Facile two-step synthesis of crispine A and harmicine by cyclopropylimine rearrangement

The synthesis of 4 and 8 is reported. These intermediates are obtained by a one-pot tandem cyclization of 1 and 6, respectively, via Bischler Napieralski reaction followed by cyclopropylimine rearrangement. Compounds 4 and 8 were reduced by sodium borohydride in methanol to afford cytotoxic alkaloid (±)-crispine A and antileishmania compound (±)-harmicine.     

Total synthesis of (-)-4,8,10-tridesmethyl telithromycin

Novel sources of antibiotics are required to address the serious problem of antibiotic resistance. Telithromycin (2) is a third-generation macrolide antibiotic prepared from erythromycin (1) and used clinically since 2004. Herein we report the details of our efforts that ultimately led to the total synthesis of (-)-4,8,10-tridesmethyl telithromycin (3) wherein methyl groups have been replaced with hydrogens. The synthesis of desmethyl macrolides has emerged as a novel strategy for preparing bioactive antibiotics.     

Effect of oxygen annealing on the photoresponse of PbSe thin films fabricated by the pulsed laser deposition method

In this work, we have fabricated lead selenide (PbSe) thin films by the pulsed laser deposition method on Si/SiO₂ substrates and investigated the effect of oxygen annealing (sensitization) in these films. The oxygen-sensitized films show high responsivity in the visible (VIS) and the near-infrared (NIR) region at room temperature without cooling. We also demonstrate the effective surface oxidation of PbSe thin films during the oxygen annealing process without treated with commonly used halogens that leads to a better photoresponse in these PbSe films.     

Photosubstitution in a trisheteroleptic ruthenium complex inhibits conjunctival melanoma growth in a zebrafish orthotopic xenograft model

In vivo data are rare but essential for establishing the clinical potential of ruthenium-based photoactivated chemotherapy (PACT) compounds, a new family of phototherapeutic drugs that are activated via ligand photosubstitution. Here a novel trisheteroleptic ruthenium complex [Ru(dpp)(bpy)(mtmp)](PF₆)₂ ([2](PF₆)₂, dpp = 4,7-diphenyl-1,10-phenanthroline, bpy = 2,2′-bipyridine, mtmp = 2-methylthiomethylpyridine) was synthesized and its light-activated anticancer properties were validated in cancer cell monolayers, 3D tumor spheroids, and in embryonic zebrafish cancer models. Upon green light irradiation, the non-toxic mtmp ligand is selectively cleaved off, thereby releasing a phototoxic ruthenium-based photoproduct capable notably of binding to nuclear DNA and triggering DNA damage and apoptosis within 24–48 h. In vitro, fifteen minutes of green light irradiation (21 mW cm⁻², 19 J cm⁻², 520 nm) were sufficient to generate high phototherapeutic indexes (PI) for this compound in a range of cancer cell lines including lung (A549), prostate (PC3Pro4), conjunctival melanoma (CRMM1, CRMM2, CM2005.1) and uveal melanoma (OMM1, OMM2.5, Mel270) cancer cell lines. The therapeutic potential of [2](PF₆)₂ was further evaluated in zebrafish embryo ectopic (PC3Pro4) or orthotopic (CRMM1, CRMM2) tumour models. The ectopic model consisted of red fluorescent PC3Pro4-mCherry cells injected intravenously (IV) into zebrafish, that formed perivascular metastatic lesions at the posterior ventral end of caudal hematopoietic tissue (CHT). By contrast, in the orthotopic model, CRMM1- and CRMM2-mCherry cells were injected behind the eye where they developed primary lesions. The maximally-tolerated dose (MTD) of [2](PF₆)₂ was first determined for three different modes of compound administration: (i) incubating the fish in prodrug-containing water (WA); (ii) injecting the prodrug intravenously (IV) into the fish; or (iii) injecting the prodrug retro-orbitally (RO) into the fish. To test the anticancer efficiency of [2](PF₆)₂, the embryos were treated 24 h after engraftment at the MTD. Optimally, four consecutive PACT treatments were performed on engrafted embryos using 60 min drug-to-light intervals and 90 min green light irradiation (21 mW cm⁻², 114 J cm⁻², 520 nm). Most importantly, this PACT protocol was not toxic to the zebrafish. In the ectopic prostate tumour models, where [2](PF₆)₂ showed the highest photoindex in vitro (PI > 31), the PACT treatment did not significantly diminish the growth of primary lesions, while in both conjunctival melanoma orthotopic tumour models, where [2](PF₆)₂ showed more modest photoindexes (PI ∼ 9), retro-orbitally administered PACT treatment significantly inhibited growth of the engrafted tumors. Overall, this study represents the first demonstration in zebrafish cancer models of the clinical potential of ruthenium-based PACT, here against conjunctival melanoma.

A new tris-heteroleptic photoactivated chemotherapy ruthenium complex induces apoptosis upon green light activation in a zebrafish orthothopic conjunctival melanoma xenograft model.     

Acetylene-Mediated Borophosphene Dirac Materials as Efficient Anode Materials for Lithium-Ion Batteries

Generally, graphynes have been generated by the insertion of acetylenic content (−C≡C−) in the graphene network in different ratios. Also, several aesthetically pleasing architectures of two-dimensional (2D) flatlands have been reported with the incorporation of acetylenic linkers between the heteroatomic constituents. Prompted by the experimental realization of boron phosphide, which has provided new insights on the boron-pnictogen family, we have modelled novel forms of acetylene-mediated borophosphene nanosheets by joining the orthorhombic borophosphene stripes with different widths and with different atomic constituents using acetylenic linkers. Structural stabilities and properties of these novel forms have been assessed using first-principles calculations. Investigation of electronic band structure elucidates that all the novel forms show the linear band crossing closer to the Fermi level at Dirac point with distorted Dirac cones. The linearity in the hole and electronic bands impose the high Fermi velocity to the charge carriers close to that of graphene. Finally, we have also unravelled the propitious features of acetylene-mediated borophosphene nanosheets as anodes in Li-ion batteries.     

Measurement of interfacial adhesion between glassy polymers using the JKR method

The surface and interfacial energies of polymers are measured using the JKR-type experiments. A novel method has been developed to prepare samples of glassy polymers for adhesion measurements. A thin layer of a polymer is coated on the surface of an O₂-plasma modified cross-linked poly(dimethylsiloxane) [PDMS] spherical cap resulting in the formation of a composite. Using the JKR theory, the surface energies of polystyrene [PS] and poly(methyl methacrylate) [PMMA] are determined from the measurements of the contact radius as a function of applied load. The results of the JKR-type experiments are compared to adhesion measurements done using the surface forces apparatus (SFA). Adhesion hysteresis was observed for PS-PS contact as well as PMMA-PMMA contact. However, no hysteresis was observed for PDMS-PDMS, PDMS-PS, and PDMS-PMMA contacts. The exact origin of the hysteresis is not clear at present. The current evidence suggests that hysteresis is due to rearrangement of the interface during contact.     

Identification and validation of potential genotoxic impurities, 1,3-dichloro-2-propanol,and 2,3-dichloro-1-propanol,at subtle levels in a bile acid sequestrant,colesevelam hydrochloride,using hyphenated GC–MS technique

Potential genotoxic impurities (PGI) and N-nitrosamine impurities in active pharmaceutical ingredients (APIs) and their determination at low levels are substantial challenges for cholesterol-lowering agents in recent years. Herein we developed a robust, reliable, rapid, accurate and validated technique of gas chromatography equipped with a mass spectrometer (GC–MS) for quantifying subtle levels of 1,3-dichloro-2-propanol (PGI-I) and 2,3-dichloro-1-propanol (PGI-II) in colesevelam hydrochloride drug substance (bile acid sequestrant). The separation of colesevelam hydrochloride, PGI-I and PGI-II was executed with chromatographic technique using a capillary column, DB-624 measuring with 30 m × 0.32 mm × 1.8 μm specification of 6% cyanopropylphenyl-94% dimethylpolysiloxane copolymer and helium carrier gas. This developed technique gave a good intensity peak without any interference and extra masses at the retention times of 11.17 min for PGI-I and 11.59 min for PGI-II, which was adequate, with mass spectra (m/z) of 79 and 62, respectively. The method’s sensitivity and linearity are demonstrated by its detection and quantification limits at subtle levels with correlation coefficients of 0.9965 for PGI-I and 0.9910 for PGI-II. The determination is mainly focused on improving sensitivity with the limits of detection and quantitation far below the specifications, which can support tighter limits. This results in a cost-effective and easily adoptable methodology having precise and accurate results in colesevelam hydrochloride API at subtle levels.