Determination of the absolute configuration of bioactive indole-containing pyrazino[2,1-b]quinazoline-3,6-diones and study of their in vitro metabolic profile

In recent decades, fungi-derived naturally occurring quinazolines have emerged as potential drug candidates. Nevertheless, most studies are conducted for bioactivity assays, and little is known about their absorption, distribution, metabolism, and elimination (ADME) properties. To perform metabolic studies, the synthesis of the naturally occurring quinazolinone, fiscalin B (1), and its chloro derivative, 4-((1H-indol-3-yl)methyl)-8,10-dichloro-1-isobutyl-1,2-dihydro-6H-pyra-zino[2,1-b]quinazoline-3,6(4H)-dione (2), disclosed as an antibacterial agent, was performed in a gram scale using a microwave-assisted polycondensation reaction with 22% and 17% yields, respec-tively. The structure of the non-natural (+)-fiscalin B was established, for the first time, by X-ray crystallography as (1R,4S)-1, and the absolute configuration of the naturally occurring fiscalin B (- )-1 was confirmed by comparison of its calculated and experimental electronic circular dichroism (ECD) spectra as (1S,4R)-1. In vitro metabolic studies were monitored for this class of natural products for the first time by ultra-high-performance liquid chromatography (UHPLC) coupled with high-resolution mass spectrometry (HRMS). The metabolic characteristics of 1 and 2 in human liver microsomes indicated hydration and hydroxylation mass changes introduced to the parent drugs.This research was supported by national funds provided by FCT—Foundation for Science and Technology and European Regional Development Fund (ERDF) and COMPETE under the Strategic Funding of CIIMAR UIDB/04423/2020 (Group of Natural Products and Medicinal Chemistry-CIIMAR) and LAQV-REQUIMTE (UIDB/50006/2020) and the project PTDC/SAU-PUB/28736/2017 (Reference: POCI-01–0145-FEDER-028736), as well as CHIRALBIOACTIVE-PI-3RL-IINFACTS-2019. This work is also a result of the project ATLANTIDA (Reference: NORTE-01-0145-FEDER-000040), supported by the Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement and through the European Regional Development Fund (ERDF). Additionally, this research was supported by the Agency for the Improvement of Higher Education Personnel (CAPES) (Finance Code 001), National Council for Scientific and Technological Development (CNPq) (Grant Number 406064/2018-05), São Paulo Research Foundation (FAPESP) (Grant Number: 2020/05965-8 and Ph.D. scholarships 2018/03035-3 and 2019/15040-4)

Transcriptional responses underlying the hormetic and detrimental effects of the plant secondary metabolite gossypol on the generalist herbivore Helicoverpa armigera

<p>Abstract</p> <p>Background</p> <p>Hormesis is a biphasic biological response characterized by the stimulatory effect at relatively low amounts of chemical compounds which are otherwise detrimental at higher concentrations. A hormetic response in larval growth rates has been observed in cotton-feeding insects in response to increasing concentrations of gossypol, a toxic metabolite found in the pigment glands of some plants in the family Malvaceae. We investigated the developmental effect of gossypol in the cotton bollworm, <it>Helicoverpa armigera</it>, an important heliothine pest species, by exposing larvae to different doses of this metabolite in their diet. In addition, we sought to determine the underlying transcriptional responses to different gossypol doses.</p> <p>Results</p> <p>Larval weight gain, pupal weight and larval development time were measured in feeding experiments and a hormetic response was seen for the first two characters. On the basis of net larval weight gain responses to gossypol, three concentrations (0%, 0.016% and 0.16%) were selected for transcript profiling in the gut and the rest of the body in a two-color double reference design microarray experiment. Hormesis could be observed at the transcript level, since at the low gossypol dose, genes involved in energy acquisition such as β-fructofuranosidases were up-regulated in the gut, and genes involved in cell adhesion were down-regulated in the body. Genes with products predicted to be integral to the membrane or associated with the proteasome core complex were significantly affected by the detrimental dose treatment in the body. Oxidoreductase activity-related genes were observed to be significantly altered in both tissues at the highest gossypol dose.</p> <p>Conclusions</p> <p>This study represents the first transcriptional profiling approach investigating the effects of different concentrations of gossypol in a lepidopteran species. <it>H. armigera</it>'s transcriptional response to gossypol feeding is tissue- and dose-dependent and involves diverse detoxifying mechanisms not only to alleviate direct effects of gossypol but also indirect damage such as pH disturbance and oxygen radical formation. Genes discovered through this transcriptional approach may be additional candidates for understanding gossypol detoxification and coping with gossypol-induced stress. In a generalist herbivore that has evolved transcriptionally-regulated responses to a variety of different plant compounds, hormesis may be due to a lower induction threshold of growth-promoting, stress-coping responses and a higher induction threshold of detoxification pathways that are costly and cause collateral damage to the cell.</p

The role of ion pairing in the chromatographic study of propranolol analogues

The partition coefficients, log P-app(RPLC), for a series of propranolol analogues have been determined by reversed phase high performance liquid chromatography. The hydrochloride salts and free base log P-app(RPLC) show that charged and uncharged species can partition into the reversed phase. An extrathermodynamic relationship was found for log P-app(RPLC) measured in two different column stationary phases, C8 and PMOS, suggesting that the same sei of compounds experience a similar trend in these elution systems. The importance of using phosphate and/or MOPS buffer is due to the fact that the latter can avoid ion-pairing partitioning, but the former does play the same role for PMOS column when the free base is considered.5341671111

Classification of commercial catuaba samples by NMR, HPLC and chemometrics

For over a century, Catuaba has been used in Brazilian folk medicine as an aphrodisiac even though the identity of the plant material employed is often uncertain. The species recommended by the Brazilian Pharmacopeia is Anemopaegma arvense (Bignoniaceae), but many other plants, regionally known as Catuaba, are commiercialised. Frequently, the quality control of such a complex system is based on chemical markers that do not supply a general idea of the system. With the advent of the metabolomics approach, a global analysis of samples becomes possible. It appears that H-1-NMR is the most useful method for such application, since it can be used as a wide-spectrum chemical analysis technique. Unfortunately, the generated spectra is complex so a possible approach is to look at the metabolite profile as a whole using multivariate methods, for example, by application of principal component analysis (PCA). In the present paper, we describe for the first time a proton high-resolution magic angle spinning nuclear magnetic resonance (H-1-HR-MAS NMR) method coupled with PCA for the metabolomic analysis of some commercial Catuaba samples, which provided a reduction in the time required for such analysis. A comparative study of HPLC, HR-MAS and liquid-NMR techniques is also reported. Copyright (c) 2007 John Wiley & Sons, Ltd.19321822

The use of the generator coordinate method for designing basis set. Application to oxo-diperoxo molybdenum complexes

The molecular and electronic structures of MoO(O(2))(2) (1), MoO(O(2))(2)(OPY) (2) and MOO(O(2))(2)(OPY)(H(2)O) (3) complexes were investigated at the Hartree-Fock and density functional method (B3LYP) calculation levels. The generator coordinate method (GCM) has been used to design basis sets that properly represent the electronic density on the Mo and O atoms for all electron calculations, while a variant of the GCM method has been employed to design a valence basis set for the Mo atom for the pseudopotential calculations. Compound 1 adopts a distorted tetragonal pyramid structure, where the four peroxo oxygen atoms are located in the same plane, which is perpendicular to the axis defined by the Mo and oxo oxygen atoms. An analysis based upon the geometrical and electronic parameters and the vibrational frequencies renders that 1 can be described as two peroxide fragments bonded to the MoO moiety. 2 and 3 complexes are bipyramidal pentagonal structures, with the OPy ligand occupying a quasi-equatorial position in the same plane as the two peroxo triangles while the H(2)O ligand is situated trans to the oxo group in 3. A comparison between theoretical and experimental results for the geometry and vibrational frequencies of 3 complex shows good agreement. The relationship between the reactivity of 1, 2 and 3 complexes and their coordination number has been established by analyzing the values of the vibrational frequencies, frontier molecular orbitals and the values of electron affinities. (C) 2002 Elsevier Science B.V. All rights reserved.58925126

Albendazole sulfoxide enantiomers: Preparative chiral separation and absolute stereochemistry

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)The enantiomeric separation of albendazole sulfoxide was carried out by simulated moving bed chromatography with variable zones (VARICOL). An overall recovery of 97% was achieved and enantiomeric ratios of 99.5% for raffinate and 99.0% for extract were attained. A total of 880 mg of (+)-albendazol sulfoxide and 930 mg of its antipode were collected after 55 cycles or 11 h of process, resulting in a mass rate of 2 g/day. Furthermore the absolute configuration of the enantiopure compounds was determined for the first time by vibrational circular dichroism (VCD) with the aid of theoretical calculations as (-)-(S) and (+)-(R)-albendazole sulfoxide. (C) 2012 Elsevier B.V. All rights reserved.12306165Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Center for Scientific Computing (NCC/GridUNESP) of the Sao Paulo State University (UNESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)FAPESP [2009/18515-1, 2008/58658-3, 2009/17138-0, 2007/02872-4

Enantiomeric HPLC resolution and absolute stereochemistry assignment of a new poligamain derivative

A new aryltetralin lignan derivative, 1, was obtained by reacting dimethyl succinate and piperonal, furnishing the lactone 4-(3\u2032,4\u2032-methylenedioxybenzyl)-4,5-dihydro-2(3H)-furanone, which was reacted once again with piperonal and LDA to give the dibenzylbutirolactone 7-hydroxyhinokinin. The cyclization of 7-hydroxyhinokinin into polygamain occurred in the presence of trifluoroacetic acid. The reduction of the furanic ring of polygamain was done by its reaction with DIBAL in THF, furnishing the diol functionalized lignin derivative 1 as single diastereomer. The enantiomeric fractions of 1 were obtained by preparative enantioselective HPLC. The absolute stereochemistry was assigned by electronic circular dichroism (ECD) and nuclear magnetic resonance (NMR) spectroscopy. An all-trans relative configuration was determined by NMR on the bases of 1H coupling constants and nuclear Overhauser effect (n.O.e.) experiments. The absolute configuration at C1 was assigned on the basis of the ECD sign at 296 nm by comparison to the ECD spectra of structural analogues with defined stereochemistry. The assignment of the absolute configuration was confirmed by applying the exciton chirality method to the well-defined ECD couplets at 285 and 200 nm allied to the two electronic transitions Lb and Bb of the aromatic moieties, respectively. Rac-1 and its enantiomeric isomers were evaluated against important bacteria responsible for dental caries. The best results obtained for the (1R,2S,3S) isomer were against Streptococcus mutans (250 \u3bcM), Streptococcus salivarius (250 \u3bcM), Streptococcus sobrinus (280 \u3bcM) and Streptococcus mitis (280 \u3bcM). The (1S,2R,3R) isomer was active only against Streptococcus sanguinis (280 \u3bcM). The enantiomeric mixture was less active than the (1R,2S,3S) isomer