ascorbic-acid and indole

Indoloquinoline (IQ) is an important class of naturally occurring antimalarial alkaloids, mainly represented by cryptolepine, isocryptolepine, and neocryptolepine. The IQ structural framework consists of four isomeric ring systems differing via the linkage of indole with quinoline as [3,2-b], [3,2-c], [2,3-c], and [2,3-b]. Structurally, IQs are planar and thus they bind strongly to the DNA which largely contributes to their biological properties. The structural rigidity and associated nonspecific cellular toxicity is a key shortcoming of the IQ structural framework for preclinical development. Thus, the lead optimization efforts were aimed at improving the therapeutic window and ADME properties of IQs. The structural modifications mainly involved attaching the basic aminoalkyl chains that positively modulates the vital physicochemical and topological parameters, thereby improves biological activity. Our analysis has found that the aminoalkylation consistently improved the selectivity index and provided acceptable in-vivo antimalarial/anticancer activity. Herein, we critically review the role of aminoalkylation in deciphering the antimalarial and cytotoxic activity of IQs.

Topics: Alkaloids; Antimalarials; Antineoplastic Agents; Cell Proliferation; Indoles; Malaria; Molecular Structure; Neoplasms; Quinolines

Streptococcus tigurinus is responsible for severe invasive infections such as infective endocarditis, spondylodiscitis and meningitis. As described, S. tigurinus isolates AZ_3aT and AZ_14 were highly virulent (HV phenotype) in an experimental model of infective endocarditis and showed enhanced adherence and invasion of human endothelial cells when compared to low virulent S. tigurinus isolate AZ_8 (LV phenotype). Here, we sought whether genetic determinants could explain the higher virulence of AZ_3aT and AZ_14 isolates. Several genetic determinants specific to the HV strains were identified through extensive comparative genomics amongst which some were thought to be highly relevant for the observed HV phenotype. These included i) an iron uptake and metabolism operon, ii) an ascorbate assimilation operon, iii) a newly acquired PI-2-like pilus islets described for the first time in S. tigurinus, iv) a hyaluronate metabolism operon, v) an Entner-Doudoroff pathway of carbohydrates metabolism, and vi) an alternate pathways for indole biosynthesis. We believe that the identified genomic features could largely explain the phenotype of high infectivity of the two HV S. tigurinus strains. Indeed, these features include determinants that could be involved at different stages of the disease such as survival of S. tigurinus in blood (iron uptake and ascorbate metabolism operons), initial attachment of bacterial pathogen to the damaged cardiac tissue and/or vegetation that formed on site (PI-2-like pilus islets), tissue invasion (hyaluronate operon and Entner-Doudoroff pathway) and regulation of pathogenicity (indole biosynthesis pathway).

Topics: Ascorbic Acid; Bacterial Adhesion; Biological Transport; Genomics; Hyaluronic Acid; Indoles; Iron; Molecular Sequence Annotation; Phenotype; Proteomics; Species Specificity; Streptococcus; Tryptophan; Virulence

Differential pulse voltammetry and more recently cyclic voltammetry have been successfully used to monitor basal levels of endogenous chemicals by means of treated carbon fibre microbiosensors inserted in specific brain regions. In this study, feasibility of concomitant in vivo recordings of stable electrophysiological signals and basal ascorbate, catecholaminergic and indolaminergic voltammetric peaks at the same cerebral site by means of a single electrically treated carbon fibre micro electrode (microbiosensor) is presented. The results indicate that these two independent techniques can be combined in vivo at a single electrode, and that voltammetric measurements of unstimulated levels of extracellular compounds do not alter concomitant basal cell firing for a period long enough (more than 6 h) to allow pharmacological manipulations.

Topics: 3,4-Dihydroxyphenylacetic Acid; Animals; Ascorbic Acid; Biosensing Techniques; Brain; Carbon; Carbon Fiber; Catechols; Electric Stimulation; Electrodes, Implanted; Electrophysiology; Feasibility Studies; Hydroxyindoleacetic Acid; Indoles; Microelectrodes; Nucleus Accumbens; Rats