucosylcer-amide synthase in chemo-resistant cancer cell NCI/ADR-RES. These findings suggest that due to certain intrinsic properties, ceramide analogs’ pro-apoptotic activity is not disrupted by the normal drug-resistance mechanisms, leading to their potential use for overcoming cancer multidrug-resistance.

To discover whether novel anti-tumor platinum agents are capable of selectively accumulating in tumor tissue, three novel potassium N-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxylhex-1-yl]-L-amino acid dichloroplatinates(II) were prepared. At a dose of 1.67 μmol kg(-1) the in vivo anti-tumor potencies of two of the compounds were higher than that of oxaliplatin. The mortality analysis indicated that these compounds resulted in a 100% survival rate, whereas oxaliplatin lead to an 80% survival rate. The organ damage examination indicated that these compounds induced less damage than oxaliplatin. The platinum accumulation in the organs, blood and bone was significantly lower than that of oxaliplatin treated mice, while the platinum accumulation in the tumor tissue was significantly higher than that of the oxaliplatin treated mice.

To construct prediction model for health workforce and hospital beds in county hospitals of Hunan by multiple linear regression.We surveyed 16 counties in Hunan with stratified random sampling according to uniform questionnaires,and multiple linear regression analysis with 20 quotas selected by literature view was done.Independent variables in the multiple linear regression model on medical personnels in county hospitals included the counties' urban residents' income, crude death rate, medical beds, business occupancy, professional equipment value, the number of devices valued above 10 000 yuan, fixed assets, long-term debt, medical income, medical expenses, outpatient and emergency visits, hospital visits, actual available bed days, and utilization rate of hospital beds. Independent variables in the multiple linear regression model on county hospital beds included the the population of aged 65 and above in the counties, disposable income of urban residents, medical personnel of medical institutions in county area, business occupancy, the total value of professional equipment, fixed assets, long-term debt, medical income, medical expenses, outpatient and emergency visits, hospital visits, actual available bed days, utilization rate of hospital beds, and length of hospitalization.The prediction model shows good explanatory and fitting, and may be used for short- and mid-term forecasting.

{2-[1-(3-Methoxycarbonylmethyl-1H-indol-2-yl)-1-methyl-ethyl]-1H-indol-3-yl}-acetic acid methyl ester (MIAM) was provided as a DNA-intercalator. For the comprehensive evaluation of this new intercalator, an assay system consisting of cell, S180 mouse, healthy mouse, spectrum, non-spectrum, and gel electrophoresis models was constructed. On the cell (S180, K562, MCF-7, HeLa and HepG2) models, MIAM selectively inhibited the viability of HeLa. On the S180 mouse model, 0.89, 8.9, 89 and 890 μmol kg(-1) of MIAM dose-dependently inhibited the tumor growth. Even at a dose of 890 μmol kg(-1), MIAM did not damage the treated S180 mice. The safety of MIAM was supported by a high spleen index and an obvious increase of body weight of the treated S180 mice. On the healthy mouse model the LD(50) value of MIAM is higher than 890 μmol kg(-1). The ultraviolet (UV), fluorescence, circular dichroism (CD), relative viscosity, melting curve, and gel electrophoresis assays of DNA with or without MIAM consistently supported an intercalation mechanism for MIAM.

N-(alpha-L-Arabinofuranos-1-yl)-L-cysteine was stereoselectively prepared from L-arabinose and l-cysteine. Its in vivo detoxification action was evaluated on lead loaded mice at the doses of 0.1, 0.2, and 0.4 mmol/kg. The results show that lead accumulation in the livers, kidneys, brains, and femurs of the treated mice could be efficiently decreased by N-(alpha-L-arabinofuranos-1-yl)-L-cysteine, even at the dose of 0.1 mmol/kg. Compared with the lead detoxification efficacy, 0.4 mmol/kg of N-(alpha-L-arabinofuranos-1-yl)-L-cysteine did not affect the essential metals in the treated mice, such as Fe, Cu, Zn, and Ca. In the apparent permeability coefficient test, the values of P(app)(A--B), P(app)(B--A), and P(app)(A--B)/P(app)(B--A) indicated that N-(alpha-L-arabinofuranos-1-yl)-L-cysteine was transported actively across the Caco-2 cell monolayer. Silico molecular modeling results predicted that N-(alpha-L-arabinofuranos-1-yl)-L-cysteine had no hepatotoxicity.

A computational study was undertaken to understand the nature of binding and the structural features that play a significant role in the binding of arylacetylene molecules to cytochrome P450 enzymes 1A1, 1A2, 2A6, and 2B1. Nine polycyclic arylacetylenes determined to be mechanism-based P450 enzyme inhibitors were studied. The lack of polar substituents in these compounds causes them to be incapable of hydrogen bonding to the polar protein residues. The four P450 enzymes of interest all have phenylalanine residues in the binding pocket for potential pi-pi interactions with the aromatic rings of the inhibitors. The inhibition potency of these arylacetylenes toward P450s 1A1 and 2B1 showed a dependence on the proximity of the inhibitor's triple bond to the prosthetic heme Fe of the enzyme. In P450 enzyme 1A2, the inhibitor's potency showed more dependence on the pi-pi interactions of the inhibitor's ring systems with the phenylalanine residues of the protein, with the proximity of the inhibitor triple bond to the heme Fe weighing in as the second most important factor. The results suggest that maximizing the pi-pi interactions with phenylalanine residues in the binding pocket and optimum proximity of the acetylene moiety to the heme Fe will provide for a substantial increase in the potency of the polyaromatic hydrocarbon mechanism-based inhibitors. A fine balance of these two aspects of binding coupled with attention to supplementing hydrophobic interactions could address potency and selectivity issues for these inhibitors.

A group of novel l -serinamides, substituted (S)-2-(benzylideneamino)-3-hydroxy-N-tetradecylpropanamides (3a–o) and substituted (S)-2-(benzylamino)-3-hydroxy-N-tetradecyl propanamides (4c, 4i, 4l, and 4o), were synthesized as potential anti-tumor lead compounds. In vitro cell viability assay results indicate treatment with 3a–o compounds resulted in significant inhibition of cell viability in the chemoresistant breast cancer cell line, MCF-7TN-R. Compounds 3i and 3l, both ortho-substituted analogs, show the greatest efficacy with IC50 values of 10.3 μM and 12.5 μM, respectively. The SAR analysis indicate that the imine functional group of 3a–o is critical for the cellular anti-viability effect, and the partial atomic charge (PAC) value of imine C atom is a valuable structural parameter for predicting the activity of these ceramide analogs.

Based on the structural analysis of fumitremorgin C (FTC), imidazoline and β-carboline amino acid benzylester, 14 novel 2-substitutedtetracyclic derivatives of tetrahydrocarboline 4a – n were prepared. We demonstrated that the exposure of MES-SA/Dx5 cells to some of 4a – n resulted in significant reduction of resistance of the cells against doxorubicin. This reduced resistance was accompanied by lowering of IC 50 value to doxorubicin from 1.55 ± 0.26 μmol/L to 0.33 ± 0.05 μmol/L for 2-(2-butyl)-derivative 4c , to 1.03 ± 0.22 μmol/L for 2-methyl-derivative 4d , to 0.46 ± 0.04 μmol/L for 2-benzyl-derivative 4f , to 0.98 ± 0.25 μmol/L for 2-indole-3-yl-methyl-derivative 4h , to 0.36 ± 0.03 μmol/L for 2-benzyloxycarbonylmethyl-derivative 4i , to 0.77 ± 0.08 μmol/L for 2-benzyloxycarbonylethyl-derivative 4j , and to 0.77 ± 0.08 μmol/L for 2-benzyloxycarbonylamino- n -butyl-derivative 4l . Proliferation assays of 4a – n indicated 4c , f , i , j were able to inhibit the proliferation of doxorubicin resistant MES-SA/Dx5 cells. The SAR analysis revealed that the benzylester form and the tetracyclic structure of 4a – n were critical for both sensitizing doxorubicin and the cellular anti-proliferative effect.