Discovery of Novel Sultone Fused Berberine Derivatives as Promising Tdp1 Inhibitors

A new type of berberine derivatives was obtained by the reaction of berberrubine with aliphatic sulfonyl chlorides. The new polycyclic compounds have a sultone ring condensed to C and D rings of a protoberberine core. The reaction conditions were developed to facilitate the formation of sultones with high yields without by-product formation. Thus, it was shown that the order of addition of reagents affects the composition of the reaction products: when sulfochlorides are added to berberrubine, their corresponding 9-O-sulfonates are predominantly formed; when berberrubine is added to pre-generated sulfenes, sultones are the only products. The reaction was shown to proceed stereo-selectively and the cycle configuration was confirmed by 2D NMR spectroscopy. The inhibitory activity of the synthesized sultones and their 12-brominated analogs against the DNA-repair enzyme tyrosyl-DNA phosphodiesterase 1 (Tdp1), an important target for a potential antitumor therapy, was studied. All derivatives were active in the micromolar and submicromolar range, in contrast to the acyclic analogs and 9-O-sulfonates, which were inactive. The significance of the sultone cycle and bromine substituent in binding with the enzyme was confirmed using molecular modeling. The active inhibitors are mostly non-toxic to the HeLa cancer cell line, and several ligands show synergy with topotecan, a topoisomerase 1 poison in clinical use. Thus, novel berberine derivatives can be considered as candidates for adjuvant therapy against cancer.     

Novel Tdp1 Inhibitors Based on Adamantane Connected with Monoterpene Moieties via Heterocyclic Fragments

Tyrosyl-DNA phosphodiesterase 1 (Tdp1) is a promising target for anticancer therapy due to its ability to counter the effects topoisomerase 1 (Top1) poison, such as topotecan, thus, decreasing their efficacy. Compounds containing adamantane and monoterpenoid residues connected via 1,2,4-triazole or 1,3,4-thiadiazole linkers were synthesized and tested against Tdp1. All the derivatives exhibited inhibition at low micromolar or nanomolar concentrations with the most potent inhibitors having IC₅₀ values in the 0.35–0.57 µM range. The cytotoxicity was determined in the HeLa, HCT-116 and SW837 cancer cell lines; moderate CC₅₀ (µM) values were seen from the mid-teens to no effect at 100 µM. Furthermore, citral derivative 20c, α-pinene-derived compounds 20f, 20g and 25c, and the citronellic acid derivative 25b were found to have a sensitizing effect in conjunction with topotecan in the HeLa cervical cancer and colon adenocarcinoma HCT-116 cell lines. The ligands are predicted to bind in the catalytic pocket of Tdp1 and have favorable physicochemical properties for further development as a potential adjunct therapy with Top1 poisons.     

Halogen-containing pyridines. 7. Synthesis and some conversions of (3,5-dichloro-2-pyridyl)hydrazine

(3,5-Dichloro-2-pyridyl)hydrazine was synthesized by the interaction of 2,3,5-trichloropyridine with hydrazine hydrate. Reaction of the former with carbonyl compounds gave N-(3,5-dichloro-2-pyridyl)hydrazones, and with acid anhydrides N-acyl derivatives were formed. Azodyestuffs containing 3,5-dichloropyridyl fragments were obtained from some of the hydrazones synthesized.For Part 6 see [1].Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1066–1079, August, 2000.     

Inelastic neutron scattering study of the lattice dynamics of LaCoO3

The lattice dynamics of lanthanum cobaltite is investigated using the coherent inelastic neutron scattering technique in a temperature range from 10 to 536 K, in which two phase transitions are observed: a change in the Co spin state and a metal-insulator phase transition. The measurements were performed using an IN8 high flux thermal neutron triple-axis spectrometer (ILL, Grenoble). Temperature changes in the phonon dispersion curves caused by the rearrangement of the electron and spin subsystems are found.     

Phonons in ZrB<Subscript>12</Subscript>

The first results of measuring dispersion curves of acoustic phonons in the ZrB₁₂ superconductor are reported. The measurements have been conducted by the inelastic neutron scattering method on an ATOS three-axis spectrometer (IR-8, Russian Research Centre “Kurchatov Institute,” Moscow) at room temperature with a single crystal grown using a 99.5%-enriched ¹¹B isotope. The results obtained have been analyzed in terms of the lattice dynamics model proposed earlier for rare-earth dodecaborides. In this model, the constants of the force interaction of Zr atoms with one another and with the boron framework have been determined.     

Influence of amorphization on the local environment and heat capacity of RNi<Subscript>5</Subscript> compound (<Emphasis Type="Italic">R</Emphasis> = La,Pr)

Heat capacity measurements of amorphous and crystallized R_16.7Ni_83.3 (RNi₅) samples (RNi₅) (R = La, Pr) in magnetic fields were performed, along with measurements of the average interatomic Ni–Ni distances and average square deviations from the interatomic distances. Changes were observed in the interatomic distances in La_16.7Ni_83.3, and in the electron component of the Pr_16.7Ni_83.3 heat capacity.     

Vibrational spectra of the YbB<Subscript>12</Subscript> Kondo insulator

The density of phonon states for the YbB₁₂ Kondo insulator is calculated from the inelastic neutron scattering spectra of this compound. It is established that thermal vibrations of rare-earth atoms predominantly occur in the low-energy range. These atoms are most weakly bound in the crystal structure of the YbB₁₂ Kondo insulator. The high-energy part of the vibrational spectrum is determined by thermal vibrations of the boron atoms forming a rigidly connected structure of the compound. It is revealed that the temperature dependence of the intensity of the phonon peak attributed to thermal vibrations of the ytterbium atoms exhibits an anomalous behavior. This circumstance suggests that the magnetoelastic coupling occurring in the structure of the YbB₁₂ Kondo insulator is relatively strong and can contribute to the magnetic excitation spectrum of this compound.     

New organobimetallic compounds containing catecholate and o-semiquinolate ligands

New organobimetallic compounds CatSn[CpM(CO)_n]₂ (2-4) were obtained by the insertion of CatSn(II) (1) into the metal-metal bond of [CpM(CO)_n]₂ (Cat - 3,6-di-tert-butylcatecholate dianion; M = Fe (2), n = 2; M = Mo (3), W (4), n = 3). The structure of CatSn[CpMo(CO)₃]₂ was determined by X-ray analysis. The oxidation of compounds 2-4 with silver(I) triflate was found to produce stable paramagnetic o-semiquinolate derivatives which keep both Sn-M bonds. New paramagnetic tin(IV) complexes were investigated by EPR spectroscopy.