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Saporito R.A.,John Carroll University | Norton R.A.,New York University | Garraffo M.H.,Clinical Mass Spectrometry Core | Spande T.F.,Laboratory of Medicinal Chemistry
Experimental and Applied Acarology | Year: 2015

The opisthonotal (oil) glands of oribatid mites are the source of a wide diversity of taxon-specific defensive chemicals, and are likely the location for the more than 90 alkaloids recently identified in oribatids. Although originally recognized in temperate oribatid species, alkaloids have also been detected in related lineages of tropical oribatids. Many of these alkaloids are also present in a worldwide radiation of poison frogs, which are known to sequester these defensive chemicals from dietary arthropods, including oribatid mites. To date, most alkaloid records involve members of the superfamily Oripodoidea (Brachypylina), although few species have been examined and sampling of other taxonomic groups has been highly limited. Herein, we examined adults of more than 60 species of Nearctic oribatid mites, representing 46 genera and 33 families, for the presence of alkaloids. GC–MS analyses of whole body extracts led to the detection of 15 alkaloids, but collectively they occur only in members of the genera Scheloribates (Scheloribatidae) and Protokalumma (Parakalummidae). Most of these alkaloids have also been detected previously in the skin of poison frogs. All examined members of the oripodoid families Haplozetidae and Oribatulidae were alkaloid-free, and no mites outside the Oripodoidea contained alkaloids. Including previous studies, all sampled species of the cosmopolitan oripodoid families Scheloribatidae and Parakalummidae, and the related, mostly tropical families Mochlozetidae and Drymobatidae contain alkaloids. Our findings are consistent with a generalization that alkaloid presence is widespread, but not universal in Oripodoidea. Alkaloid presence in tropical, but not temperate members of some non-oripodoid taxa (in particular Galumnidae) deserves further study. © 2015 Springer International Publishing Switzerland Source


Donia M.,University of Catania | Maksimovic-Ivanic D.,University of Belgrade | Mijatovic S.,University of Belgrade | Mojic M.,University of Belgrade | And 8 more authors.
Cell Cycle | Year: 2011

The No-derivative of the HIV protease inhibitor saquinavir (Saq-No) is a nontoxic variant of the parental drug with enhanced anticancer activity on several cell lines. However, it is still unclear whether the p53 status of the target cell might influence the sensitivity to Saq-NO. In this study we evaluated the in vitro and in vivo activity of Saq-NO on the p53-deficient hormone resistant prostate cancer PC-3 cells. We demonstrate that the absence of functional p53 is not essential for the capacity of Saq-NO to reduce prostate cancer cell growth. In contrast to its previously described cytostatic action in B16 and C6 cell lines, Saq-NO exerted cytotoxic effects in PC-3 cells leading to dominant induction of apoptosis and enhanced production of proapoptotic Bim. In addition, differently from saquinavir, Saq-NO restored TRAIL sensitivity that was correlated with increased expression of DR5 independent from ROS/RNS production and YY1 repression. NFκB activation may be responsible of the Saq-NO induced DR5 expression. Moreover, Saq-NO but not saquinavir, exerted synergistic activity with conventional cytostatic therapy. In agreement with these in vitro studies, Saq-NO inhibited the in vivo growth of PC-3 cells xenotransplants to a greater extent than the parental compound. Taken together, these data indicate that Saq-NO possesses powerful and suitable in vitro and in vivo chemotherapeutic potential to be further studied as a novel drug for the treatment of prostate cancer in the clinical setting. © 2011 Landes Bioscience. Source


Castellano S.,University of Salerno | Spannhoff A.,University of Texas M. D. Anderson Cancer Center | Milite C.,University of Salerno | Dal Piaz F.,University of Salerno | And 13 more authors.
Journal of Medicinal Chemistry | Year: 2012

Arginine methylation is a common post-translational modification that is crucial in modulating gene expression at multiple critical levels. The arginine methyltransferases (PRMTs) are envisaged as promising druggable targets, but their role in physiological and pathological pathways is far from being clear due to the limited number of modulators reported to date. In this effort, enzyme activators can be invaluable tools useful as gain-of-function reagents to interrogate the biological roles in cells and in vivo of PRMTs. Yet the identification of such molecules is rarely pursued. Herein we describe a series of aryl ureido acetamido indole carboxylates (dubbed "uracandolates"), able to increase the methylation of histone (H3) or nonhistone (polyadenylate-binding protein 1, PABP1) substrates induced by coactivator-associated arginine methyltransferase 1 (CARM1), both in in vitro and cellular settings. To the best of our knowledge, this is the first report of compounds acting as CARM1 activators. © 2012 American Chemical Society. Source


Keemink J.,Catholic University of Leuven | Wuyts B.,Catholic University of Leuven | Nicolai J.,Catholic University of Leuven | Jonghe S.D.,Rega Institute for Medical Research | And 6 more authors.
International Journal of Pharmaceutics | Year: 2015

Abstract Compound libraries that are screened for biological activity commonly contain heterocycles. Besides potency, drug-like properties need to be evaluated to ensure in vivo efficacy of test compounds. In this context, we determined hepatic and intestinal disposition profiles for 17 heterocyclic compounds. All studied compounds showed rapid uptake in suspended rat hepatocytes, whereas metabolism was poor and the rate-limiting step in hepatic elimination. In vitro assays demonstrated a relatively low solubility and high intestinal permeability. Based on these in vitro data, heterocycles were categorized in the biopharmaceutics classification system (BCS) and the biopharmaceutics drug disposition classification system (BDDCS) to predict disposition characteristics before clinical data are available. Our findings emphasized the importance to use hepatocytes in addition to microsomes to study metabolism, since the latter lack non-microsomal enzymes and cellular context. Moreover, intracellular exposure should be considered to gain insight in the relevant fraction of the compound available at the enzymatic site. Finally, the study reveals discrepancies associated with the classification of heterocycles in BCS versus BDDCS. These probably originate from the binary character of both systems. © 2015 Elsevier B.V. Source


Mijatovic S.,University of Belgrade | Maksimovic-Ivanic D.,University of Belgrade | Timotijevic G.,University of Belgrade | Miljkovic D.,University of Belgrade | And 8 more authors.
Free Radical Biology and Medicine | Year: 2010

The new chemical entity GIT-27NO was created by the covalent linkage of a NO moiety to the anti-inflammatory isoxazoline VGX-1027. The compound has been shown to possess powerful anticancer effects both in vitro and in vivo. However, its effects on nonsolid and metastatic forms of tumors have not yet been investigated. We have studied the effects of GIT-27NO on the highly invasive mouse mammary TA3Ha cell line in vitro and in vivo. In contrast to the conventional exogenous NO donor sodium nitroprusside, GIT-27NO successfully enhanced intracellular NO concentration in TA3Ha cells. Intracellular accumulation of NO was followed by marked decrease in TA3Ha cell viability accompanied by typical apoptotic features. Interestingly, inverted membrane phosphatidylserine residues, reduced volume of nucleus, condensed chromatin, and terminal fragmentation of DNA were associated with inhibited caspase-3 activity and transcription of the genes encoding caspase-3, -8, and -9. In parallel, GIT-27NO rapidly but transiently prevented the loss of p53 through phosphorylation on Ser 20 and provided the necessary signals for the execution of downstream processes without p53 de novo synthesis. The caspase-independent apoptotic-like death process triggered by GIT-27NO could be mediated by markedly down-regulated expression of the antiapoptotic Bcl-2 molecule observed in TA3Ha cells exposed to GIT-27NO. In agreement with these in vitro data, GIT-27NO efficiently suppressed the growth of the ascites form and associated lethality of tumor induced by TA3Ha cells in mice. © 2010 Elsevier Inc. Source

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