Abeta aggregation inhibitors. Part 1: Synthesis and biological activity of phenylazo benzenesulfonamides

Phenylazo benzenesulfonamides were designed and synthesized as beta-amyloid (Abeta40) fibril assembly inhibitors, and evaluated for inhibition of Abeta40 aggregation and neurotoxicity using rat cortical neurons. Compound 2 (LB-152) was the most potent compound in this study, and the para-NMe(2) group on the end of the phenylazo moiety may play an important role in preventing Abeta40 fibril formation. LB-152 provides a new lead for further development of potential beta-amyloid aggregation inhibitors to treat AD.     

Biological ion exchanger resins. VII. Counter-ion activity coefficients in solutions of biological polyelectrolytes.

The single ion activity coefficients of K+ and Cl- counter-ions were determined in concentrated polyelectrolyte solutions. The polyelectrolytes investigated included DNA and several proteins. Results indicate that ion gradients of up to 40:1 do not lower the counter-ion activity coefficient below 0.5. Thus, published values of the intracellular activity coefficient of K+ are not incompatible with cellular models utilizing cytoplasmic ion exchange.     

Pleuromutilin derivatives having a purine ring. Part 3: Synthesis and antibacterial activity of novel compounds possessing a piperazine ring spacer

SAR studies on the water-soluble thioether pleuromutilin analogue 6, which has excellent in vitro and in vivo antibacterial activities, led to discovery of the novel pleuromutilin derivatives having a piperazine ring spacer. These derivatives displayed potent and well-balanced in vitro antibacterial activity against various drug-susceptible and -resistant Gram-positive bacteria. In particular, the promising pleuromutilin analogues 37 and 40 were found to exhibit strong in vivo efficacy against Staphylococcus aureus Smith.     

Metallocene basicity. VII. Protonation of ring substituted ferrocenophanes

The protonation of a series of eleven alkyl and dialkylferrocenophanes has been examined using ¹H NMR. In trifluoroboric acid, the protonated species are found to be long-lived on the NMR time scale and stable to decomposition. In many cases the conformations of the protonated species could be determined. In all cases, it was found that only one conformation was observed in solution indicating a strong structural preference presumedly driven by the steric demands of the ring substituents and the bridges. Several examples of spin-spin coupling between the iron-hydrogen and the ring hydrogens are reported.     

Screening of Indian plants for biological activity: Part XIV

Alcoholic extracts of 300 botanically identified plant materials from 275 plant species have been tested for various biological activities including chemotherapeutic and pharmacological screenings. Biological activities have been observed in 111 extracts. Follow-up studies have been carried out in some plants with confirmed activity. The active principles and results of these studies are reported.     

Screening of Indian plants for biological activity: Part XVI

Alcoholic extracts of 288 of plant materials from 199 plant species have been tested for various biological activities including chemotherapeutic and pharmacological screening. Biological activities, ranging from moderate to good degree, have been observed in 61 plants extracts. Follow up studies have been carried out in these extracts and some of them have shown moderate degree of activities at this Institute. However, none of the extracts was found to be good enough for further development. Results of the present studies, along with chemical investigations on different species of similar genera which were screened earlier, are also discussed.     

NMR studies on angiotensin II: Histidine and phenylalanine ring stacking and biological activity

The conformations of angiotensin II and the antagonist [Sar¹, Ile⁸]angiotensin II in dimethylsulfoxide have been examined by high resolution proton magnetic resonance spectroscopy at 400MHz. The chemical shifts for the aromatic protons of the phenylalanine residue in angiotensin II are consistent with shielding and restricted rotation for this side-chain. The chemical shifts for the histidine C₂ and C₄ protons in angiotensin II also indicate shielding, whereas these same protons in the antagonist [Sar¹, Ile⁸]angiotensin II do not demonstrate this shielding influence. These findings suggest a stacking interaction for the histidine and phenylalanine side-chains in angiotensin II which is important for activating angiotensin receptors.     

The influence of different glycosylation patterns on factor VII biological activity

In this study the bioactivity of three differently glycosylated blood coagulation factor VII (FVII) variants (human plasma FVII, recombinant human FVII produced in CHO and BHK cell cultures) were analyzed and compared. Surface plasmon resonance studies of FVII interaction with soluble and full length TF together with FVII autoactivation assays revealed that BHK-derived FVII has the highest bioactivity, while human plasma and CHO-derived FVII showed very similar bioactivity. The affinity of FVII variants to TF correlates with FVII autoactivation rates – the higher the affinity, the faster the autoactivation rate.     

Cyclic analogs of insect oostatic peptides: synthesis, biological activity, and NMR study

Cyclic peptides 2a-2c, derived from the sequence of the C-terminal shortened analogs of the oostatic decapeptide H-Tyr-Asp-Pro-Ala-Pro-Pro-Pro-Pro-Pro-Pro-OH (1a), were synthesized and assayed on their effect in a reproduction of the flesh fly Neobellieria bullata. The cyclization of the N-terminal linear tetra- and pentapeptides 1b and 1c to the cyclotetra- and cyclopentapeptides 2b and 2c decreased the oostatic activity by one order of magnitude. The cyclodecapeptide 2a, which emerged spontaneously during the pentapeptide cyclization, was quite inactive. Comparative 1H and 13C NMR study on a conformation of the cyclopeptides 2a-2c, and their linear precursors 1b and 1c revealed that a space structure of the cyclic analogues 2b and 2c is too restricted to adopt a biological conformation necessary for receptor binding and therefore only minor oostatic activity is observed after their application. The lack of the oostatic activity in the case of the more flexible dimeric analogue 2a is ascribed to the size of its molecule and its overall shape that is not compatible with a receptor binding.     

Quaternary salts of 4,3' and 4,4' bis-pyridinium monooximes. Part 2: synthesis and biological activity

In continuation of our investigations of unsymmetrical bisquaternary monooximes, we synthesized four new series of compounds bridged by hexyl, heptyl, octyl and nonyl groups. All eight monooximes viz., dibromides of 1-(4-hydroxyiminomethylpyridinium)6-(3/4-carbamoylpyridinium)hexane, 1-(4-hydroxyiminomethylpyridinium)-7-(3/4-carbamoylpyridinium)heptane, 1-(4-hydroxyiminomethylpyridinium)-8-(3/4-carbamoylpyridinium)octane, 1-(4-hydroxyiminomethylpyridinium)-9-(3/4-carbamoylpyridinium)nonane as well as the corresponding bis-oximes were synthesized and characterized by spectral data. Their ability to reactivate tetraethylpyrophosphate (TEPP) inhibited mouse total brain cholinesterase was investigated and compared with the conventional oxime 2-pyridinealdoxime chloride (2-PAM). Mouse brain homogenate was used as the source of acetylcholinesterase. Among all the compounds, tested the compound with the hexylene bridge (6b) and a 3-carbamoyl group on the second pyridine ring was found to be the most active acetylcholinesterase reactivator (72%) which is greater than that of 2-PAM (56%). However, the activity was reversed; as the chain length increased from a heptylene to a nonylene bridge, they potentiated the inhibitory effect of TEPP rather than reactivation. It is interesting to note that compound 6b with a carbamoyl group at the 3rd position of the pyridine ring showed dose dependent reactivation whereas the corresponding compound 6a with the carbamoyl group present at the 4th position of the pyridine ring showed reactivation at lower concentration (30 microM) and potentiation of TEPP inhibition at higher concentrations (100 and 300 microM).