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Radical surgical debridement after Fournier gangrene (FG) can totally change anatomical balance between structures and compromise urogenital function. This is particularly true when the suspensory ligament and the lower abdominal wall are involved, leading to erection and sexual intercourse dysfunction.We present the case of a 48-year-old man, who underwent emergency debridement and split-thickness skin graft (STSG) of inferior abdominal wall, pubis, scrotal bag and penile shaft after Fournier gangrene.Five months after the emergency procedure, bilateral medial thigh flaps recreated the scrotal compartment, whereas a pedicled composite anterolateral thigh flap including fascia lata could cover the lower abdominal wall and rebuilt the penile suspensory ligament (PSL).Healing was uneventful and the patient returned to a normal sexual life with satisfactory erection and intercourse.Composite and/or chimeric anterolateral thigh fascia lata flaps have been previously used as a reliable option for complex defects, including tendon and ligaments. We describe here, the first case in the literature of a penile suspensory ligament reconstruction.

Investigations into iminopyridine chromium complexes have unveiled their potential as precatalysts for the polymerization of (di)olefins (Organometallics2018, 37, 4827–4840). A Cr-to-ligand electron transfer, with the ligand (L) in the monoanionic radical state and Cr in a physical trivalent oxidation state, proved to be fundamental for facilitating ethylene polymerization by the complex with the unsubstituted aldimine (Cr-pH, where X = H). In the absence of structural data, we embarked on a detailed study by ultraviolet–visible–near-infrared (UV–vis–NIR) spectroscopy and density functional theory to elucidate the structural and electronic features driving electron transfer in Cr-pH. The Cr-to-L electron transfer is facilitated by the presence of two tetrahydrofurans in the metal’s coordination sphere in the monoligated form or by the formation of a bis-ligated species. The UV–vis–NIR spectra of Cr-pH, coupled with electrospray ionization mass spectroscopy data, indicate the coexistence of multiple species. Successively, we enlarged the library of chromium complexes by appending different substituents (i.e., CH3, OCH3, and CF3) at the p-N-aryl 4-position. While Cr-pCH3and Cr-pOCH3display electronic features analogous to those of Cr-pH, Cr-pCF3stands out as an exception, likely containing only monoligated species. Cr-pCF3emerged as the most active catalyst, producing ultra-high-molecular weight poly(ethylene) with a unimodal and narrow molecular weight distribution event at 40 °C.

ABSTRACTCurrent treatment for celiac disease (CD) is adhering to a gluten-free diet (GFD), although its long-term molecular effects are still undescribed. New molecular features detectable in stool may improve and facilitate noninvasive clinical management of CD. For this purpose, fecal small non-coding RNAs (sncRNAs) and gut microbiome profiles were concomitantly explored in CD subjects in relation to strict (or not) GFD adherence over time. In this observational study, we performed small RNA and shotgun metagenomic sequencing in stool from 63 treated CD (tCD) and 3 untreated subjects as well as 66 sex- and age-matched healthy controls. tCD included 51 individuals on strict GFD and with negative transglutaminase (TG) serology (tCD-TG-) and 12 symptomatic with not strict/short-time of GFD adherence and positive TG serology (tCD-TG+). Samples from additional 40 healthy adult individuals and a cohort of 19 untreated pediatric CD subjects and 19 sex/age matched controls were analyzed to further test the outcomes. Several miRNA and microbial profiles were altered in tCD subjects (adj. p < .05). Findings were validated in the external group of adult controls. In tCD-TG-, GFD duration correlated with five miRNA levels (p < .05): for miR-4533-3p and miR-2681-3p, the longer the diet adherence, the less the expression differed from controls. tCD-TG+ and untreated pediatric CD patients showed a similar miRNA dysregulation. Immune-response, trans-membrane transport and cell death pathways were enriched in targets of identified miRNAs. Bifidobacterium longum, Ruminococcus bicirculans, and Haemophilus parainfluenzaeabundances shifted (adj. p < .05) with a progressive reduction of denitrification pathways with GFD length. Integrative analysis highlighted 121 miRNA-bacterial relationships (adj. p < .05). Specific molecular patterns in stool characterize CD subjects, reflecting either the long-term GFD effects or the gut inflammatory status, in case of a not strict/short-time adherence. Our findings suggest novel host-microbial interplays and could help the discovery of biomarkers for GFD monitoring over time.

Le but de cette étude était d’évaluer les effets d’une expansion palatine rapide EPR par une analyse de la posture et de la démarche chez des sujets avec déficit transversal du maxillaire.

The purpose of this study was to evaluate the effects of the rapid palatal expansion (RPE) on posture and gait analysis in subjects with maxillary transverse discrepancies.

We report the discovery and characterization of two porous Ce(III)-based metal–organic frameworks (MOFs) with the V-shaped linker molecules 4,4′-sulfonyldibenzoate (SDB2–) and 4,4′-(hexafluoroisopropylidene)bis(benzoate) (hfipbb2–). The compounds of framework composition [Ce2(H2O)(SDB)3] (1) and [Ce2(hfipbb)3] (2) were obtained by using a synthetic approach in acetonitrile that we recently established. Structure determination of 1was accomplished from 3D electron diffraction (3D ED) data, while 2could be refined against powder X-ray diffraction (PXRD) data using the crystal structure of an isostructural La-MOF as the starting model. Their framework structures consist of chain-like inorganic building units (IBUs) or hybrid-BUs that are interconnected by the V-shaped linker molecules to form framework structures with channel-type pores. The composition of both compounds was confirmed by PXRD, elemental analysis, as well as NMR and IR spectroscopy. Interestingly, despite the use of (NH4)2[CeIV(NO3)6] in the synthesis, cerium ions in both MOFs occur exclusively in the + III oxidation state as determined by X-ray absorption near edge structure (XANES) and X-ray photoelectron spectroscopy (XPS). Thermal analyses reveal remarkably high thermal stabilities of ≥400 °C for the MOFs. Initial N2sorption measurements revealed the peculiar sorption behavior of 2which prompted a deeper investigation by Ar and CO2sorption experiments. The combination with nonlocal density functional theory (NL-DFT) calculations adds to the understanding of the nature of the different pore diameters in 2. An extensive quasi-simultaneous in situ XANES/XRD investigation was carried out to unveil the formation of Ce-MOFs during the solvothermal syntheses in acetonitrile. The crystallization of the two Ce(III)-MOFs presented herein as well as two previously reported Ce(IV)-MOFs, all obtained by a similar synthetic approach, were studied. While the XRD patterns show time-dependent MOF crystallization, the XANES data reveal the presence of Ce(III) intermediates and their subsequent conversion to the MOFs. The addition of acetic acid in combination with the V-shaped linker molecule was identified as the crucial factor for the formation of the crystalline Ce(III/IV)-MOFs.

Only few reports exist regarding the coexistence of multiple sclerosis (MS) and autoimmune myopathies. We describe the case of a man with a long history of undiagnosed left lower limb motor impairment who was hospitalized for subacute onset of a myopathic syndrome. In addition, neurological examination revealed sensory impairment and pyramidal signs in the left limbs. Muscle biopsy revealed a necrotizing myopathy and serum anti-signal recognition particle (SRP) antibodies were found. Brain and spinal cord MRI displayed several non-enhancing demyelinating lesions, and CSF-restricted oligoclonal bands were detected. Multimodal evoked potentials showed increased latency of central conduction. Total body PET-CT did not reveal malignancies. A final diagnosis of anti-SRP necrotizing autoimmune myopathy (NAM) and MS was made, and subsequent therapy with azathioprine resulted in a complete stability for both diseases during the follow up. To the best of our knowledge this is the first reported case of concomitant NAM and MS.

The main purpose of this article is to provide some practical insights into acid–base disorders interpretation, comparing the three most widespread diagnostic approaches. After a brief summary of the history of blood gas analysis and the shift from a purely chemical approach to more clinically useful applications, the pros and cons of the different methodologies are compared and discussed. Reviewing the most important publications in the field, the authors attempt to show that each diagnostic strategy is acceptable, although the one based on base-excess calculation perhaps seems too ‘rough’ to understand the mixed disorders, whereas the Stewart approach is attractive from a chemical point of view, but unsuitable for the emergency physician because of the cumbersome calculations needed. Finally, the anion gap and ‘expected compensation’ approach seems to be more comprehensive and feasible at the bedside.

Introduction: Due to the increase in knowledge about cancer pathways, there is a growing interest in finding novel potential drugs. Quinazoline is one of the most widespread scaffolds amongst bioactive compounds. A number of patents and papers appear in the literature regarding the discovery and development of novel promising quinazoline compounds for cancer chemotherapy. Although there is a progressive decrease in the number of patents filed, there is an increasing number of biochemical targets for quinazoline compounds.Areas covered: This paper provides a comprehensive review of the quinazolines patented in 2007 – 2010 as potential anticancer agents. Information from articles published in international peer-reviewed journals was also included, to give a more exhaustive overview.Expert opinion: From about 1995 to 2006, the anticancer quinazolines panorama has been dominated by the 4-anilinoquinazolines as tyrosine kinase inhibitors. The extensive researches conducted in this period could have caused the progressive reduction in the ability to file novel patents as shown in the 2007 – 2010 period. However, the growing knowledge of cancer-related pathways has recently highlighted some novel potential targets for therapy, with quinazolines receiving increasing attention. This is well demonstrated by the number of different targets of the patents considered in this review. The structural heterogeneity in the patented compounds makes it difficult to derive general pharmacophores and make comparisons among claimed compounds. On the other hand, the identification of multi-target compounds seems a reliable goal. Thus, it is reasonable that quinazoline compounds will be studied and developed for multi-target therapies.

Quantitative Structure Activity Relationship (QSAR) is a well known cheminformatic tool for the discovery of novel biologically active compounds. However, when large and heterogeneous datasets are mined, it is not possible to derive a QSAR equation able to predict in a satisfactory manner the activity of the compounds. Thus, QSAR models are often inadequate for virtual screening purpose. Herein we present a novel approach to multitarget classification QSAR models, useful to assess the selectivity profile of the tyrosine kinases inhibitors. A descriptor‐based clusterization process was employed, that allowed the generation of models with high accuracies and independent from the chemical classification of the compounds (i.e. from the scaffold type). The herein proposed methodology can lead to QSAR models useful for virtual screening processes.

Cannabidiol (CBD), a prominent psychoinactive component of cannabis with negligible affinity for known cannabinoid receptors, exerts numerous pharmacological actions, including anti‐inflammatory and immunosuppressive effects, the underlying mechanisms of which remain unclear. In the current study, we questioned whether CBD modulates activation of mast cells, key players in inflammation. By using the rat basophilic leukemia mast cell line (RBL‐2H3), we demonstrate that CBD (3–10 μM) augments β‐hexosaminidase release, a marker of cell activation, from antigen‐stimulated and unstimulated cells via a mechanism, which is not mediated by Gi/Goprotein‐coupled receptors but rather is associated with a robust rise in intracellular calcium ([Ca2+]i) levels sensitive to clotrimazole and nitrendipine (10–30 μM). This action, although mimicked by Δ9‐tetrahydrocannabinol (THC), is opposite to that inhibitory, exerted by the synthetic cannabinoids WIN 55,212‐2 and CP 55,940. Moreover, the vanilloid capsaicin, a full agonist of transient receptor potential channel VR1, did not affect [Ca2+]ilevels in the RBL‐2H3 cells, thus excluding the involvement of this receptor in the CBD‐mediated effects. Together, these results support existence of yet‐to‐be identified sites of interaction, i.e., receptors and/or ion channels associated with Ca2+influx of natural cannabinoids such as CBD and THC, the identification of which has the potential to provide for novel strategies and agents of therapeutic interest.

Casein kinase 2 (CK2) is a ubiquitous, essential, and highly pleiotropic protein kinase whose abnormally high constitutive activity is suspected to underlie its pathogenic potential in neoplasia and infective diseases. Using a combined virtual screening approach, we have identified the pyrazoloquinazoline tricyclic system as a novel scaffold to design new kinase CK2 inhibitors.

The side chain orientation of the tyrosine residue included in a peptide, which is an excellent substrate of Syk tyrosine kinase, was fixed in different conformations by either incorporating the tyrosine in cyclic structures (6-OH-Tic, 5-OH-Aic, and Hat derivatives) or adding a sterically bulky substituent in the tyrosine side chain moiety (β-MeTyr). Synthetic peptides containing tyrosine analogues displaying different side chain orientations were analyzed by NMR techniques and tested as potential substrates of the nonreceptor tyrosine kinases Syk, Csk, Lyn, and Fyn. The “rotamer scan” of the phosphorylatable residue generated optimal substrates in terms of both phosphorylation efficiency and selectivity for Syk tyrosine kinase, while the peptidomimetics were not recognized by the other tyrosine kinases. In particular, l-β-MeTyr and d-Hat containing peptides resulted to be both suitable substrates for the specific monitoring of Syk and consensus sequence scaffolds for the design of potential inhibitors highly selective for this tyrosine kinase.

The synthesis, scavenging activity, and cytoprotective profiles of histidyl-containing carnosine analogues bearing hydrazide or 1,2-diol moieties is reported. Some compounds have demonstrated higher aldehyde-sequestering efficiency than carnosine and were also efficient in protecting SH-SY5Y neuroblastoma cells and rat hippocampal neurons from 4-hydroxy-trans-2,3-nonenal (HNE)-mediated death. The cytoprotective efficacy of these compounds suggests their potential use as therapeutic agents for disorders that involve excessive membrane lipids peroxidation and HNE-mediated neuronal toxicity.

First isolated and characterized in 1900 by Gulewitsch, carnosine ( -alanyl-L-hystidine) is a dipeptide commonly present in mammalian tissue, and in particular in skeletal muscle cells; it is responsible for a variety of activities related to the detoxification of the body from free radical species and the by-products of membrane lipids peroxidation, but recent studies have shown that this small molecule also has membraneprotecting activity, proton buffering capacity, formation of complexes with transition metals, and regulation of macrophage function. It has been proposed that carnosine could act as a natural scavenger of dangerous reactive aldehydes from the degradative oxidative pathway of endogenous molecules such as sugars, polyunsaturated fatty acids (PUFAs) and proteins. In particular, it has been recently demonstrated that carnosine is a potent and selective scavenger of ,-unsaturated aldehydes, typical by-products of membrane lipids peroxidation and considered second messengers of the oxidative stress, and inhibits aldehyde-induced protein-protein and DNA-protein cross-linking in neurodegenerative disorders such as Alzheimers disease, in cardiovascular ischemic damage, in inflammatory diseases. The research for new and more potent scavengers for HNE and other ,-unsaturated aldehydes has produced a consistent variety of carnosine analogs, and the present review will resume, through the scientific literature and the international patents, the most recent developments in this field.

We investigated the mechanism of cell death induced by a furoquinolinone derivative, namely, 4-hydroxymethyl-1,6,8-trimethylfuro[2,3-h]quinolin-2(1H)-one (HOFQ), in the dark. Mitochondrial depolarization was found to be a causative event in HOFQ-induced apoptosis that was blunted either by replacing the 4-hydroxymethyl group with a methyl one, or by 4-methylpyrazole, an inhibitor of alcohol dehydrogenase (ADH). In vitro enzymatic assay demonstrated that HOFQ is a substrate of ADH. In isolated mitochondria HOFQ was without effect, whereas in the presence of ADH and NAD⁺ it caused the opening of the permeability transition pore, indicating that HOFQ-oxidized products affect mitochondrial function directly. Finally, an analogue bearing the formyl group at the C-4 position mimicked all the effects exerted by HOFQ. In conclusion, these results suggest that the direct action on mitochondria of HOFQ-oxidized products are responsible for their cytotoxicity, which might be exacerbated, but hardly determined, by photodynamic action and/or binding to DNA.

For many years proteins have been investigated as therapeutic agents, but unfortunately their potential advantages could not be completely exploited. The main drawbacks are their intrinsic short life in the body, immunological adverse reaction and proteolytic digestion. Among all the approaches studied for overcoming these problems, PEGylation (the modification of molecules with polyethylene glycol [PEG]) achieved the most interesting results, leading to a novel series of products that have already reached the market, and hopefully other promising agents will soon be available. Since the first studies in this field, the conjugation of PEG to a protein has shown the possibility of improving the pharmacokinetic profile of a linked drug. In the last few years this technology, firstly developed for proteins, has been transferred to non-peptide drugs, opening a new area of investigation that is now receiving increasing interest. This leads to new opportunities for many therapeutic treatments as it is possible to use molecules that could not before be exploited due to limitations such as inadequate water solubility, high nonspecific toxicity and poor pharmacokinetic profiles. In this review the most recent achievements in PEGylation of protein, peptide and non-peptide drugs are described concerning the binding chemistry, and many examples from the literature are reported, in the fields of both protein therapeutics and non-peptide drugs.

Despite the high antitumor activity of camptothecins, few derivatives have been developed and tested for human treatment of solid tumors, due to unpredictable toxicity mainly connected to their poor water solubility. We report the conjugation of the antitumor agent 10-amino-7-hydroxy camptothecin (SN-392) to linear or branched poly(ethylene glycol)s (PEGs) of different loading capacity through a tri- or tetrapeptide spacer selectively cleaved by lysosomal enzymes (cathepsins). A synthetic strategy based on the chemoselective acylation of the aromatic amino group in the presence of the unprotected C20 tertiary alcohol allowed high overall yields. Two conjugates demonstrated good stability at physiological pH and in mouse plasma (nonspecific proteases) but slowly released the drug payload in the presence of the lysosomal enzyme cathepsin B1. Compound 3, selected for in vivo experiments, was very active against P388, P388/ADM leukaemia, and Meth A fibrosarcoma cell lines, scoring T/C% values comparable with the camptothecin derivative CPT-11. Pharmacokinetic studies indicated that 3 acts as a reservoir of 10-amino-7-ethylcamptothecin, as the mean residence time (MRT) is about 3-fold higher than that of the free drug.

The side-chain orientation of a tyrosine residue located in a peptide, which is an excellent substrate of Syk tyrosine kinase (A. M. Brunati, A. Donella-Deana, M. Ruzzene, O. Marin, L. A. Pinna, FEBS Letters, 1995, Vol. 367, pp. 149–152), was fixed in the gauche (+) or gauche (−) conformation by using the 7-hydroxy-1,2,3,4-tetrahydro isoquinoline-3-carboxylic (Htc) structure. The tyrosine trans conformation was blocked by using an aminobenzazepine-type (Hba) structure. The proposed side-chain orientations were confirmed by the analysis of the ¹H-NMR parameters: chemical shifts, coupling constants, and nuclear Overhauser effects to the tyrosine constraints in the different analogs. This “rotamer scan” of the phosphorylatable residue allowed us to generate optimal substrates in terms of both phosphorylation efficiency and selectivity for Syk tyrosine kinase. In contrast, these conformationally restricted tyrosine analogs were not tolerated by the Src-related tyrosine kinases Lyn and c-Fgr. © 2003 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 71: 478–488, 2003

Furobenzoxazin-3-one, a new tricyclic nucleus, was synthesised in two different and straightforward routes: the first route consisted of condensing a furan ring onto a preconstituted 1,4-benzoxazinone nucleus, and the other in condensing a 1,4-oxazine ring onto the appropriate benzofuran system obtained from coumarin by ring contraction. (© Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002)

A new furoquinolinone derivative, namely 4-hydroxymethyl-1,6,8-trimethylfuro[2,3-h]quinolin-2(1H)-one (HOFQ), was synthesized and its biological activity studied. By UVA activation, HOFQ induced strong antiproliferative effects in Ehrlich ascite cells, which lost their ability to transmit the tumor by transplantation. HOFQ exhibited poor genotoxicity and absence of skin phototoxicity. Actually, HOFQ sensitization forms DNA-protein cross-linkages but not interstrands cross-links. Therefore, HOFQ appears to be a new promising drug for PUVA photochemotherapy and photopheresis.

New tetracyclic psoralenlike compounds have been synthesized, which are characterized by two furan rings angularly condensed on the coumarin nucleus and are therefore called difurocoumarins. This structural feature may favour the intercalation into the DNA helix and then monofunctionally photoreaction with DNA bases. Their synthesis started from 5,7dihydroxy4methylcoumarin, which was condensed with αhaloketones; the resulting ketoethers were then cyclized to give the title compounds.

AbstractWe designed and synthesized the hybrid 6, prepared combining the minor groove binders distamycin A and pyrrolo [2,1-c][1,4] benzodiazepine (PBD) 4, related to the natural occurring anthramycin (2) and DC-81 (3). In this paper, the effects of the compound 6on molecular interactions between DNA and transcription factor Sp1 were studied. The results obtained demonstrate that PBD-distamycin hybrid is a powerful inhibitor of Sp1/DNA interactions.

The synthesis, biological activity, and DNA-binding properties of a series of four hybrids prepared by combining polypyrrole minor groove binders and pyrrolo[2,1-c][1,4]benzodiazepine (PBD) 13, related to the naturally occurring anthramycin (3) and DC-81 (4), have been described, and structure−activity relationships have been discussed. These hybrids 22−25 contain from one to four pyrrole units, respectively. To investigate sequence selectivity and stability of drug/DNA complexes, DNase I footprinting and arrested polymerase chain reaction (PCR) were performed on human c-myc oncogene, estrogen receptor gene, and human immunodeficiency virus type 1 long terminal repeat (HIV-1 LTR) gene sequences. The antiproliferative activity of the hybrids has been tested in vitro on human myeloid leukemia K562 and T-lymphoid Jurkat cell lines and compared to antiproliferative effects of the natural product distamycin A 1, its tetrapyrrole homologue 17, DC 81 (4), and the PBD methyl ester 12. The results obtained demonstrate that the hybrids 22−25 exhibit different DNA-binding activity with respect to both distamycin A 1 and PBD 12. In addition, a direct relationship was found between number of pyrrole rings present in the hybrids 22−25 and stability of drug/DNA complexes. With respect to antiproliferative effects, it was found that the increase in the length of the polypyrrole backbone leads to an increase of in vitro antiproliferative effects, i.e., the hybrid 25 containing the four pyrroles is more active than 22, 23, and 24 both against K562 and Jurkat cell lines.

Several A-ring-modified analogues of the DNA-binding antitumor agent DC-81 (5) have been synthesized in order to study structure−reactivity/cytotoxicity relationships. For two molecules (23 and 30) the modifications required the addition of a fourth ring to give the novel dioxolo[4,5-h]- and dioxano[5,6-h]pyrrolo[2,1-c][1,4]benzodiazepin-11-one (PBD) ring systems, respectively. Another three analogues (34, 38, and 48) have the native benzenoid A-ring replaced with pyridine, diazine, or pyrimidine rings to give the novel pyrrolo[2,1-c][1,4]pyridodiazepine, pyrrolo[2,1-c][1,4]diazinodiazepine, and pyrrolo[2,1-c][1,4]pyrimidinodiazepine systems, respectively. The other new analogues (16a,b) have extended chains at the C8-position of the DC-81 structure. During the synthesis of these compounds, a novel tin-mediated regiospecific cleavage reaction of the dioxole intermediate 18 was discovered, leading to the previously unknown iso-DC-81 (20). In addition, an unusual simultaneous nitration−oxidation reaction of 4-(3-hydroxypropoxy)-3-methoxybenzoic acid (8) was found to produce 3-(4-carboxy-2-methoxy-5-nitrophenoxy)propanoic acid (9), a key intermediate, in high yield. In general, the results of cytotoxicity and DNA-binding studies indicated that none of the changes made to the A-ring of the PBD system significantly improved either binding affinity or cytotoxicity in comparison to DC-81. This result suggests that the superior potency of natural products such as anthramycin (1), tomaymycin (2), and sibiromycin (3) is due entirely to differences in C-ring structure, and in particular exo or endo unsaturation at the C2-position and C2-substituents containing unsaturation. This study also provided information regarding the influence of A-ring substitution pattern on the relative stability of the interconvertible N10−C11 carbinolamine, carbinolamine methyl ether, and imine forms of PBDs.

1,4,6,8-Tetramethyl-2H-furo[2,3-h]quinolin-2-one (FQ) is an angelicin isoster characterized by a strong photosensitizing activity. FQ shows a significant antiproliferative activity also in the dark, i.e., without UVA activation. The cytotoxic activity of FQ in the dark was detected in HeLa cells and in normal human lymphocytes; FQ showed notable antiproliferative effects, barely lower in comparison with ellipticine, used as a reference. Similar results were obtained studying the FQ's capacity for forming chromosome aberrations. For both FQ and ellipticine, the chromosomal damage correlated closely with cell killing; when compared with ellipticine at the same levels of survival, FQ appeared to be muchless genotoxic. Using alkaline elution we have investigated the ability of FQ to damage DNA. The formation of equivalent amounts of single-strand breaks (SSB) and DNA-protein cross-links (DPC) was observed; in addition, these lesions appeared to be located at the same sites in DNA. Experiments carried out with neutral elution demonstrated the formation of double-strand breaks (DSB). All these data are consistent with an inhibition of topoisomerase II; this hypothesis was confirmed performing an enzymatic test in vitro using topoisomerase II from Drosophila melanogaster embryos. Environ. Mol. Mutagen. 29:256-264, 1997 © 1997 Wiley-Liss, Inc.

Synthesis of isoponcimarin, 7-(3'-methyl-2',3'-epoxy-butiloxy)-8-(3"-methyl-2"-oxobutyl) coumarin, a natural coumarin isolated from Poncirus trifoliata L., was obtained starting from acetyl osthenol. From the intermediate 7-acetoxy-8-(3'-methyl-2'-oxobutyl) coumarin, the coumarin derivatives isomeranzin and dihydrooroselone were also prepared

We study the existence and uniqueness of the strict solutions of an initial value problem for a nonautonomous Kolmogorov equation in a space of unbounded functions

With the aim of obtaining new potential photochemotherapeutic agents, having increased antiproliferative activity and decreased undesired effects, we have prepared some new furoquinolinones. Two of them have been studied in detail:  1,4,6,8-tetramethyl-2H-furo[2,3-h]quinolin-2-one (8), and 4,6,8,9-tetramethyl-2H-furo[2,3-h]quinolin-2-one (10). These compounds form a molecular complex with DNA, undergoing intercalation inside the duplex macromolecule, as shown by linear flow dichroism. The complexed ligands, by subsequent irradiation with UV-A light, photobind with the macromolecule forming only monocycloadducts with thymine with cis-syn configuration. In order to evaluate the electronic effects induced by the nitrogen atom in position 1 of 8, semiempirical calculations have been performed on both 4,6,4‘-trimethylangelicin (TMA) and 8. The results obtained do not clearly differentiate between the two molecules which, at this level of approximation, show the possibility of photoreaction with both the 3,4- and 8,9-olefinic bonds for 8 and the 3,4- and 4‘,5‘-bonds for TMA. In the lower energy conformation of intercalated 8, the furan ring is turned toward the minor groove of the polynucleotide, in such a way that photoreaction of this ring with thymine is favored. These compounds unexpectedly inhibit DNA and RNA synthesis in Ehrlich cells, in the dark. They also show a strong photoantiproliferative activity, 2 orders of magnitude higher than 8-methoxypsoralen (8-MOP), the most used drug for photochemotherapy. Their mutagenic activity on Escherichia coli is similar to that of TMA and 8-MOP. On the basis of these results, the compounds should deserve evaluation of their activity in the treatment of hyperproliferative skin diseases.

T2bacteriophage sensitization has been studied using two furocoumarins capable of linking co­valently to DNA to the same extent but producing different damages, psoralen and 4,5′-dimethylangelicin. Psoralen is a well-known linear furocoumarin capable of inducing in DNA both mono-adducts and cross-links; 4,5′-dimethylangelicin is a new angular compound known as a pure mo­nofunctional reagent. In the sensitization of T2mature virions both drugs proved very active, yielding survival curves practically superimposable; on the contrary, in the experiments with the T2veg­etative form, i. e. its DNA inside the host, 4,5′-dimethylangelicin resulted much less effective, resembling the picture observed in the inactivation of the host bacteria. This result did not appear related to an enhancement of DNA repair by a Weigle effect. The different killing activity of 4,5′-dimethylangelicin can be explained supposing that this drug is capable of inducing cross-links in T2DNA inside the virus core, in which it exists in a very folded form, but not in the same DNA after injection into the host bacteria.

Treatment of dimethylated psoralen and angelicin in the 4', 5'-position leads to the formation of 1,3-dioxane derivatives, resulting from the condensation of an 1,3-dioxane ring to the 4', 5'-positions of the dihydrofurocoumarin moiety. The structures of these new compounds, 4a, 1 1a-dihydro-4a, 11a-dimethyl-8H-pyrano [3', 2':5,6]benzofuro[3,2-e]-1, 3-dioxan-8-one (C15H14O5) (1) and 7a, 11a-dihydro-7a, 11a-dimethyl-2H-pyrano[2', 3':4, 5]benzofuro[3, 2-d](1, 3)dioxan-2-one (C15H14O5) (2) have been assigned by1H and13C NMR measurements, mass spectrometry results, and X-ray analysis. Compound (1): triclinic,P¯1,a=9.847(2),b=8.927(2),c=8.334(2) Å,a=95.98(2),ß=108.81(3), ?=106.73(3)°; compound (2): triclinic,P¯1,a=7.296(4),b=7.481(2),c=11.812(4) Å,a=91.67(2),ß=95.97(4), ?=94.20(3)°. The structures were solved by direct methods and refined by full-matrix least squares toR=0.050 (1) and 0.056 (2). In both compounds the coumarin rings can be regarded as coplanar, while the five-membered ring adopts an envelope conformation and the 1,3-dioxane ring a chair conformation.

A detailed study of the furocoumarins present in the seeds of Citrus trifoliata L. revealed the presence of isopimpinellin, prangenin and prangenin hydrate in addition to the already reported bergapten and imperatorin. The amount of these compounds, referred to the starting dry material, were: Imperatorin 0.15%, bergapten 0.06%, whereas isopimpinellin, prangenin and prangenin hydrate were found in the order of less than 0.01%.

5-hydroxymarmesin administered to leaves of Ficus carica and to cut ends of Ruta graveolens has been efficaciously and selectively converted into bergapten while no radioactivity was observed in the other isolated furocoumarins.