Comparative haemolytic activity of bis(phenylmethyl) disulphide, bis(phenylethyl) disulphide and bis(phenylpropyl) disulphide in rats.

Thiols and disulphides make an important contribution to the organoleptic characteristics of foodstuffs, and many such compounds are approved for use as food flavours. Some thiols and disulphides are haemolytic agents in vivo. The haemolysis is caused by oxidative damage to erythrocytes initiated by "active oxygen" species formed during redox cycling between the thiol and disulphide. In all cases so far examined, the haemolytic activity of a thiol or disulphide in vivo is correlated with its ability to cause oxidative damage to red cells in vitro. In the present study, the in vitro and in vivo effects of three aryl-alkyl disulphides have been compared. Bis(phenylmethyl) and bis(phenylpropyl) disulphide induced no oxidative damage in vitro, and, as expected, caused no haemolysis in rats. In contrast, bis(phenylethyl) disulphide, while causing little or no oxidative damage in vitro, was a potent haemolytic agent in vivo. It is suggested that this effect is due to dehydrogenation of the ethyl disulphide to the ethenyl derivative in vivo. Bis(phenylethenyl) disulphide was found to cause extensive oxidative damage to red cells in vitro and severe haemolytic anaemia in rats. The results of this study show that the in vivo toxicity of thiols and disulphides cannot always be predicted on the basis of their effects in vitro.     

Discovery of novel alkylated (bis)urea and (bis)thiourea polyamine analogues with potent antimalarial activities

A series of alkylated (bis)urea and (bis)thiourea polyamine analogues were synthesized and screened for antimalarial activity against chloroquine-sensitive and -resistant strains of Plasmodium falciparum in vitro. All analogues showed growth inhibitory activity against P. falciparum at less than 3 μM, with the majority having effective IC(50) values in the 100-650 nM range. Analogues arrested parasitic growth within 24 h of exposure due to a block in nuclear division and therefore asexual development. Moreover, this effect appears to be cytotoxic and highly selective to malaria parasites (>7000-fold lower IC(50) against P. falciparum) and is not reversible by the exogenous addition of polyamines. With this first report of potent antimalarial activity of polyamine analogues containing 3-7-3 or 3-6-3 carbon backbones and substituted terminal urea- or thiourea moieties, we propose that these compounds represent a structurally novel class of antimalarial agents.     

Physicochemical Properties and Pharmacological Activity of Mn(II), Fe(II), Co(II), Cu(II), AND Zn(II) Gluconates

Pharmaceutical Chemistry Journal -     

Complexes between pilocarpine and cobalt(II), nickel(II), copper(II), and zinc(II) ions

The properties of pilocarpine as a ligand toward the halides of cobalt(II), nickel(II), copper(II), and zinc(II) were investigated. Pilocarpine behaved as a monodentate ligand, giving rise to compounds with the general formula methyl(pilocarpine)2X2. The coordinating geometry at the metal ion was pseudotetrahedral in every case. PMR studies showed that the pyridine-type nitrogen of the imidazole ring of pilocarpine was the donor atom of the ligand.     

Synthesis and evaluation of 1,omega-diaryl-l,omega-alkanediamines related to the fibrinolytic bis(tetrahydroisoquinolines) and bis(benzylamines).

Since the previously investigated bis(tetrahydroisoquinolines) 1 and bis(benzylamines) 2 may be classified as 1,omega-diaryl-1,omega-alkanediamines, it appeared worthwhile to examine this structural concept as a guideline for predicting significant fibrinolytic activity. The prototype bis compounds 7, 14, 15, and 29-31, which were synthesized for this purpose, incorporate such molecular modifications as replacement of the tetrahydroisoquinoline nuclei of series 1 with tetrahydrobenzazepine (7) and tetrahydropyridoindole (14-15) nuclei. The latter compounds, as well as 29-31 which possess features common to both series 1 and 2, showed good to moderate activity in the standard rat (ip) screen. Significant departures from the 1,omega-diaryl-1,omega-alkanediamine structural concept led to compounds (35 and 40) of weak to moderate activity.     

青蒿素类似物的研究 Ⅶ.双(二氢青蒿素)醚和双(二氢脱氧青蒿素)醚类化合物的合成

Some ethers, of bis(dihydroqinghaosu) Ⅲ and bis(dihydrodeoxyqinghaosu) Ⅳ were prepared in order to study the structure-activity relationships and to search for new antimalarials. Compounds Ⅲ were sythesized by condensation of glycol with two moles of dihydroqinghaosu using boron trifluoride etherate as catalyst. Compounds Ⅳ were prepared from ethers of bis (dihydroqinghaosu) by reduction with zinc and acetic acid.The bis-ethers were evaluated against chloroquine-resistant strain of plasmodium berghei in mice. Compounds Ⅲ were less potent than methyl-dihydroqinghaosu (Ⅰ) and compounds Ⅳ were inactive.     

The immunopharmacology of paclitaxel (Taxol), docetaxel (Taxotere), and related agents

Paclitaxel (Taxol) and docetaxel (Taxotere) are among the most unique, and successful, chemotherapeutic agents used for the treatment of breast and ovarian cancer. Both agents have anti-mitotic properties derived from binding to tubulin and excessive stabilization of microtubules. Their anti-neoplastic effects derive from this mechanism. Distinct from their effects on microtubule stabilization, paclitaxel, docetaxel, and related taxanes display immunopharmacological traits. In this review, we discuss their induction of pro-inflammatory genes and proteins; the current hypotheses on the molecular mechanism for this induction, especially its relationship to the lipopolysaccharide (LPS) signaling pathway. We also discuss the structure-activity relationships (SAR) that govern gene induction, especially the striking differences between the SAR for murine and human cells in vitro. Lastly, we discuss the immunopharmacological traits of paclitaxel and docetaxel in terms of their relevance to human clinical pharmacology and toxicology and their activity in animal models of autoimmune disorders.     

Synthesis and Characterization of Cr(III), Mn(III), Fe(III), VO(IV), Zr(IV) and UO2(VI) Complexes of Schiff Base Derived from Isonicotinoyl Hydrazone

2-hydroxy-5-chloro-3-nitroacetophenone isonicotinoyl hydrazone as a Schiff base ligand and its complexes with Cr(III), Mn(III), Fe(III), VO(IV), Zr(IV) and UO₂(VI) metal ions have been synthesized. The ligands as well as their metal complexes were well characterized using various physicochemical techniques such as elemental analyses, molar conductance measurements, magnetic measurements, thermal analysis, electronic and IR spectral studies. On the basis of these studies, square pyramidal stereochemistry for Mn(III) and VO(IV) complexes while octahedral stereochemistry for all the other complexes have been suggested. The complexes were found to be stable up to 60-70° and thermal decomposition of the complexes ended with respective metal oxide as a final product. The thermal data have been analyzed for kinetic parameters using Broido and Horowitz-Metzger methods. The synthesized Schiff base ligand and its complexes were also tested for their antimicrobial activity using various microorganisms.