1,2,3-Triazolo[4,5-e]-1,2,4-triazolo[3,4-c]pyrimidines

Some new 1,2,3-triazolo[4,5-e]-1,2,4-triazolo[3, 4 -c]pyrimidmes were prepared starting from the corresponding 1,2,3-triazolo[4,5-d]pyrimidines via the formation of the 1,2,4-triazole ring. Thus suitable hydrazino derivatives 6 were condensed with triethyl orthoformate, triethyl orthoacetate and triethyl orthobenzoate to give the expected tricyclic derivatives 7 , 8 and 9 . Intramolecular cyclization of the ethoxycarbonylhydrazino derivatives 10 gave the tricyclic compounds 11 bearing an hydroxyl group in the 3 position. The v-triazolo-s-triazolopyrimidine derivatives were tested towards the A₁ and A_2A adenosine receptors in binding assays, but they did not show any receptor affinity.     

Dipeptides containing D-serine or D-isoserine from the same (R)-aziridine-2-imide by a simple reversal of the synthetic procedure

The ring expansion of 3-unsubstituted (R)-aziridine-2-imide-containing dipeptide under acidic conditions gives rise to oxazoline-5-imide regio and stereoselectively, which can be hydrolysed to the dipeptide containing D-isoserine. On the other hand, the ring opening of 3-unsubstituted (R)-aziridine-2-ester dipeptide, easily obtained from the same (R)-aziridine, gives the regioisomeric dipeptide containing D-serine.     

An Experimental Evidence of a Metal−Metal Bond in μ‐Carbonylhexacarbonyl[μ‐(5‐oxofuran‐2(5H)‐ylidene‐κC,κC)]‐dicobalt(Co−Co)[Co2(CO)6(μ‐CO)(μ‐C4O2H2)]

The orthorhombic crystal structure of [Co₂(CO)₆(μ‐CO)(μ‐C₄O₂H₂)] ( 1 ) was determined at 150 K (Fig. 1). Two C−H⋅⋅⋅O bonds connect the molecules, forming waving ribbons along the b axis. The experimental electron density, determined with the aspherical‐atom formalism, was analyzed with the topological theory of molecular structure. The presence of the Co−Co bond critical point indicates for the first time the existence of a metal−metal bond in a system with bridged ligands. The bond critical properties of the intramolecular bonds and of the intermolecular interactions show features similar to those found in [Mn₂(CO)₁₀], confirming our previously established bonding classification for organometallic and coordination compounds.     

Labdane Diterpenoids from Salvia tingitana Etl. Synergize with Clindamycin against Methicillin-Resistant Staphylococcus aureus

Quorum-sensing (QS) is a regulatory mechanism in bacterial communication, important for pathogenesis control. The search for small molecules active as quorum-sensing inhibitors (QSI) that can synergize with antibiotics is considered a good strategy to counteract the problem of antibiotic resistance. Here the antimicrobial labdane diterpenoids sclareol (1) and manool (2) extracted from Salvia tingitana were considered as potential QSI against methicillin-resistant Staphylococcus aureus. Only sclareol showed synergistic activity with clindamycin. The quantification of these compounds by LC–MS analysis in the organs and in the calli of S. tingitana showed that sclareol is most abundant in the flower spikes and is produced by calli, while manool is the major labdane of the roots, and is abundant also in the leaves. Other metabolites of the roots were abietane diterpenoids, common in Salvia species, and pentacyclic triterpenoids, bearing a γ-lactone moiety, previously undescribed in Salvia. Docking simulations suggested that 1 and 2 bind to key residues, involved in direct interactions with DNA. They may prevent accessory gene regulator A (AgrA) binding to DNA or AgrA activation upon phosphorylation, to suppress virulence factor expression. The antimicrobial activity of these two compounds probably achieves preventing upregulation of the accessory gene regulator (agr)-regulated genes.     

A New Kid on the Block: Sacituzumab Govitecan for the Treatment of Breast Cancer and Other Solid Tumors

Human trophoblast cell-surface antigen-2 (Trop-2) is a membrane glycoprotein involved in cell proliferation and motility, frequently overexpressed in epithelial tumors. Thus, it represents an attractive target for anticancer therapies. Sacituzumab govitecan (SG) is a third-generation antibody-drug conjugate, consisting of an anti-Trop-2 monoclonal antibody (hRS7), a hydrolyzable linker, and a cytotoxin (SN38), which inhibits topoisomerase 1. Specific pharmacological features, such as the high antibody to payload ratio, the ultra-toxic nature of SN38, and the capacity to kill surrounding tumor cells (the bystander effect), make SG a very promising drug for cancer treatment. Indeed, unprecedented results have been observed with SG in patients with heavily pretreated advanced triple-negative breast cancer and urothelial carcinomas, and the drug has already received approval for these indications. These results are coupled with a manageable toxicity profile, with neutropenia and diarrhea as the most frequent adverse events, mainly of grades 1–2. While several trials are exploring SG activity in different tumor types and settings, potential biomarkers of response are under investigation. Among these, Trop-2 overexpression and the presence of BRCA1/2 mutations seem to be the most promising. We review the available literature concerning SG, with a focus on its toxicity spectrum and possible biomarkers of its response.     

Reactions of Co2(CO)8 and of Co2(CO)6L (L = 3-pentyn-1-ol, 1,4-butyn-diol or 2-methyl-3-butyn-2-ol) with 2(diphenylphosphino)ethyl-trietoxysilane and tris(hydroxymethyl)phosphine for applications to new sol-gel materials

The complex Co₂(CO)₆[μ-η²-(H₃CCCCH₂CH₂OH)] (1) with the ligand 3-pentyn-1-ol (pol) has been synthesized following established procedures. Its structure has been determined by X-ray analysis. The complex Co₂(CO)₆(mbo) (mbo = 2-methyl-3-butyn-2-ol, HCCC(CH₃)₂OH), (3), along with the already known Co₂(CO)₆(bud) (bud = 1,4-butyn-diol, HOCH₂CCCH₂OH) (2), and Co₂(CO)₈ were reacted with 2(diphenylphosphino)ethyl-triethoxysilane [Ph₂PCH₂CH₂Si(OCH₂CH₃)₃] (dpts) and tris(hydroxymethyl)phosphine [P(CH₂OH)₃] (thp). With dpts, mono- and di-substituted complexes were obtained: these were characterized by analytical and spectroscopic techniques. The structures of Co₂(CO)₆(dpts)₂ (5) and of Co₂(CO)₄(pol)(dpts)₂ (8) have been determined by X-ray analysis.Complex (1) was reacted with 3-(triethoxysilyl)propyl isocyanate [(H₃CCH₂O)₃Si(CH₂)₃NCO] (tsi): the new complex Co₂(CO)₆[H₃CCCCH₂CH₂OC(O)NH(CH₂)₃Si(OCH₂CH₃)₃] (9) was obtained and spectroscopically characterized. The complex has also been reacted with tetraethyl orthosilicate (teos); a new inorganic-organometallic material was obtained. Complex (5) has been grafted on the mesoporous material SBA-15. The hybrid inorganic-organometallic materials obtained have been characterized by inductively coupled plasma-mass spectrometry (ICP-MS), infrared spectroscopy (FT-IR) under vacuum conditions, X-ray diffraction (XRD) and scanning electron microscopy coupled to EDS probe (SEM-EDS).     

Preparation and characterization of aryl or heteroaryl(3-indolyl)methylium o-benzenedisulfonimides

An initial study has been accomplished into the synthetic feasibility of the preparation of diarylcarbenium salt via the direct coupling of aryl (or heteroaryl) aldehydes and arenes (or heteroaryl analogues) in the presence of a strong organic Br?nsted acid. A number of stabilized aryl or heteroaryl(3-indolyl)carbenium ions, never previously prepared in the solid state, have been isolated in excellent yields as highly stable o-benzenedisulfonimide salts and have been fully characterized. Their purity has been proven by spectroscopic methods and chemical reduction with NaBH(4). An X-ray crystal structure analysis has been performed on one of the products: an azafulvenium species was shown to be the exclusive structure in the solid state.     

Identification and structural characterization by LC‐ESI‐IONTRAP and LC‐ESI‐TOF of some metabolic conjugation products of homovanillic acid in urine of neuroblastoma patients

The levels of urinary catecholamine metabolites, such as homovanillic acid (HVA) and vanillylmandelic acid, are routinely used as a clinical tool in the diagnosis and follow‐up of neuroblastoma (NB) patients. Recently, in the Clinical Pathology Laboratory Unit of G. Gaslini Children Hospital, a commercial method that employs liquid chromatography coupled to electrochemical detection (LC‐EC) has been introduced for the measurement of these metabolites in the routine laboratory practice. Using this LC‐EC method, an unknown peak could be observed only in samples derived from NB patients. To investigate the nature of this peak, we used a combination of liquid chromatography‐time‐of‐flight mass spectrometry (LC‐TOF‐MS) and liquid chromatography‐ion trap tandem mass spectrometry (LC‐IT‐MS). The first approach was used to obtain the elemental composition of the ions present in this new signal. To get additional structural information useful for the elucidation of unknown compounds, the ion trap analyzer was exploited. We were able to identify not just one, but three unknown signals in urine samples from NB patients which corresponded to three conjugated products of HVA: HVA sulfate and two glucuronoconjugate isomers. The enzymatic hydrolysis with β‐glucuronidase confirmed the proposed structures, while the selective alkaline hydrolysis allowed us to distinguish the difference between phenol‐ and acyl‐glucuronide of HVA. The latter was the unknown peak observed in LC‐EC separations of urine samples from NB patients. Copyright © 2012 John Wiley & Sons, Ltd.     

Fluorinated PLGA Nanoparticles for Enhanced Drug Encapsulation and 19F NMR Detection

In the continuous search for multimodal systems with combined diagnostic and therapeutic functions, several efforts have been made to develop multifunctional drug delivery systems. In this work, through a covalent approach, a new class of fluorinated poly(lactic-co-glycolic acid) co-polymers (F-PLGA) were designed that contain an increasing number of magnetically equivalent fluorine atoms. In particular, two novel compounds, F₃-PLGA and F₉-PLGA, were synthesized and their chemical structure and thermal stability were analyzed by solution NMR, DSC, and TGA. The obtained F-PLGA compounds were proven to form in aqueous solution colloidal stable nanoparticles (NPs) displaying a strong ¹⁹F NMR signal. The fluorinated NPs also showed an enhanced ability to load hydrophobic drugs containing fluorine atoms compared to analogous pristine PLGA NPs. Preliminary in vitro studies showed high cell viability and the NP ability to intracellularly deliver and release a functioning drug.