Preferential inhibition of xanthine oxidase by 2-amino-6-hydroxy-8-mercaptopurine and 2-amino-6-purine thiol

<p>Abstract</p> <p>Background</p> <p>The anticancer drug, 6-mercaptopurine (6MP) is subjected to metabolic clearance through xanthine oxidase (XOD) mediated hydroxylation, producing 6-thiouric acid (6TUA), which is excreted in urine. This reduces the effective amount of drug available for therapeutic efficacy. Co-administration of allopurinol, a suicide inhibitor of XOD, which blocks the hydroxylation of 6MP inadvertently enhances the 6MP blood level, counters this reduction. However, allopurinol also blocks the hydroxylation of hypoxanthine, xanthine (released from dead cancer cells) leading to their accumulation in the body causing biochemical complications such as xanthine nephropathy. This necessitates the use of a preferential XOD inhibitor that selectively inhibits 6MP transformation, but leaves xanthine metabolism unaffected.</p> <p>Results</p> <p>Here, we have characterized two such unique inhibitors namely, 2-amino-6-hydroxy-8-mercaptopurine (AHMP) and 2-amino-6-purinethiol (APT) on the basis of IC₅₀values, residual activity in bi-substrate simulative reaction and the kinetic parameters like <it>K</it>_m, <it>K</it>_i, <it>k</it>_cat. The IC₅₀values of AHMP for xanthine and 6MP as substrate are 17.71 ± 0.29 μM and 0.54 ± 0.01 μM, respectively and the IC₅₀values of APT for xanthine and 6MP as substrates are 16.38 ± 0.21 μM and 2.57 ± 0.08 μM, respectively. The <it>K</it>_ivalues of XOD using AHMP as inhibitor with xanthine and 6MP as substrate are 5.78 ± 0.48 μM and 0.96 ± 0.01 μM, respectively. The <it>K</it>i values of XOD using APT as inhibitor with xanthine and 6MP as substrate are 6.61 ± 0.28 μM and 1.30 ± 0.09 μM. The corresponding <it>K</it>_mvalues of XOD using xanthine and 6MP as substrate are 2.65 ± 0.02 μM and 6.01 ± 0.03 μM, respectively. The results suggest that the efficiency of substrate binding to XOD and its subsequent catalytic hydroxylation is much superior for xanthine in comparison to 6MP. In addition, the efficiency of the inhibitor binding to XOD is much more superior when 6MP is the substrate instead of xanthine. We further undertook the toxicological evaluation of these inhibitors in a single dose acute toxicity study in mice and our preliminary experimental results suggested that the inhibitors were equally non-toxic in the tested doses.</p> <p>Conclusion</p> <p>We conclude that administration of either APT or AHMP along with the major anti-leukemic drug 6MP might serve as a good combination cancer chemotherapy regimen.</p

Two unusual neuro-psychiatric manifestations of malaria in a tertiary care hospital: a review of literature

Malaria, a highly prevalent parasitic disease in tropical country, have some atypical neuro-psychiatric manifestations seen in both vivax and falciparum malaria. We are reporting two cases of unusual neuro-psychiatric manifestations of malaria admitted in our hospital, one with intralobar haemorrhage and other with atypical psychiatric features. The rarity of the presentation has been highlighted with possible pathogenesis discussed after literature review

Magnetic Clusters in Mictomagnetic Copper - Manganese Alloys

322 p.Thesis (Ph.D.)--University of Illinois at Urbana-Champaign, 1974.U of I OnlyRestricted to the U of I community idenfinitely during batch ingest of legacy ETD

Spectra of centrosymmetric rare earth complexes: Pr<SUP>3+</SUP> (HAPI) single crystal

Polarized low-temperature absorption spectrum of centrosymmetric Pr<SUP>3+</SUP>-antipyrene tri-iodide single crystal has been recorded. Electronic transitions to the <SUP>1</SUP>D2 and <SUP>3</SUP>P<SUB>0</SUB>,<SUB>1</SUB>,<SUB>2</SUB> states have been found to be forbidden. Associated vibronic lines have been analyzed. Lattice, metal-ligand, and ligand internal (such as C=0) modes appear in the spectrum. Crystal field parameters have been evaluated and found to be large. Participation of &#8719; electrons in the bonding has been suggested

Spectra of centrosymmetric rare-earth complexes: Nd<SUP>3+</SUP>-hexakis-antipyrine tri-iodide single crystals

Polarized absorption spectra of centrosymmetric neodymium hexakis-antipyrine tri-iodide single crystals at 77 and 20&#176; K have been discussed. The spectrum is complicated by the appearance of a large number of vibronic lines. A phase transition destroying the inversion symmetry occurs between 77 and 20&#176;K and this was used as a tool to locate the 0-0 lines. Some of the 0-0 lines have been shown to be magnetic dipole allowed. The calculated crystal-field parameters (Stevens) are B20=200 cm-1; B40=-130 cm-1; B60=60 cm-1; B43=3250 cm-1; B63=1000 cm-1; B66=400 cm-1

Love wave in porous layer under initial stress over heterogeneous elastic half-space under gravity and initial stress

En este trabajo se estudió el efecto de las tensiones iniciales y la gravedad sobre la propagación de las ondas de Love, lo anterior en la superficie de una capa porosa sobre un semiespacio heterogéneo. Se consideraron dos tipos de límite en superficies libres: (a) límite rígido y (b) límite libre de tracción. La propagación de las ondas de Love ha sido investigada bajo supuestos medios, tanto en los casos de frontera como en un estudio comparativo de dos casos. En ambos, se obtuvieron las ecuaciones de dispersión y las velocidades de fase. Se presentan los cálculos numéricos de forma gráfica. Este estudio de las ondas de Love en el medio supuesto revela que la presencia de tensión inicial en el medio espacio y la ausencia de tensión inicial en la capa, el desplazamiento de la velocidad de fase en un límite rígido es mayor que el límite libre de tracción. doi: https://doi.org/10.22201/igeof.00167169p.2021.60.3.191

A simple method for the removal of 4-methoxybenzyl group

90-92Removal of 4-methoxybenzyl group from a series of compounds having various protecting groups has been achieved by treatment with 80% acetic acid in water at 80° C for 4 hours</span