Remarkable stereospecific conjugate additions to the Hsp90 inhibitor celastrol

Celastrol, an important natural product and Hsp90 inhibitor with a wide range of biological and medical activities and broad use as a biological probe, acts by an as yet undetermined mode of action. It is known to undergo Michael additions with biological sulfur nucleophiles. Here it is demonstrated that nucleophiles add to the pharmacophore of celastrol in a remarkable stereospecific manner. Extensive characterization of the addition products has been obtained using NMR spectrometry, nuclear Overhauser effects, and density functional theory to determine facial selectivity and gain insight into the orbital interactions of the reactive centers. This stereospecificity of celastrol may be important to its protein target selectivity.     

Synthesis and alkali metal complexation studies of novel cage-functionalized cryptands

The synthesis of novel cage-functionalized cryptands 1–5 containing adamantane-, 2-oxaadamantane- or noradamantane-moiety [i.e., 1,3-diethyladamantano[2.2.0]cryptand (1), 1,3-diethoxyadamantano[2.2.2]cryptand (2), 1,3-di[(ethyloxy)methyl]adamantano[2.2.2]-cryptand (3), 1,3-di[(ethyloxy)methyl]-2-oxaadamantano[2.2.3]cryptand (4), and 1,2-diethyloxynoradamantano[2.2.2]cryptand (5)] and their alkali metal binding properties are reported. The results obtained by extraction experiments showed that all the cryptands displayed lower extraction capabilities than the parent [2.2.2]cryptand. However, cryptands 1 and 2 showed much higher selectivity toward K⁺ than the reference [2.2.2]cryptand. When the third bridge is enlarged by two additional CH₂-groups as well as by two oxygen atoms, as in cryptands 3 and 4, the complexational abilities for bigger cations (K⁺, Rb⁺ and Cs⁺) are enhanced. Cryptand 5 displayed very good extraction capabilities of all cations, but showed practically no selectivity towards any of the alkali metal cation. The experimental findings are corroborated by calculation studies consisting of force field based conformational search using Monte Carlo method followed by investigation of the stabilities of the complexes of cryptands with Na⁺ and K⁺ metal ions in chloroform by means of quantum chemical calculations at the density functional theory level.     

New Mechanistic Proposal for Some Heptamolybdate-Ion-Catalyzed Isomerizations

Heptamolybdate-ion(HM)-catalyzed C(2) epimerization of D-glucose and racemization of D-glyceraldehyde proceed with comparable rates and activation parameters; HM catalyzes the isomerization of glucal and galactal triacetates as well. For all of the above transformations, a common, new mechanism is proposed that invokes stabilization of 3-oxa-allylic cation species by the central Mo(VI) atom.     

Gas Phase H/D Exchange of Sodiated Amino Acids: Why Do We See Zwitterions?

The gas-phase interaction of sodiated amino acids and sodiated amino acid methyl esters with various deuterium donors is investigated by combining results of H/D exchange reactions with those from density functional theory and molecular dynamics calculations. Discrepancy between experimentally and theoretically obtained structures for sodium cationized amino acids is explained by deuterium donor caused perturbation of the most stable amino acid conformation. Detailed study of H/D exchange mechanism on sodiated amino acids shows that the H/D exchange reaction is preceded by a multistep quasi-isoenergetic transition (perturbation) from a charge solvated to zwitterionic structure in the amino acid. Although the computation refers to the system AlaNa(+) and D(2)O, these mechanisms apply to all amino acids, except those where a functional side-chain group takes part in the perturbation process. The suggested perturbation mechanism applies also for other deuterium donors such as CD(3)OD or even ND(3) and indicates that a single water molecule suffices to convert the sodiated amino acid from charge solvated to zwitterionic form.     

Posets Generated by Irreducible Elements

Let J be a fixed partially ordered set (poset). Among all posets in which J is join-dense and consists of all completely join-irreducible elements, there is an up to isomorphism unique greatest one, the Alexandroff completion L. Moreover, the class of all such posets has a canonical set of representatives, C ₀ L, consisting of those sets between J and L which intersect each of the intervals I _j =[j ,j ] (jJ), where j and j denote the greatest element of L less than, respectively, not greater than j. The complete lattices in C ₀ L form a closure system C L, consisting of all Dedekind–MacNeille completions of posets in C ₀ L. We describe explicitly those L for which C ₀ L, respectively, C L is a (complete atomic) Boolean lattice, and similarly, those for which C L is distributive (or modular). Analogous results are obtained for C L, the closure system of all posets in C ₀ L that are closed under meets of less than elements (where is any cardinal number).     

Ringerweiterung durch Fragmentierung. Synthese von 15-Pentadecanolid (Exaltolid®)

Ring Enlargement by Fragmentation. Synthesis of 15-Pentadecanolide (Exaltolide®) The title compound was synthesized from 1-(3′-hydroxypropyl)-2-oxocyclododecane-1-carbonitrile ( 3 ), using two different routes (Scheme). The CN group of 3 was converted to the Me₃N⁺ residue in 5 which underwent, upon NaH treatment, a fragmentation leading to the ring-enlargement product 6 . The same product was observed after heating the ring-enlarged dimethylamine oxide 14 , prepared from 3 by Bu₄NF treatment and conversion of the CN into the dimethylamine-oxide moiety. Ozonolysis of the methylidene double bond in 6 and reduction of the resulting C = O to a CH₂ group gave Exaltolide® ( 8 ).     

Hydrogen Bonding and Solvent Effects on Complexation of Alkali Metal Cations by Lower Rim Calix[4]arene Tetra(O-[N-acetyl-D-phenylglycine methyl ester]) Derivative

Complexation of alkali metal cations with 5,11,17,23-tetra-tert-butyl-26,28,25,27-tetrakis(O-methyl-D-α-phenylglycylcarbonylmethoxy)calix[4]arene (L) was studied by means of spectrophotometric, conductometric and potentiometric titrations at 25 °C. The solvent effect on the binding ability of L was examined by using two solvents with different affinities for hydrogen bonding, viz. methanol and acetonitrile. Despite the presence of intramolecular NH···O=C hydrogen bonds in L, which need to be disrupted to allow metal ion binding, this calix[4]arene amino acid derivative was shown to be an efficient binder for smaller Li⁺ and Na⁺ cations in acetonitrile (lg K _LiL  > 5, lg K _NaL  = 7.66), moderately efficient for K⁺ (lg K _KL  = 4.62), whereas larger Rb⁺ and Cs⁺ did not fit in its hydrophilic cavity. The complex stabilities in methanol were significantly lower (lg K _NaL  =  4.45, lg K _KL  = 2.48). That could be explained by different solvation of the cations and by competition between the cations and methanol molecules (via hydrogen bonds) for amide carbonyl oxygens. The influence of cation solvation on complex stability was most pronounced in the case of Li⁺ for which, contrary to the quite stable LiL ⁺ complex in acetonitrile, no complexation was observed in methanol under the conditions used.     

Synthesis,photochemical synthesis and antitumor evaluation of novel derivatives of thieno[3',2':4,5]thieno[2,3-c]quinolones

The novel derivatives of thieno[3',2':4,5]thieno[2,3-c]quinolones 6a, 6b, 7, 10a and 10b were synthesized in multistep synthesis starting from thiophene-3-carboxaldehyde and malonic acid reacting in aldol condensation or from 3-bromothiophenes or methyl 4-bromothiophene-2-carboxylate reacting in Heck reaction. They resulted in corresponding substituted thienylacrylic acids 3a-c, which were cyclized into thieno[2,3-c]thiophene-2-carbonyl chlorides 4a-c and converted into thieno[2,3-c]thiophene-2-carboxamides 5a-d. Prepared carboxamides were photochemically dehydrohalogenated into corresponding substituted thieno[3',2':4,5]thieno[2,3-c]quinolones 6a-d. Compound 7 was prepared from 6d by alkylation with N-[3-(dimethylamino)propyl]chloride hydrochloride in the presence of NaH. Compounds 10a and 10b were prepared from 6c in the multistep synthesis over acid 8 and acid chloride 9. Compounds 6a, 6b, 7, 10a and 10b were found to exert cytostatic activities against malignant cell lines: pancreatic carcinoma (MiaPaCa2), breast carcinoma (MCF7), cervical carcinoma (HeLa), laryngeal carcinoma (Hep2), colon carcinoma (CaCo-2), melanoma (HBL), and human fibroblast cell lines (WI-38). The compound 6b, which bears the 3-dimethylaminopropyl substituent on quinolone nitrogen and methoxycarbonyl substituent on position 9, exhibited marked antitumor activity. On the contrary, compound 7, which also bears the 3-dimethylaminopropyl substituent on the quinolone nitrogen but anilido substituent on position 9, exhibited less antitumor activity than the others.     

A Chemometric Investigation on the Functional Potential in High Power Ultrasound (HPU) Processed Strawberry Juice Made from Fruits Harvested at two Stages of Ripeness

This work aimed to investigate the influence of high-power ultrasound (HPU) technology on the stability of bioactive compounds in strawberry juices obtained from fruits with different stages of ripeness (75% vs. 100%) and stored at 4 °C for 7 days. HPU parameters were amplitude (25, 50, 75, and 100%), pulses (50 vs. 100%) and treatment time (5 vs. 10 min). Amplitude and pulse had a significant effect (p ≤ 0.05) on all bioactive compounds except flavonols and hydroxycinnamic acids. The treatment duration of 5 min vs. 10 min had a significant positive impact on the content of anthocyanins, flavonols and condensed tannins, while the opposite was observed for total phenols, whereas no statistically significant effect was observed for hydroxycinnamic acids. The temperature changes during HPU treatment correlated positively with almost all HPU treatment parameters (amplitude, pulse, energy, power, frequency). Optimal parameters of HPU were obtained for temperature changes, where the highest content of a particular group of bioactive compounds was obtained. Results showed that by combining fruits with a certain ripeness and optimal HPU treatment, it would be possible to produce juices with highly preserved bioactive compounds, while HPU technology has prospects for application in functional food products.