α‑Glucosidase Inhibitors from Preussia minimoides Rangel-Grimaldo, Manuel; Rivero-Cruz, Isabel; Madariaga-Mazón, Abraham ...
Journal of natural products (Washington, D.C.),
03/2017, Letnik:
80, Številka:
3
Journal Article
Recenzirano
Extensive fractionation of an extract from the grain-based culture of the endophytic fungus Preussia minimoides led to the isolation of two new polyketides with novel skeletons, minimoidiones A (1) ...and B (2), along with the known compounds preussochromone C (3), corymbiferone (4), and 5-hydroxy-2,7-dimethoxy-8-methylnaphthoquinone (5). The structures of 1 and 2 were elucidated using 1D and 2D NMR data analysis, along with DFT calculations of 1H NMR chemical shifts. The absolute configuration of 1 was established by a single-crystal X-ray diffraction analysis and TDDFT-ECD calculations. Compounds 1–4 significantly inhibited yeast α-glucosidase.
Salvinorin A is the main bioactive compound in Salvia divinorum, an endemic plant with ancestral use by the inhabitants of the Mazateca mountain range (Sierra Mazateca) in Oaxaca, México. The main ...use of la pastora, as locally known, is in spiritual rites due to its extraordinary hallucinogenic effects. Being the first known nonalkaloidal opioid-mediated psychotropic molecule, salvinorin A set new research areas in neuroscience. The absence of a protonated amine group, common to all previously known opioids, results in a fast metabolism with the concomitant fast elimination and swift loss of activity. The worldwide spread and psychotropic effects of salvinorin A account for its misuse and classification as a drug of abuse. Consequently, salvinorin A and Salvia divinorum are now banned in many countries. Several synthetic efforts have been focused on the improvement of physicochemical and biological properties of salvinorin A: from total synthesis to hundreds of analogues. In this Review, we discuss the impact of salvinorin A in chemistry and neuroscience covering the historical relevance, isolation from natural sources, synthetic efforts, and pharmacological and safety profiles. Altogether, the chemistry behind and the taboo that encloses salvinorin A makes it one of the most exquisite naturally occurring drugs.
From an extract prepared from the grain-based culture of Malbranchea flavorosea two new polyketides, namely, 8-chloroxylarinol A (1) and flavoroseoside (2), along with the known compounds xylarinol A ...(3), xylarinol B (4), massarigenins B and C (5 and 6), and clavatol (7), were isolated. The structures of 1 and 2 were elucidated using spectroscopic methods and corroborated by single-crystal X-ray diffraction analysis. In the case of compound 2 the absolute configuration at the stereogenic centers was established according to the method of Flack. In addition, the X-ray structure of compound 6 is reported for the first time. Compounds 3, 4, and 6 significantly inhibited yeast α-glucosidase. Compound 6 also inhibited the postprandial peak during an oral sucrose tolerance assay when tested in vivo, using normal and NA/STZ-induced hyperglycemic mice.
Calmodulin Inhibitors from Natural Sources: An Update Mata, Rachel; Figueroa, Mario; González-Andrade, Martín ...
Journal of natural products (Washington, D.C.),
03/2015, Letnik:
78, Številka:
3
Journal Article
Recenzirano
Calmodulin (CaM) plays a central role in regulating a myriad of cellular functions in physiological and pathophysiological processes, thus representing an important drug target. In previous reviews, ...our group has reported relevant information regarding natural anti-CaM compounds up to 2009. Natural sources continue to provide a diverse and unique reservoir of CaM inhibitors for drug and research tool discovery. This review provides an update of natural products with reported CaM inhibitory properties, which includes around 70 natural products and some synthetic analogues, belonging to different structural classes. Most of these natural inhibitors were isolated from fungi and plants and belong to the stilbenoid, polyketide, alkaloid, and peptide structural classes. These products were discovered mainly using a fluorescence-based method on rationally designed biosensors, which are highly specific, low-cost, and selective and have short reaction times. The effect of several antimitotic drugs on Ca2+-hCaM is also described.
•μ-OR biased agonists represent promising analgesics with improved therapeutic profiles.•Protein-ligand interactions might account for biased ligands functional selectivity.•Databases of μ-OR ligands ...may be a valuable source to rescue missing biased agonists.
Biased activation of G-protein-coupled receptors (GPCRs) is shifting drug discovery efforts and appears promising for the development of safer drugs. The most effective analgesics to treat acute pain are agonists of the μ opioid receptor (μ-OR), a member of the GPCR superfamily. However, the analgesic use of opioid drugs, such as morphine, is hindered by adverse effects. Only a few μ-OR agonists have been reported to selectively activate the Gi over β-arrestin signaling pathway, resulting in lower gastrointestinal dysfunction and respiratory suppression. Here, we discuss the strategies that led to the development of biased μ-OR agonists, and potential areas for improvement, with an emphasis on structural aspects of the ligand–receptor recognition process.
Compound 3, a trimeric anthranilic acid peptide, and another three metabolites were isolated from an organic extract from the culture medium of Malbranchea flocciformis ATCC 34530. The chemical ...structure proposed previously for 3 was unequivocally assigned via synthesis and X‐ray diffraction analysis. Tripeptide 3 showed insulinotropic properties by decreasing the postprandial peak in healthy and hyperglycemic mice. It also increased glucose‐induced insulin secretion in INS‐1E at 5 μM, specifically at higher glucose concentrations. These results revealed that 3 might act as an insulin sensitizer and a non‐classical insulin secretagogue. Altogether, these findings are in harmony with the in vivo oral glucose tolerance test and acute oral hypoglycemic assay. Finally, the chemical composition of the extract was established by the Global Natural Products Social Molecular Network platform. Phylogenetic analysis using the internal transcribed spacer region revealed that M. flocciformis ATCC 34530 is related to the Malbrancheaceae.
Bioassay-guided fractionation of an extract prepared from the culture medium and mycelium of Purpureocillium lilacinum allowed the isolation of two calmodulin (CaM) inhibitors, namely, acremoxanthone ...C (1) and acremonidin A (2). The absolute configuration of 1 was established as 2R, 3R, 1′S, 11′S, and 14′R through extensive NMR spectroscopy and molecular modeling calculations at the DFT B3LYP/DGDZVP level, which included the comparison between theoretical and experimental specific rotation, 3 J C,H, and 3 J H,H values. Compounds 1 and 2 bind to the human calmodulin (hCaM) biosensor hCaM M124C-mBBr, with dissociation constants (K d) of 18.25 and 19.40 nM, respectively, 70-fold higher than that of chlorpromazine (K d = 1.24 μM), used as positive control. Docking analysis using AutoDock 4.2 predicted that 1 and 2 bind to CaM at a similar site to that which KAR-2 binds, which is unusual. Furthermore, a novel, sensible, and specific fluorescent biosensor of hCaM, i.e., hCaM T110C-mBBr, was constructed; this device is labeled at a site where classical inhibitors do not interact and was successfully applied to measure the interaction of 1 with CaM. This is the first report of xanthone–anthraquinone heterodimers in species of Paecilomyces or Purpureocillium genera.
Opioids are potent painkillers, however, their therapeutic use requires close medical monitoring to diminish the risk of severe adverse effects. The G-protein biased agonists of the μ-opioid receptor ...(MOR) have shown safer therapeutic profiles than non-biased ligands. In this work, we performed extensive all-atom molecular dynamics simulations of two markedly biased ligands and a balanced reference molecule. From those simulations, we identified a protein–ligand interaction fingerprint that characterizes biased ligands. Then, we built and virtually screened a database containing 68,740 ligands with proven or potential GPCR agonistic activity. Exemplary molecules that fulfill the interacting pattern for biased agonism are showcased, illustrating the usefulness of this work for the search of biased MOR ligands and how this contributes to the understanding of MOR biased signaling.
This work aimed to discover protein tyrosine phosphatase 1B (PTP1B) inhibitors from a small molecule library of natural products (NPs) derived from selected Mexican medicinal plants and fungi to find ...new hits for developing antidiabetic drugs. The products showing similar IC
50
values to ursolic acid (UA) (positive control, IC
50
= 26.5) were considered hits. These compounds were canophyllol (
1
), 5-
O
-(β-D-glucopyranosyl)-7-methoxy-3′,4′-dihydroxy-4-phenylcoumarin (
2
), 3,4-dimethoxy-2,5-phenanthrenediol (
3
), masticadienonic acid (
4
), 4′,5,6-trihydroxy-3′,7-dimethoxyflavone (
5
),
E
/
Z
vermelhotin (
6
), tajixanthone hydrate (
7
), quercetin-3-
O
-(6″-benzoyl)-β-D-galactoside (
8
), lichexanthone (
9
), melianodiol (
10
), and confusarin (
11
). According to the double-reciprocal plots,
1
was a non-competitive inhibitor,
3
a mixed-type, and
6
competitive. The chemical space analysis of the hits (IC
50
< 100 μM) and compounds possessing activity (IC
50
in the range of 100–1,000 μM) with the BIOFACQUIM library indicated that the active molecules are chemically diverse, covering most of the known Mexican NPs’ chemical space. Finally, a structure–activity similarity (SAS) map was built using the Tanimoto similarity index and PTP1B absolute inhibitory activity, which allows the identification of seven scaffold hops, namely, compounds
3
,
5
,
6
,
7
,
8
,
9
, and
11
. Canophyllol (
1
), on the other hand, is a true analog of UA since it is an SAR continuous zone of the SAS map.
Natural products are an invaluable source of molecules with a large variety of biological activities. Interest in natural products in drug discovery is documented in an increasing number of ...publications of bioactive secondary metabolites. Among those, medicinal plants are one of the most studied for this endeavor. An ever thriving area of opportunity within the field concerns the discovery of antidiabetic natural products. As a result, a vast amount of secondary metabolites are isolated from medicinal plants used against diabetes mellitus but whose information has not been organized systematically yet. Several research articles enumerate antidiabetic compounds, but the lack of a chemical database for antidiabetic metabolites limits their application in drug development. In this work, we present DiaNat-DB, a comprehensive collection of 336 molecules from medicinal plants reported to have
in vitro
or
in vivo
antidiabetic activity. We also discuss a chemoinformatic analysis of DiaNat-DB to compare antidiabetic drugs and natural product databases. To further explore the antidiabetic chemical space based on DiaNat compounds, we searched for analogs in ZINC15, an extensive database listing commercially available compounds. This work will help future analyses, design, and development of new antidiabetic drugs. DiaNat-DB and its ZINC15 analogs are freely available at
http://rdu.iquimica.unam.mx/handle/20.500.12214/1186
.
Medicinal plants are widely used against diabetes mellitus. Here, we provide DiaNat-DB, the first publicly available database of secondary metabolites from medicinal plants, chemically characterized, and integrated with antidiabetic activity.
PDF
