Autistic traits, sensory sensitivity and eating disturbances in a sample of young adults referring to a generalized mental health clinic.

PURPOSE: The relationship between autistic traits and eating disturbances has been given considerable attention over the last decades. The rise of a dimensional approach to psychopathology has expanded the way we think about autism, acknowledging that subthreshold autistic manifestations span across the general population and are more pronounced in psychiatric patients. Here we investigated the prevalence of eating disorders and its potential relationship with autistic traits and sensory sensitivity in a group of patients who were referred for the first time to a mental health outpatient clinic, without a formal diagnosis yet. METHODS: 259 young adults (between 18 and 24 years old) completed: the Eating Attitude Test (EAT-26), the Swedish Eating Assessment for Autism Spectrum Disorders (SWEAA), the Autism Quotient (AQ), the Ritvo Autism Asperger Diagnostic Scale-Revised (RAADS-R), and the Sensory Perception Quotient-Short Form 35 item (SPQ-SF35). RESULTS: 23.55% of participants scored above the cut-off at the EAT-26, suggesting that they presented a risk for eating disorders and should be assessed by a specialized clinician; associations emerged between hypersensitivity in the touch and vision domain and both the EAT-26 and the SWEAA; the presence of autistic traits was largely associated with eating disturbances. CONCLUSIONS: This study underlines the significance of the eating domain as a central psychopathological feature in the distress experienced by young adults with general psychiatric symptoms and psychological suffering; it adds evidence to the association between autistic traits and eating disorders and opens to new research questions about the role of subthreshold autistic traits in general psychopathology. LEVEL OF EVIDENCE: Level I: Evidence obtained from experimental studies.

Bifunctional carbazole derivatives for simultaneous therapy and fluorescence imaging in prion disease murine cell models.

Prion diseases are characterized by the self-assembly of pathogenic misfolded scrapie isoforms (PrPSc) of the cellular prion protein (PrPC). In an effort to achieve a theranostic profile, symmetrical bifunctional carbazole derivatives were designed as fluorescent rigid analogues of GN8, a pharmacological chaperone that stabilizes the native PrPC conformation and prevents its pathogenic conversion. A focused library was synthesized via a four-step route, and a representative member was confirmed to have native fluorescence, including a band in the near-infrared region. After a cytotoxicity study, compounds were tested on the RML-infected ScGT1 neuronal cell line, by monitoring the levels of protease-resistant PrPSc. Small dialkylamino groups at the ends of the molecule were found to be optimal in terms of therapeutic index, and the bis-(dimethylaminoacetamido)carbazole derivative 2b was selected for further characterization. It showed activity in two cell lines infected with the mouse-adapted RML strain (ScGT1 and ScN2a). Unlike GN8, 2b did not affect PrPC levels, which represents a potential advantage in terms of toxicity. Amyloid Seeding Assay (ASA) experiments showed the capacity of 2b to delay the aggregation of recombinant mouse PrP. Its ability to interfere with the amplification of the scrapie RML strain by Protein Misfolding Cyclic Amplification (PMCA) was shown to be higher than that of GN8, although 2b did not inhibit the amplification of human vCJD prion. Fluorescent staining of PrPSc aggregates by 2b was confirmed in living cells. 2b emerges as an initial hit compound for further medicinal chemistry optimization towards strain-independent anti-prion compounds.

D-Ring-Modified Analogues of Luotonin A with Reduced Planarity: Design, Synthesis, and Evaluation of Their Topoisomerase Inhibition-Associated Cytotoxicity.

A- and D-ring-modified luotonin-inspired heterocycles have been synthesized and were evaluated for their activity against the viability of four cancer cell lines in vitro, namely, MCF7, HCT116, JURKAT, and NCI-H460. The analysis of results indicated that two of the synthesized derivatives displayed good inhibition against the growth of the human colon cancer HCT116 cell line, with potencies lower than but in the same order of magnitude as camptothecin (CPT). These two luotonin analogues also showed an activity similar to that of the highly potent alkaloid CPT as inhibitors of topoisomerase I and also inhibited topoisomerase II. These results show that complete planarity is not a strict requirement for topoisomerase inhibition by luotonin-related compounds, paving the way to the design of analogues with improved solubility.

Crassiflorone derivatives that inhibit Trypanosoma brucei glyceraldehyde-3-phosphate dehydrogenase (TbGAPDH) and Trypanosoma cruzi trypanothione reductase (TcTR) and display trypanocidal activity.

Crassiflorone is a natural product with anti-mycobacterial and anti-gonorrhoeal properties, isolated from the stem bark of the African ebony tree Diospyros crassiflora. We noticed that its pentacyclic core possesses structural resemblance to the quinone-coumarin hybrid 3, which we reported to exhibit a dual-targeted inhibitory profile towards Trypanosoma brucei glyceraldehyde-3-phosphate dehydrogenase (TbGAPDH) and Trypanosoma cruzi trypanothione reductase (TcTR). Following this basic idea, we synthesized a small library of crassiflorone derivatives 15-23 and investigated their potential as anti-trypanosomatid agents. 19 is the only compound of the series showing a balanced dual profile at 10 µM (% inhibitionTbGAPDH = 64% and % inhibitionTcTR = 65%). In phenotypic assay, the most active compounds were 18 and 21, which at 5 µM inhibited Tb bloodstream-form growth by 29% and 38%, respectively. Notably, all the newly synthesized compounds at 10 µM did not affect viability and the status of mitochondria in human A549 and 786-O cell lines, respectively. However, further optimization that addresses metabolic liabilities including solubility, as well as cytochromes P450 (CYP1A2, CYP2C9, CYP2C19, and CYP2D6) inhibition, is required before this class of natural product-derived compounds can be further progressed.

Design, synthesis and antiproliferative activity of decarbonyl luotonin analogues.

A small library of benzimidazole-fused pyrrolo[3,4-b]quinoline has been synthesized from readily available benzimidazole 2-carbaldehyde and various substituted arylamines in good to excellent yields utilizing an intramolecular Povarov reaction catalyzed by boron trifluoride diethyl etharate as the key final step. The compounds thus synthesized can be considered as decarbonyl analogues of the anticancer alkaloid luotonin A and were evaluated in a DNA relaxation assay for their ability to inhibit human topoisomerase I. Interestingly, two of the compounds showed a remarkable activity that is comparable to that of the standard drug camptothecin. The compounds were also evaluated for their cytotoxic effect in four highly aggressive human cancer cell lines, namely KB, MDA-MB231 (breast), LNCap (prostate), and HT1080 (fibrosarcoma). Some of the compounds obtained showed promising cytotoxicities for these four cell lines.

Tetrahydroisoquinoline-Derived Urea and 2,5-Diketopiperazine Derivatives as Selective Antagonists of the Transient Receptor Potential Melastatin 8 (TRPM8) Channel Receptor and Antiprostate Cancer Agents.

Tetrahydroisoquinoline derivatives containing embedded urea functions were identified as selective TRPM8 channel receptor antagonists. Structure-activity relationships were investigated, with the following conclusions: (a) The urea function and the tetrahydroisoquinoline system are necessary for activity. (b) Bis(1-aryl-6,7dimethoxy-1,2,3,4-tetrahydroisoquinolyl)ureas are more active than compounds containing one tetrahydroisoquinoline ring and than an open phenetylamine ureide. (c) Trans compounds are more active than their cis isomers. (d) Aryl substituents are better than alkyls at the isoquinoline C-1 position. (e) Electron-withdrawing substituents lead to higher activities. The most potent compound is the 4-F derivative, with IC50 in the 10(-8) M range and selectivities around 1000:1 for most other TRP receptors. Selected compounds were found to be active in reducing the growth of LNCaP prostate cancer cells. TRPM8 inhibition reduces proliferation in the tumor cells tested but not in nontumor prostate cells, suggesting that the activity against prostate cancer is linked to TRPM8 inhibition.

B-ring-aryl substituted luotonin A analogues with a new binding mode to the topoisomerase 1-DNA complex show enhanced cytotoxic activity.

Topoisomerase 1 inhibition is an important strategy in targeted cancer chemotherapy. The drugs currently in use acting on this enzyme belong to the family of the camptothecins, and suffer severe limitations because of their low stability, which is associated with the hydrolysis of the δ-lactone moiety in their E ring. Luotonin A is a natural camptothecin analogue that lacks this functional group and therefore shows a much-improved stability, but at the cost of a lower activity. Therefore, the development of luotonin A analogues with an increased potency is important for progress in this area. In the present paper, a small library of luotonin A analogues modified at their A and B rings was generated by cerium(IV) ammonium nitrate-catalyzed Friedländer reactions. All analogues showed an activity similar or higher than the natural luotonin A in terms of topoisomerase 1 inhibition and some compounds had an activity comparable to that of camptothecin. Furthermore, most compounds showed a better activity than luotonin A in cell cytotoxicity assays. In order to rationalize these results, the first docking studies of luotonin-topoisomerase 1-DNA ternary complexes were undertaken. Most compounds bound in a manner similar to luotonin A and to standard topoisomerase poisons such as topotecan but, interestingly, the two most promising analogues, bearing a 3,5-dimethylphenyl substituent at ring B, docked in a different orientation. This binding mode allows the hydrophobic moiety to be shielded from the aqueous environment by being buried between the deoxyribose belonging to the G(+1) guanine and Arg364 in the scissile strand and the surface of the protein and a hydrogen bond between the D-ring carbonyl and the basic amino acid. The discovery of this new binding mode and its associated higher inhibitory potency is a significant advance in the design of new topoisomerase 1 inhibitors.

A minimal model of tumor growth inhibition.

The preclinical development of antitumor drugs greatly benefits from the availability of models capable of predicting tumor growth as a function of the drug administration schedule. For being of practical use, such models should be simple enough to be identifiable from standard experiments conducted on animals. In the present paper, a stochastic model is derived from a set of minimal assumptions formulated at cellular level. Tumor cells are divided in two groups: proliferating and nonproliferating. The probability that a proliferating cell generates a new cell is a function of the tumor weight. The probability that a proliferating cell becomes nonproliferating is a function of the plasma drug concentration. The time-to-death of a nonproliferating cell is a random variable whose distribution reflects the nondeterministic delay between drug action and cell death. The evolution of the expected value of tumor weight obeys two differential equations (an ordinary and a partial differential one), whereas the variance is negligible. Therefore, the tumor growth dynamics can be well approximated by the deterministic evolution of its expected value. The tumor growth inhibition model, which is a lumped parameter model that in the last few years has been successfully applied to several antitumor drugs, is shown to be a special case of the minimal model presented here.