Acetyl Group In Position Research Articles

Formyl- and acetylindols: Vibrational spectroscopy of an expectably pharmacologically active compound family

In the peresent paper, indole and its seven derivatives were compared, namely 3-formylindole, 1-methyl-3-formylindole, 1-ethyl-3-formylindole, 3-acetylindole, 1-methyl-3-acetylindole, 1-ethyl-3-acetylindole and 1,3-diacetylindole. The substitution of indole in position 3 with aldehydes and with alkyl groups cause only minor changes in the molecular geometry, however, substantially larger alterations are found in the charge distribution and in the vibrational force constants. The appearance of the aldhyde groups increased the degree of association as it was observable on the shape of infrared NH stretching band and its shifts. The alkyl substitution shifts the aldehyde carbonyl stretch band frequencies to somewhat higher values. The effect of the second acetyl group in position 1 is not comparable with those of the 1-alkyl groups. The latter effect is observable in the molecular geometry, however, it is more pronounced in the changes of the net charge distribution, the vibrational force constants and the infrared spectra.

Molecular Determinant of Regioselective Hydroxylation of Docetaxel by CYP3A4

The metabolism of taxanes by human liver microsomes is regioselective: the major metabolite of paclitaxel formed by CYP2C8 results from the hydroxylation on the taxane ring at C-6. Hydroxylations on the lateral chain at C-13 are catalyzed by CYP3A4 on either the tert -butyl of docetaxel or the C-3’ phenyl of paclitaxel. Furthermore, the presence of the acetyl group in position 10, has been shown to play an important role in determining the regioselective oxidation by CYP. The biotransformation of a series of docetaxel analogues by human liver microsomes and recombinant CYP expressed in HEK293 cells was examined by high-performance liquid chromatography/mass spectrometry. The formation of derivatives was lost when the tert -butyl of docetaxel was replaced by an ethyl group. Addition of an aliphatic chain at either position 7 or 10 led to the formation of oxidized metabolites, whereas addition at both 7 and 10 totally impaired the production of derivatives. Similarly, the insertion of a phenylbenzoyl group in position 10 prevented the biotransformation of the molecule. The site of hydroxylation could be clearly located on the aliphatic chain inserted in position 10, but remained on the tert -butyl at C-13 when the aliphatic chain was added in position 7. These reactions were catalyzed only by CYP3A4: recombinant CYP3A4 generated the same metabolites as liver microsomes did, whereas neither CYP3A5 nor 2C8 or 2C9 could form derivatives. In conclusion, the presence of substituents in position 10 of the docetaxel molecule plays a pivotal role in determining the site of oxidation by CYP3A4.

(+)-Cyclazosin Derivatives as α1-Adrenoceptor Antagonists

The prazosin-related compound (+)-cyclazosin [(+)-1] is an α 1 -adrenoceptor antagonist with moderate selectivity for the α 1 b -adrenoceptor subtype (selectivity ratio: α 1 b /α 1 a = 90, α 1 b /α 1 d = 24). To improve its pharmacological profile, the novel chiral derivatives (+)-2-(+)-5, bearing a bromo, a methyl, a methoxy or an acetyl group in position 5 of the 2-furoyl moiety, were synthesized and evaluated for their α 1 -adrenoceptor blocking activity. All the compounds displayed, like (+)-1, high and preferential affinity for the α 1 b -adrenoceptor in binding and functional assays. Interestingly, in functional assays, compounds (+)-3 and (+)-4 showed, in comparison with (+)-1, an increase in the α 1 B /α 1 A selectivity (407 and 724 vs. 44), whereas compound (+)-5 exhibited an improved α 1 B / α 1 D selectivity (1513 vs. 138).

Regioselective metabolism of taxoids by human CYP3A4 and 2C8: structure-activity relationship.

Paclitaxel and docetaxel are metabolized by liver microsomal monooxygenases into inactive metabolites further eliminated from the body via the bile route. In spite of their close chemical structure, the two drugs are oxidized by two different enzymes; CYP2C8 catalyzes the 6-hydroxylation on the taxane ring of paclitaxel, whereas CYP3A4 oxidizes docetaxel on the tert-butyl group of the lateral chain in C13. Since paclitaxel and docetaxel differ only by two substitutions, the role of individual modifications was investigated; the regioselectivity of hydroxylation was assessed by high-pressure liquid chromatography/mass spectrometry, and enzymes implicated in individual reactions were identified using human liver microsomes and recombinant P450 expressed in Ad293 cells. The biotransformation of docetaxel, 10-deacetylpaclitaxel, and 10-deacetylbaccatin III was steadily increased (2- to 5-fold) by the addition of an acetyl group in position 10, suggesting that the presence of a hydrophobic group in position 10 stimulated hydroxylation by P450 proteins. The absence of the lateral chain at C13 in baccatin III severely impaired the metabolism supported by CYP3A4. The presence of a tert-butyl group in the lateral chain of docetaxel favored the hydroxylation on the tert-butyl by CYP3A4, whereas the presence of a phenyl group in the lateral chain facilitated the oxidation on the taxane ring by CYP2C8. Collectively, these data strongly suggested that the structure of the lateral chain and the nature of substituent in position 10 play an important role in determining the regioselective oxidation by P450 proteins and modulate the reaction rate by human liver microsomes.

N-substituted benzamides inhibit nuclear factor-κB and nuclear factor of activated T cells activity while inducing activator protein 1 activity in T lymphocytes

N-substituted benzamides are compounds that have recently been reported to inhibit nuclear factor-κB (NF-κB) activity and induce apoptosis in a pre-B cell line. In this study, we focused on the effects of N-substituted benzamides on transcriptional regulation in Jurkat T cells. We used a model system where the cells can be stimulated either through TCR/CD28 or by treatment of the cells with PMA and ionomycin to induce transcription factors typical for T lymphocyte activation. Treatment of the Jurkat cells with procainamide did not influence the transcription factor profile of stimulated cells, while treatment with a derivative having an acetyl group in position 4 of the aromatic ring inhibited NF-κB and nuclear factor of activated T cells (NFAT) activity. Declopramide, which contains a chloride in position 3 of the aromatic ring, was inactive in this system, whereas also the acetylated derivative of this compound inhibited NF-κB and NFAT activity. In contrast, the transcriptional activity and nuclear expression of activator protein 1 induced by TCR/CD28 stimulation or PMA and ionomycin treatment was enhanced by the acetylated variants of the N-substituted benzamides. Finally, we investigated the effect of N-substituted benzamides on intact promoters for two genes central in immune regulation; the CD40 ligand (CD40L) and IL-2 promoters. The transcriptional activity of the CD40L promoter as well as surface expression of the CD40L induced by signaling through TCR/CD28 was inhibited by addition of acetylated N-substituted benzamides, while the transcriptional activity of the IL-2 promoter was enhanced. Taken together, these data indicate that derivatives of N-substituted benzamides are potential drug candidates for quantitative as well as qualitative modulation of immune functions.

Analysis of side group motion in O-acetyl-starch using regioselective 2-O-acetyl-starches by means of dielectric spectroscopy

The complex dielectric constant of O-acetyl-starches with regioselective and the statistical distribution of substituents at the anhydroglucose unit (AGU) are measured in an extended frequency range from 10mHz to 2MHz and in the low temperature range from −120 to 0°C. The experimentally determined relaxation spectra are evaluated with the well-known model function of Havriliak–Negami for relaxation processes. In the case of 2-O-acetyl-starch two significant relaxations are detected which are associated with the orientational motion of the methylolgroup at the AGU and the acetylgroup in position C-2. The activation energies are 48 and 60kJ/mol, respectively. Owing to that assignment of relaxations at the AGU with acetylation in position C-2 has proved that it is possible to describe further relaxation processes in acetylated amylomaize starch with a statistical substitution pattern. It was found that an additional relaxation process is associated with the dynamics of the acetylgroup at the position C-6 at the AGU and characterized by a lower activation energy of 28kJ/mol.From the analytical point of view these results of dielectric spectroscopy analysis demonstrate that the mobility of the side groups depend significantly on the position at the AGU and the type of substituent in their frequency and temperature dependence.

New cucurbitacine glycosides fromGratiola officinalis L.

Eight new cucurbitacine glycosides were isolated from “hedgehyssop”Gratiola officinalis L. Their structures were determined by two-dimensional NMR techniques and mass spectrometry. For the first time cucurbitacine I derivatives with an acetyl group in position 16 are described.

Partial deacetylation of 1,6-anhydro-2,3,4-tri-O-acetyl-β-d-glucopyranose byAureobasidium pullulans cells

The ability of 58 yeasts and yeast-like organisms representing 44 genera to deacetylate 1,6-anhydro-2,3,4-tri-0-acetyl-β-d-glucopyranose was investigated.Aureobasidium pullulans strains can perform this deacetylation selectively.A. pullulans CCY 27-1-11 and 27-1-14 release preferentially the acetyl group in position C(4), whereas the subspeciesA. pullulans CCY 27-1-14a (with no pigmentation) preferentially releases the acetyl group in position C(2).A. pullulans cells catalyzing the selective deacetylation of 1,6-anhydro-2,3,4-tri-O-acetyl-β-D-glucopyranose were permeabilized and immobilized on a matrix of polyethyleneimine cross-linked with 2-chloromethyloxirane.

Influence of spatial effects on the oxidation of cardenolides and bufadienolides containing aldehyde groups

The reactivity of a number of aglycones and glycosides with a cardiac action containing a carbonyl group at C10 is considered. The study was based on the use of the oxidation reaction in the presence of diethylamine, the excess of which after the binding of the hydrochloric acid liberated in the reaction was backtitrated with percholoric acid in methanol. The rate constants of 15 compounds have been determined and it has been established that their reactivity depends on their structure: the nature of the linkage of the A/B rings of the steroid skeleton, the position of a double bond in it, the introduction of a sugar or acetyl group in position 3 of the aglycon, and the nature of the sugar.