The molecular structure of asphaltene: an unfolding story

From detailed chemical and thermal degradation studies, a host of structural units have been identified in Alberta asphaltenes. It has been shown that the extent of aromatic condensation is low and that highly condensed pericyclic aromatic structures are present in very low concentrations. From the available data reported to date, it is concluded that petroleum asphaltenes were mainly derived through the catalytic cyclization, aromatization and condensation of n-alkanoic, probably fatty acids, precursors.     

Comparative psychology 25 years after.

Examined articles published in the Journal of Comparative and Physiological Psychology (JCPP) and Animal Behavior (AB) in the 25 yrs since F. A. Beach first surveyed the literature in 1950. In the JCPP, the number of species studied remained relatively low in view of the greatly increased number of articles published, while the reverse was true of AB, whose articles were also more diversified in terms of number of species. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Grapefruit juice increases felodipine oral availability in humans by decreasing intestinal CYP3A protein expression

The increase in oral availability of felodipine and other commonly used medications when taken with grapefruit juice has been assumed to be due to inhibition of CYP3A4, a cytochrome P450 that is present in liver and intestine. To evaluate the effect of repeated grapefruit juice ingestion on CYP3A4 expression, 10 healthy men were given 8 oz of grapefruit juice three times a day for 6 d. Before and after receiving grapefruit juice, small bowel and colon mucosal biopsies were obtained endoscopically, oral felodipine kinetics were determined, and liver CYP3A4 activity was measured with the [14C N-methyl] erythromycin breath test in each subject. Grapefruit juice did not alter liver CYP3A4 activity, colon levels of CYP3A5, or small bowel concentrations of P-glycoprotein, villin, CYP1A1, and CYP2D6. In contrast, the concentration of CYP3A4 in small bowel epithelia (enterocytes) fell 62% (P = 0.0006) with no corresponding change in CYP3A4 mRNA levels. In addition, enterocyte concentrations of CYP3A4 measured before grapefruit juice consumption correlated with the increase in Cmax when felodipine was taken with either the 1st or the 16th glass of grapefruit juice relative to water (r = 0. 67, P = 0.043, and r = 0.71, P = 0.022, respectively). We conclude that a mechanism for the effect of grapefruit juice on oral felodipine kinetics is its selective downregulation of CYP3A4 in the small intestine.     

Operant conditioning of heart rate in free-moving dogs

Measurements of total body water and total exchangeable sodium, by isotopic dilution, and of total body potassium by whole body counting of the naturally occurring 40K isotope, were performed on stabilised paraplegic or tetraplegic subjects. Nineteen patients were investigated by the complete set of tests, six by only body counting. The results of total body potassium are expressed, following a uniform scale, as "relative values", which were established by the processing of reference values, from numberous paired healthy subjects.     

Ventricular electrical instability in the conscious dog: effects of psychologic stress and beta adrenergic blockade

The effect of psychologic stress on cardiac vulnerability was examined in 10 conscious dogs. The repetitive extrasystole threshold was employed as a measure of susceptibility to ventricular fibrillation. Instrumental aversive conditioning constituted a stressful environment. The repetitive extrasystole threshold decreased by nearly 50 percent during 3 days in which the animals were exposed to the stressful environment. When Tolamolol hydrochloride, a cardioselective beta adrenoceptor blocking agent, was administered before a stress session, the repetitive extrasystole threshold was unaltered from the control value. Thus, stress-evoked changes in cardiac vulnerability are mediated through the sympathetic nervous system.     

Anthracycline and anthraquinone anticancer agents: current status and recent developments

The clinical treatment of neoplastic diseases relies on the complementary procedures of surgery, radiation treatment, immunotherapy and chemotherapy. The latter technique has matured from its earliest applications of mustard alkylating agents in the 1940s to an increasingly rationally based discipline, which is contributing significantly to the management of human malignancies. As the field of chemotherapy matured, several promising natural anticancer agents were identified. However, a more urgent need soon arose from the common experience of clinically limiting toxicities of most anticancer drugs, i.e. the necessity to develop less toxic clinical drug candidates. Thus, the medicinal chemist turned towards analog development involving certain anthraquinones. Hand-in-hand with this considerable synthetic effort, which uncovered several promising clinical leads, biochemical pharmacology, or study of the mechanisms of action of clinical anticancer agents, afforded deeper insight into drug metabolism and mode of action. More recently, therefore, the field of synthetic organic chemistry, which has been complemented by the methods of microbial chemistry, has been faced with new synthetic challenges, occasioned by the identification of hitherto unrecognized cellular targets for anticancer drugs, such as topoisomerases and helicases. The armementarium of the oncologist currently includes about 40-50 clinically useful chemical agents. The paradigm of cytotoxic anticancer agents is doxorubicin, an anthracycline, which is still amongst the most widely prescribed and effective of anticancer agents. The review attempts to summarize the discovery of anthracyclines and the elucidation of their several mechanisms of action and efforts towards improvement of their therapeutic efficacy.     

Pyrroloquinoline and pyridoacridine alkaloids from marine sources

Marine organisms are a rich source for natural products. Pyrrolo[4,3, 2-de]quinolines and pyrido[4,3,2-mn]acridines are of major interest as metabolites in sponges and ascidians. Many of these compounds have generated interest both as challenging problems for structure elucidation and synthesis as well as for their cytotoxicities. The isolation, structure proof, biological activities, chemical properties and synthesis have attracted the attention of chemists, biologists and pharmacists. The principal structural feature of these alkaloids is the core of a planar iminoquinone moiety which can intercalate into DNA and cleave the DNA double helix or inhibit the action of topoisomerase II. Of the makaluvamines, makaluvamine F and A are the most cytotoxic to the HCT 116 cell line. The enhanced toxicity of the makaluvamines towards xrs-6 cells shows that all of the makaluvamines, except makaluvamine B, act like m-AMSA and etoposide in inhibiting topo iso merases via cleavable complex formation, or via the direct induction of DNA double-strand breaks. They are also amongst the most potent inhibitors of topoisomerase II. Both makaluvamine A and C can decrease tumor size in a solid human tumor model. Discorhabdin A and C in contrast are of high cytotoxicity, but they exhibit no inhibition of topoisomerase II. As representatives of the derivatives of pyrido[4,3,2-mn]acridine, cystodytins, kuanoniamines and diplamine are the most potent to inhibit HCT replication. Eilatin, as a 1,10-phenanthroline derivative, can form complexes with metal ions. It has been shown that these metal complexes can bind to DNA by intercalation. The new members of the pyrrolo[4,3,2-de]quinolines and pyrido[4,3, 2-mn]acridines, such as veiutamine, discorhabdin G, tsitsikammamines, epinartins, arnoamines as well as sagitol are reviewed. Some successful syntheses of pyrrolo[4,3,2-de]quinoline ring system and pyrido[4,3,2-mn]acridine ring system are also reviewed in this article.