Some papaverine derivatives

Heating papaverine with chloral hydrate and benzoyl chloride formed products of the replacement of the hydrogen at the 15-C atom of papaverine: 15-(β-trichloro-α-hydroxyethyl)papaverine and 15-benzoylpapaverine. In reactions with monochloro- and trichloroacetic acids under mild conditions in the cold, salts at the nitrogen atom were formed: the monochloroacetate and the trichloroacetate. The products were characterized by the results of TLC (type KSK silica gel fixed with gypsum), elementary analyses, and IR and PMR spectroscopy.     

Some papaverine derivatives

Heating papaverine with chloral hydrate and benzoyl chloride formed products of the replacement of the hydrogen at the 15-C atom of papaverine: 15-(-trichloro--hydroxyethyl)papaverine and 15-benzoylpapaverine. In reactions with monochloro- and trichloroacetic acids under mild conditions in the cold, salts at the nitrogen atom were formed: the monochloroacetate and the trichloroacetate. The products were characterized by the results of TLC (type KSK silica gel fixed with gypsum), elementary analyses, and IR and PMR spectroscopy.V. I. Nikitin Institute of Chemistry, Academy of Sciences of the Tadzhik SSR, Dushanbe. Translated from Khimiya Prirodnykh Soedinenii, No. 4, pp. 500–502, July–August, 1984.     

Chromone derivatives which bind to human hair

Chromone derivatives bearing a quaternary ammonium functionality which bind to human hair were synthesised. The radical scavenging activity, according to the DPPH assay, of the chromone derivatives is considerably lower compared with flavonoids. The compounds show interesting UV absorption properties that depend on the position of a methoxy substituent. A bathochromic shift of 29 nm was observed when the methoxy group on the ammonium salts were shifted from position 7 to position 6.     

Bioactive aromatic derivatives from endophytic fungus, Cytospora sp

Two new benzyl gamma-butyrolactone analogues, (R)-5-((S)-hydroxy(phenyl)-methyl)dihydrofuran-2(3H)-one (1) and its 6-acetate (2), and a new naphthalenone derivative (8), together with eight additional known aromatic derivatives, (S)-5-((S)-hydroxy(phenyl)-methyl)dihydrofuran-2(3H)-one (3), (S)-5-benzyl-dihydrofuran-2(3H)-one (4), 5-phenyl-4-oxopentanoic acid (5), gamma-oxo-benzenepentanoic acid methyl ester (6), 3-(2,5-dihydro-4-hydroxy-5-oxo-3-phenyl-2-furyl)propionic acid (7), (3R)-5-methylmellein (9), integracins A (10) and B (11) were isolated from Cytospora sp., an endophytic fungus isolated from Ilex canariensis from Gomera. The structures of these compounds were elucidated by detailed spectroscopic analysis, comparison with reported data, and chemical interconversion. The absolute configurations of the new compounds (1, 2, 8) were established on the basis of optical rotation or CD spectra analysis. Preliminary studies showed antimicrobial activity of these compounds against the fungi Microbotryum violaceum, Botrytis cinerea and Septoria tritici, the alga Chlorella fusca, and the bacterium Bacillus megaterium.     

Bioactive nonanolide derivatives isolated from the endophytic fungus Cytospora sp

Cytospolides F-Q (6-17) and decytospolides A and B (18 and 19), 14 unusual nonanolide derivatives, were isolated from Cytospora sp., an endophytic fungus from Ilex canariensis. The structures were elucidated by means of detailed spectroscopic analysis, chemical interconversion, and X-ray single crystal diffraction. The solution- and solid-state conformers were compared by the combination of experimental methods (X-ray, NMR) supported by DFT calculations of the conformers. Absolute configurations were assigned using the modified Mosher's method and solution- and solid-state TDDFT ECD calculations. In an in vitro cytotoxicity assay toward the tumor cell lines of A549, HCT116, QGY, A375, and U973, the γ-lactone 17 demonstrated a potent growth inhibitory activity toward the cell line A-549, while nonanolide 16 with (2S) configuration showed the strongest activity against cell lines A-549, QGY, and U973. A cell cycle analysis indicated that compound 16 can significantly mediate G1 arrest in A549 tumor cells, confirming the important role of the C-2 methyl in the growth inhibition toward the tumor line. The discovery of an array of new nonanolides demonstrates the productivity of the fungus, and it is an example of chemical diversity, extending the nonanolide family by derivatives formed by ring cleavage, oxidation, esterification, and Michael addition.     

Loop-length-dependent folding of G-quadruplexes

Guanine-rich DNA sequences can form a large number of structurally diverse quadruplexes. These vary in terms of strand polarity, loop composition, and conformation. We have derived guidelines for understanding the influence of loop length on the structure adopted by intramolecular quadruplex-forming sequences, using a combination of experimental (using CD and UV melting data) and molecular modeling and simulation techniques. We find that a parallel-stranded intramolecular quadruplex structure is the only possible fold when three single residue loops are present. When single thymine loops are present in combination with longer length loops, or when all loops are longer than two residues, both parallel- and antiparallel-folded structures are able to form. Multiple conformations of each structure are likely to coexist in solution, as they were calculated to have very similar free energies.     

Hydroxylated polychlorinated biphenyls selectively bind transthyretin in blood and inhibit amyloidogenesis: rationalizing rodent PCB toxicity

Polychlorinated biphenyls (PCBs) and their hydroxylated metabolites (OH-PCBs) are known to bind to transthyretin (TTR) in vitro, possibly explaining their bioaccumulation, rodent toxicity, and presumed human toxicity. Herein, we show that several OH-PCBs bind selectively to TTR in blood plasma; however, only one of the PCBs tested binds TTR in plasma. Some of the OH-PCBs displace thyroid hormone (T4) from TTR, rationalizing the toxicity observed in rodents, where TTR is the major T4 transporter. Thyroid binding globulin and albumin are the major T4 carriers in humans, making it unlikely that enough T4 could be displaced from TTR to be toxic. OH-PCBs are excellent TTR amyloidogenesis inhibitors in vitro because they bind to the TTR tetramer, imparting kinetic stability under amyloidogenic denaturing conditions. Four OH-PCB/TTR cocrystal structures provide further insight into inhibitor binding interactions.     

Telomestatin and diseleno sapphyrin bind selectively to two different forms of the human telomeric G-quadruplex structure

The human telomeric sequence d[T(2)AG(3)](4) has been demonstrated to form different types of G-quadruplex structures, depending upon the incubation conditions. For example, in sodium (Na(+)), a basket-type G-quadruplex structure is formed. In this investigation, using circular dichroism (CD), biosensor-surface plasmon resonance (SPR), and a polymerase stop assay, we have examined how the addition of different G-quadruplex-binding ligands affects the conformation of the telomeric G-quadruplex found in solution. The results show that while telomestatin binds preferentially to the basket-type G-quadruplex structure with a 2:1 stoichiometry, 5,10,15,20-[tetra-(N-methyl-3-pyridyl)]-26-28-diselena sapphyrin chloride (Se2SAP) binds to a different form with a 1:1 stoichiometry in potassium (K(+)). CD studies suggest that Se2SAP binds to a hybrid G-quadruplex that has strong parallel and antiparallel characteristics, suggestive of a structure containing both propeller and lateral, or edgewise, loops. Telomestatin is unique in that it can induce the formation of the basket-type G-quadruplex from a random coil human telomeric oligonucleotide, even in the absence of added monovalent cations such as K(+) or Na(+). In contrast, in the presence of K(+), Se2SAP was found to convert the preformed basket G-quadruplex to the hybrid structure. The significance of these results is that the presence of different ligands can determine the type of telomeric G-quadruplex structures formed in solution. Thus, the biochemical and biological consequences of binding of ligands to G-quadruplex structures found in telomeres and promoter regions of certain important oncogenes go beyond mere stabilization of these structures.     

Synthesis of selectively deuterated and tritiated lupane derivatives with cytotoxic activity

The aim of this work was to synthesize deuterated and tritiated analogues of highly oxidized lupane derivatives known from our group. We selected compounds that previously showed very high cytotoxic activity on multiple cancer cell lines in order to further investigate the mechanism of their action. From starting material (compounds 1–4), we obtained benzyl platanate (5) and its reaction with deuteromethyltriphenylphosphonium iodide gave deuterated compound 6. Following benzyl deprotection gave free acid 7 and oxidation with SeO₂ gave 30-oxo-[29-²H₂]lup-20(29)-en-28-oic acid (8), which is one of the most active compounds synthesized in our group to date (IC₅₀ 6 μmol/L on CEM cell line). The alkylation of benzyl 2-hydroxy-3-oxolupa-1,20(29)-dien-28-oate (9) with methyliodide or deuteromethyliodide followed by a series of deprotection and hydrogenation steps gave compounds 10–14, where 2β-[31-²H₃]methoxy-3-oxolupan-20(29)-en-28-oic acid (13) is especially interesting, it showed lower activity on CEM cell line (IC₅₀ 10 μmol/L) however, it was very active against Ph1—positive human leukemia BV-173 (IC₅₀ 0.91 μmol/L) and against human myelogenous leukemia K562 (IC₅₀ 0.52 μmol/L). Selectively labelled [3α-²H] and [3α-³H] methyl 3β-acetoxy-21,22-dioxolup-18-en-28-oates 24, 25 were prepared in three steps by reduction of corresponding 3-oxo derivatives and they showed moderate activity on CEM cell line (IC₅₀ 10 μmol/L). In total, 11 labelled compounds (6–8, 11, 14, 18, 19, 21, 22, 24 and 25) have not been reported before.     

Anion bridged nanosheet from self-assembled G-quadruplexes

A novel, non-covalent polymeric nanosheet has been produced through small molecule self-assembly; the structure has been characterized by solution NMR, solid-state NMR, powder XRD and AFM.     

Preparation of selectively protected protoescigenin derivatives for synthesis of escin analogs and neoglycoconjugates

Protoescigenin, the main aglycone of horse chestnut saponin mixture known as escin, was selected as substrate for exploratory chemistry towards selective protection, followed by propargyl ether formation and subsequent condensation with azido-monosaccharides, to obtain novel triazole linked conjugates of the triterpene.      

Enzymatic synthesis of tryptamine and its halogen derivatives selectively labeled with hydrogen isotopes

Nine isotopomers of tryptamine and its halogen derivatives, labeled with deuterium, tritium in side chain, i.e., [(1R)-²H]-, [(1R)-³H]-, 5-F-[(1R)-²H]-, 5-F-[(1R)-³H]-, 5-Br-[(1R)-²H]-, double labeled [(1R)-²H/³H]-, 5-F-[(1R)-²H/³H]-, and ring labeled [4-²H]-, and [5-²H]-tryptamine, were obtained by enzymatic decarboxylation of l-Trp and its appropriate derivatives in deuteriated or tritiated media, respectively. Intermediates: [5′-²H]-l-Trp used for further decarboxylation was synthesized by enzymatic coupling of [5-²H]-indole with S-methyl-l-cysteine, and [4′-²H]-l-Trp was obtained by isotope exchange ¹H/²H of the authentic l-Trp dissolved in heavy water induced by UV-irradiation. Doubly labeled [(1R)-²H/³H]- and 5-F-[(1R)-²H/³H]-tryptamine were obtain by decarboxylation of l-Trp or [5′-F]-l-Trp carried out in ²H³HO incubation medium.     

Synthesis of pyrroloisoquinolines from papaverine

papaverine and its derivatives react with p-chlorophenacyl bromide to give the corresponding quaternary salts, which are converted into pyrrolo[2,1-a]isoquinolines by the action of bases.     

盐酸罂粟碱的荧光光谱分析法研究

以荧光光谱法研究了经过浓H2 SO4 酸化处理后的盐酸罂粟碱的荧光光谱特征 ,测定了盐酸罂粟碱与 β 环糊精的包络反应常数和热力学参数 ,且在1 0 6× 1 0 -7～ 3 1 8× 1 0 -6mol L范围内荧光强度与盐酸罂粟碱的浓度呈良好线性关系 ,提出了在β 环糊精介质体系中测定盐酸罂粟碱含量的新方法。检测限为 3.2 0× 1 0 -8mol L。     

Diverse polymorphism of G-quadruplexes as a kinetic phenomenon

Knowledge of forces that drive conformational transitions of G-quadruplexes is crucial for understanding the molecular basis of several key cellular processes. It can only be acquired by combining structural, thermodynamic and kinetic information. Existing biophysical and structural evidences on polymorphism of intermolecular G-quadruplexes have shown that the formation of a number of these structures is a kinetically controlled process. Reported kinetic models that have been used to describe the association of single strands into quadruplex structures seem to be inappropriate since the corresponding model-predicted activation energies turn out to be negative. By contrast, we propose here a novel kinetic model that successfully describes experimentally monitored folding/unfolding transitions of G-quadruplexes and gives positive activation energies for all elementary steps, including those describing association of two single strands into bimolecular quadruplex structures. It is based on a combined thermodynamic and kinetic investigation of polymorphic behavior of bimolecular G-quadruplexes formed from d(G4T4G4) and d(G4T4G3) strands in the presence of Na(+) ions, monitored by spectroscopic (UV, CD) and calorimetric (DSC) techniques. According to our experiment and model analysis the topology of the measured G-quadruplexes is clearly flexible with the conformational forms that respond to the rate of temperature change at which global unfolding/folding transitions occur.     

Tuning supramolecular G-quadruplexes with mono- and divalent cations

Supramolecular G-quadruplexes (SGQs) are formed via the cation promoted self-assembly of guanine derivatives into stacks of planar hydrogen-bonded tetramers. Here, we present results on the formation of SGQs made from the 8-(m-acetylphenyl)-2′-deoxyguanosine (mAGi) derivative in the presence of various mono- and divalent cations. NMR and HR ESI-MS data indicate that varying the cation can efficiently tune the molecularity, the fidelity and stability (thermal and kinetic) of the resulting SGQs. The results show that, parallel to the previously reported potassium-templated hexadecamer (mAGi₁₆·3K⁺), Na⁺, Rb⁺ and NH₄⁺ also promote the formation of similar supramolecules with high fidelity and molecularity. In contrast, the divalent cations Pb²⁺, Sr²⁺ and Ba²⁺ template the formation of octamers (mAGi₈), with the latter two inducing higher thermal stabilities. Molecular dynamics simulations for the hexadecamers containing monovalent cations enabled critical insights that help explain the experimental observations.     

Metallo-responsive switching between hexadecameric and octameric supramolecular G-quadruplexes

We report the metallo-responsive high fidelity switching between hexadecameric and octameric supramolecular G-quadruplexes triggered by a change in the metal cation promoter from potassium to strontium, respectively.