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Mycalin A (MA) is a polybrominated C-15 acetogenin isolated from the marine sponge Mycale rotalis. Since this substance displays a strong antiproliferative bioactivity towards some tumour cells, we have now directed our studies towards the elucidation of the MA interactome through functional proteomic approaches, (DARTS and t-LIP-MS). DARTS experiments were performed on Hela cell lysates with the purpose of identifying MA main target protein(s); t-LiP-MS was then applied for an in-depth investigation of the MA–target protein interaction. Both these techniques exploit limited proteolysis coupled with MS analysis. To corroborate LiP data, molecular docking studies were performed on the complexes. Finally, biological and SPR analysis were conducted to explore the effect of the binding. Mortalin (GRP75) was identified as the MA’s main interactor. This protein belongs to the Hsp70 family and has garnered significant attention due to its involvement in certain forms of cancer. Specifically, its overexpression in cancer cells appears to hinder the pro-apoptotic function of p53, one of its client proteins, because it becomes sequestered in the cytoplasm. Our research, therefore, has been focused on the possibility that MA might prevent this sequestration, promoting the re-localization of p53 to the nucleus and facilitating the apoptosis of tumor cells.

Starting from D-xylonolactone and D-ribonolactone, several five-membered bromolactones, related to the C1–C5 portion of mycalin A lactone, have been synthesized. The bromination of D-ribonolactone with HBr/AcOH, without a subsequent transesterification step, has been studied for the first time, giving us most of the acetylated lactones investigated in the present study. For each compound, where possible, both the C-3 alcohol and the corresponding acetate were prepared. Evaluation of their anti-tumor activity showed that all the acetates possess a good cytotoxicity towards human melanoma (A375), human cervical adenocarcinoma (HeLa) and human metastatic melanoma (WM266) cancer cells, comparable or even higher than that displayed by the original mycalin A lactone. Lactone acetates derived from D-ribonolactone showed the higher selectivity of action, exhibiting a strong cytotoxicity on all the tested tumor cells but only a limited toxicity on healthy human dermal fibroblast (HDF) cells, used as a control. Wound healing assays showed that two of these substances inhibit the migration of the WM266 cells.

Cyclic adenosine diphosphate ribose (cADPR) is a cyclic nucleotide involved in the Ca2+ homeostasis. In its structure, the northern ribose, bonded to adenosine through an N1 glycosidic bond, is connected to the southern ribose through a pyrophosphate bridge. Due to the chemical instability at the N1 glycosidic bond, new bioactive cADPR derivatives have been synthesized. One of the most interesting analogues is the cyclic inosine diphosphate ribose (cIDPR), in which the hypoxanthine replaced adenosine. The efforts for synthesizing new linear and cyclic northern ribose modified cIDPR analogues led us to study in detail the inosine N1 alkylation reaction. In the last few years, we have produced new flexible cIDPR analogues, where the northern ribose has been replaced by alkyl chains. With the aim to obtain the closest flexible cIDPR analogue, we have attached to the inosine N1 position a 2″,3″-dihydroxypentyl chain, possessing the two OH groups in a ribose-like fashion. The inosine alkylation reaction afforded also the O6-alkylated regioisomer, which could be a useful intermediate for the construction of new kinds of cADPR mimics.

In this note we report the synthesis of a doubly acylated cis-THF-diol product synthesised in three steps by the stereoselective RuO4-catalysed oxidative cyclisation of 1,5-hexadiene, followed by benzoylation and acetylation. This substance is one of the substrates chosen to probe a new developed oxidative procedure to transform bis-acylated THF-diols into bis-acylated 1,4-diketones. This new derivative was fully characterised by spectroscopic methods.

The title compound, C31H48O6, is a polyoxygenated epoxy steroid obtained by a multi-step synthesis involving oxidation of 7-dehydrocholesterol. It crystallizes in the P212121 space group; however, the absolute structure of the molecule in the crystal could not be determined by resonant scattering. The configuration at the C5 and C6 positions is in both cases of the α-type, as is that of the C atoms of the epoxy ring. Molecules in the crystal form chains parallel to the b axis by hydrogen bonding between O—H donors and carbonyl O-atom acceptors. Some atoms of the alkyl chain are disordered over two orientations, with a refined occupancy ratio of 0.511 (10):0.489 (10).

The title compound, C22H34O6, is one of the products obtained by oxidation of squalene with the catalytic system RuO4(cat.)/NaIO4. It crystallizes in the P-1 space group, with four crystallographically independent molecules related by a pseudo-C2 symmetry axis. The structural analysis also shows that the title compound is isomeric with two products previously reported in the literature and that are obtained by the same reaction procedure. In particular, out of the seven chiral C atoms present in the molecule, the title compound shows the opposite configuration at, respectively, four and two chiral centres with respect to the isomeric compounds.

The title compound, C22H34O6, is a product of oxidation of squalene with the catalytic system RuO4(cat.)/NaIO4. The asymmetric unit contains two crystallographically independent molecules of very similar geometry approximately related by the non-crystallographic translation vector c/2. As a consequence, the average diffracted intensity in the hkl layers with odd l is systematically lower than in the layers with even l. In one molecule, the lactone ring and part of the adjacent tetrahydrofuran ring are disordered over two orientations with refined occupancy ratio of 0.831 (10):0.169 (10). The crystal structure is mainly governed by van der Waals forces.

The title compound, C12H20N4O5, crystallizes in the monoclinic space group P21, with four crystallographically independent molecules in the asymmetric unit. The four molecules have a very similar conformation that is basically determined by the formation of two intramolecular hydrogen bonds between the amino NH2 donors and the carbonyl and ring O-atom acceptors, forming, respectively, R(6) and R(7) ring motifs.. In the crystal, intermolecular hydrogen bonding leads to the formation of R22(10) ring patterns, involving one amide CONH2 donor and an imidazole N-atom acceptor. The cluster of the four independent molecules has approximate non-crystallographic C2 point symmetry. The structural analysis also shows that during the synthesis of the title compound, the reductive cleavage of the d-ribose ring of the inosine precursor proceeds stereoselectively, with retention of configuration.

Mycalin A, a polybrominated C15 acetogenin isolated from the encrusting sponge Mycale rotalis, displays an antiproliferative activity on human melanoma (A375) and cervical adenocarcinoma (HeLa) cells and induces cell death by an apoptotic mechanism. Various analogues and degraded derivatives of the natural substance have been prepared. A modification of the left-hand part of the molecule generates the most active substances. A structurally simplified lactone derivative of mycalin A, lacking the C1–C3 side chain, is the most active among the synthesized compounds exhibiting a strong cytotoxicity on both A375 and HeLa cells but not but not on human dermal fibroblast (HDF) used as healthy cells. Further evidence on a recently discovered chlorochromateperiodate-catalyzed process, used to oxidise mycalin A, have been collected.

Cyclic N1-pentylinosine monophosphate (cpIMP), a novel simplified inosine derivative of cyclic ADP-ribose (cADPR) in which the N1-pentyl chain and the monophosphate group replace the northern ribose and the pyrophosphate moieties, respectively, was synthesized. The role played by the position of the phosphate group in the key cyclization step, which consists in the formation of a phosphodiester bond, was thoroughly investigated. We have also examined the influence of the phosphate bridge on the ability of cpIMP to mobilize Ca2+ in PC12 neuronal cells in comparison with the pyrophosphate bridge present in the cyclic N1-pentylinosine diphosphate analogue (cpIDP) previously synthesized in our laboratories. The preliminary biological tests indicated that cpIMP and cpIDP induce a rapid increase of intracellular Ca2+ concentration in PC12 neuronal cells.

In this note, we report the discovery of a novel pyridinium chlorochroamte-catalyzed process in which an α-bromomethyl-tetrahydrofuran bond was oxidatively cleaved to give a γ-lactone functionality. The title compound was synthesized from a C15 polybrominated acetogenin compound, isolated from the marine sponge Mycale rotalis, by benzoylation followed by pyridinium chlorochromate-catalyzed oxidation. This new degraded derivative was fully characterized by 1H-NMR, 13C-NMR, FTIR (Fourier transform infrared), EIMS (Electron impact mass spectrometry) and HRESIMS (High-resolution electrospray ionisation mass spectrometry).

The synthesis of four novel platinum complexes, bearing N6-(6-amino-hexyl)adenosine or a 1,6-di(adenosin-N6-yl)-hexane respectively, as ligands of mono-functional cisplatin or monochloro(ethylendiamine)platinum(II), is reported. The chemistry exploits the high affinity of the charged platinum centres towards the N7 position of the adenosine base system and a primary amine of an alkyl chain installed on the C6 position of the purine. The cytotoxic behaviour of the synthesized complexes has been studied in A549 adenocarcinomic human alveolar basal epithelial and MCF7 human breast adenocarcinomic cancer cell lines, in order to investigate their effects on cell viability and proliferation.

In the last years ruthenium tetroxide is increasingly being used in organic synthesis. Thanks to the fine tuning of the reaction conditions, including pH control of the medium and the use of a wider range of co-oxidants, this species has proven to be a reagent able to catalyse useful synthetic transformations which are either a valuable alternative to established methods or even, in some cases, the method of choice. Protocols for oxidation of hydrocarbons, oxidative cleavage of C–C double bonds, even stopping the process at the aldehyde stage, oxidative cleavage of terminal and internal alkynes, oxidation of alcohols to carboxylic acids, dihydroxylation of alkenes, oxidative degradation of phenyl and other heteroaromatic nuclei, oxidative cyclization of dienes, have now reached a good level of improvement and are more and more included into complex synthetic sequences. The perruthenate ion is a ruthenium (VII) oxo-species. Since its introduction in the mid-eighties, tetrapropylammonium perruthenate (TPAP) has reached a great popularity among organic chemists and it is mostly employed in catalytic amounts in conjunction with N-methylmorpholine N-oxide (NMO) for the mild oxidation of primary and secondary alcohols to carbonyl compounds. Its use in the oxidation of other functionalities is known and recently, its utility in new synthetic transformations has been demonstrated. New processes, synthetic applications, theoretical studies and unusual transformations, published in the last eight years (2006–2013), in the chemistry of these two oxo-species, will be covered in this review with the aim of offering a clear picture of their reactivity. When appropriate, related oxidative transformations mediated by other metal oxo-species will be presented to highlight similarities and differences. An historical overview of some aspects of the ruthenium tetroxide chemistry will be presented as well.

Herein, we report on the synthesis of a small set of linear precursors of an inosine analogue of cyclic ADP-ribose (cADPR), a second messenger involved in Ca2+ mobilization from ryanodine receptor stores firstly isolated from sea urchin eggs extracts. The synthesized compounds were obtained starting from inosine and are characterized by an N1-alkyl chain replacing the “northern” ribose and a phosphate group attached at the end of the N1-alkyl chain and/or 5′-sugar positions. Preliminary Ca2+ mobilization assays, performed on differentiated C2C12 cells, are reported as well.

The antiviral activity of certain acyclic nucleosides drew our attention to the fact that the replacement of the furanose ring by an alkyl group bearing hydroxyl(s) could be a useful structural modification to modulate the biological properties of those nucleosides. Herein, we report on the synthesis of some novel acadesine analogues, where the ribose moiety is mimicked by a d-ribityl or by a hydroxybutyl chain.

The substitution of a hydroxyl group by a fluorine atom in a potential drug is an efficient reaction that can, in principle, improve its pharmacological properties. Herein, the synthesis of the novel compound 5′-fluoro-5′-deoxyacadesine (5′-F-AICAR), a strict analogue of AICAR that cannot be 5′-phosphorylated to ZMP by cellular kinases, is reported.

The solid-phase synthesis of the first example of a new diphosphate AICAR derivative is reported. The new substance is characterized by the presence of a 5'-phosphate group while a second phosphate moiety is installed on a 5-hydroxypentyl chain attached to the 4-N-position of AICAR. Cyclization of the diphosphate derivative by pyrophosphate bond formation allowed for the formation of a novel AICAR-based cyclic ADP-ribose (cADPR) mimic.

A novel bis-iodurated polyether compound, based on an unprecedented tetra-THF backbone, has been isolated as a trace by-product of the oxidation of squalene with the catalytic system RuO2(cat.)/NaIO4. The double erythro configuration of the central portion of the molecule furnishes the first indirect support of the previously postulated pathway operating in the oxidative pentacyclization of the isoprenoid substrate. A bidirectional double oxidative bis-cyclization is invoked to explain the formation of this compound. The isolated substance was successfully subjected to a double rearrangement-ring expansion to give a novel bis-THF-bis-THP compound.

Smenamides are an intriguing class of peptide/polyketide molecules of marine origin showing antiproliferative activity against lung cancer Calu-1 cells at nanomolar concentrations through a clear pro-apoptotic mechanism. To probe the role of the activity-determining structural features, the 16-epi-analogue of smenamide A and eight simplified analogues in the 16-epi series were prepared using a flexible synthetic route. The synthetic analogues were tested on multiple myeloma (MM) cell lines showing that the configuration at C-16 slightly affects the activity, since the 16-epi-derivative is still active at nanomolar concentrations. Interestingly, it was found that the truncated compound 8, mainly composed of the pyrrolinone terminus, was not active, while compound 13, essentially lacking the pyrrolinone moiety, was 1000-fold less active than the intact substance and was the most active among all the synthesized compounds.

In recent years considerable attention has been given to the use of natural substances as anticancer drugs. The natural antioxidant dipeptide L-carnosine belongs to this class of molecules because it has been proved to have a significant anticancer activity both in vitro and in vivo. Previous studies have shown that L-carnosine inhibits the proliferation of human colorectal carcinoma cells by affecting the ATP and Reactive Oxygen Species (ROS) production. In the present study we identified the Hypoxia-Inducible Factor 1α (HIF-1α) as a possible target of L-carnosine in HCT-116 cell line. HIF-1α protein is over-expressed in multiple types of human cancer and is the major cause of resistance to drugs and radiation in solid tumours. Of particular interest are experimental data supporting the concept that generation of ROS provides a redox signal for HIF-1α induction, and it is known that some antioxidants are able to suppress tumorigenesis by inhibiting HIF-1α. In the current study we found that L-carnosine reduces the HIF-1α protein level affecting its stability and decreases the HIF-1 transcriptional activity. In addition, we demonstrated that L-carnosine is involved in ubiquitin-proteasome system promoting HIF-1α degradation. Finally, we compared the antioxidant activity of L-carnosine with that of two synthetic anti-oxidant bis-diaminotriazoles (namely 1 and 2, respectively). Despite these three compounds have the same ability in reducing intracellular ROS, 1 and 2 are more potent scavengers and have no effect on HIF-1α expression and cancer cell proliferation. These findings suggest that an analysis of L-carnosine antioxidant pathway will clarify the mechanism underlying the anti-proliferative effects of this dipeptide on colon cancer cells. However, although the molecular mechanism by which L-carnosine down regulates or inhibits the HIF-1α activity has not been yet elucidated, this ability may be promising in treating hypoxia-related diseases.

The title compound, C20H16O7, contains a cis-fused γ-lactone tetrahydrofuran ring system functionalized with two benzoyloxy groups. Both rings adopt an envelope conformation. The molecule assumes an elongated shape and exibits non-crystallographic C2 symmetry. The benzoyloxy groups are almost planar [maximum deviations of 0.0491 (15) and 0.0336 (17) Å for the O atoms] and their mean planes are inclined to one another by 16.51 (4)°. The crystal packing features weak C—H...O interactions. The aryl groups of adjacent molecules are parallel shifted with face-to-face contacts and a shortest intermolecular C...C distance of 3.482 (4) Å.

The title compound, C20H18O6, prepared from d-mannitol by a two-step procedure, is a functionalized fused bis-tetrahydrofuran. In the central fragment, consisting of two fused tetrahydrofuran rings, one O atom and its two adjacent C atoms, a methylene and a bridgehead C atom, are disordered over two sets of sites with an occupancy ratio of 0.735 (9):0.265 (9). In the major component, the ring containing the disordered O atom is a half-chair conformation with twisted methylene and benzoate-substituted C atoms, whereas the other ring has a half-chair or T-form conformation. In the minor component, the ring with the disordered O atom has an envelope conformation, with the O atom as the flap, and the other ring has a half-chair conformation, with the O atom and the other bridgehead CH atom being twisted. The two aromatic rings are inclined to one another by 20.00 (12)°. In the crystal, adjacent molecules are linked via C—H...π interactions, forming chains propagating along [010].

The title compound, C31H48O7, a polyoxygenated steroid, was obtained by chemical oxidation of 7-dehydrocholesteryl acetate. The molecular geometry features trans A/B and C/D junctions at the steroid core with the acetyl groups in the equatorial position and a fully extended conformation for the alkyl side chain. A chair conformation is observed for rings A and C while ring B adopts a half-chair conformation. The five-membered ring D has an envelope conformation, with the C atom bearing the methyl group at the flap. The terminal isopropyl group and one acetyl group are disordered over two sets of sites with 0.774 (8):0.226 (8) and 0.843 (7):0.157 (7) ratios, respectively. An intramolecular S(6) O—H...O hydrogen-bonding motif involving a hydroxy donor and acceptor is observed. In the crystal, chains of molecules running along the b axis are formed via O—H...O hydrogen bonds between hydroxy donors and carbonyl acceptors of the ordered acetyl group, giving rise to a C(14) motif. The chains are wrapped around the 21 screw axes.

The title compound, C8H13N10+·Cl−, is the monochlorhydrate salt of an aromatic bis(diaminotriazole). The cation is centrosymmetric, lying about an inversion centre (Ci symmetry) because the acidic H atom is disordered over two centrosymmetrically related ring N atoms, with equal multiplicity. It is noteworthy that protonation occurs at an N atom of the ring, instead of at the C—NH2 or N—NH2 amino groups. The chloride anions are also in special positions, as they lie on binary axes, and so the crystallographically independent unit contains half of a formula unit. The N atom of the C—NH2 group is sp2-hybridized and the amino group is coplanar with the triazole ring [dihedral angle = 5 (3)°], while the N atom of the N—NH2 amino group is pyramidal. The C=C bonds are in E conformations and the cation is flat because the conformation of the carbon chain is fully extended. The chloride anions are hexacoordinated, in a distorted trigonal–prismatic geometry, and they are involved, as acceptors, in six hydrogen bonds. Chains of hydrogen-bonded cations, running along c and a + c, are generated by c-glide and C2 rotation, respectively. This combination of N—H...Cl and N—H...N hydrogen bonds leads to the formation of a three-dimensional network.