Insights into the in Vitro and in Vivo SAR of Abscisic Acid - Exploring Unprecedented Variations of the Side Chain via Cross-Coupling-Mediated Syntheses

2018 ◽  
Vol 2018 (12) ◽  
pp. 1403-1415 ◽  
Author(s):  
Jens Frackenpohl ◽  
Erwin Grill ◽  
Guido Bojack ◽  
Rachel Baltz ◽  
Marco Busch ◽  
...  
Keyword(s):  
Abscisic Acid ◽  
Cross Coupling ◽  
Side Chain

scholarly journals d-Sedoheptulose-7-phosphate is a common precursor for the heptoses of septacidin and hygromycin B

2018 ◽  
Vol 115 (11) ◽  
pp. 2818-2823 ◽  
Author(s):  
Wei Tang ◽  
Zhengyan Guo ◽  
Zhenju Cao ◽  
Min Wang ◽  
Pengwei Li ◽  
...  
Keyword(s):  
Gene Cluster ◽  
Carbon Chain ◽  
Side Chain ◽  
Hygromycin B ◽  
Nucleoside Antibiotics ◽  
Common Precursor ◽  
Encoding Genes ◽  
Poultry Farming

Seven-carbon-chain–containing sugars exist in several groups of important bacterial natural products. Septacidin represents a group of l-heptopyranoses containing nucleoside antibiotics with antitumor, antifungal, and pain-relief activities. Hygromycin B, an aminoglycoside anthelmintic agent used in swine and poultry farming, represents a group of d-heptopyranoses–containing antibiotics. To date, very little is known about the biosynthesis of these compounds. Here we sequenced the genome of the septacidin producer and identified the septacidin gene cluster by heterologous expression. After determining the boundaries of the septacidin gene cluster, we studied septacidin biosynthesis by in vivo and in vitro experiments and discovered that SepB, SepL, and SepC can convert d-sedoheptulose-7-phosphate (S-7-P) to ADP-l-glycero-β-d-manno-heptose, exemplifying the involvement of ADP-sugar in microbial natural product biosynthesis. Interestingly, septacidin, a secondary metabolite from a gram-positive bacterium, shares the same ADP-heptose biosynthesis pathway with the gram-negative bacterium LPS. In addition, two acyltransferase-encoding genes sepD and sepH, were proposed to be involved in septacidin side-chain formation according to the intermediates accumulated in their mutants. In hygromycin B biosynthesis, an isomerase HygP can recognize S-7-P and convert it to ADP-d-glycero-β-d-altro-heptose together with GmhA and HldE, two enzymes from the Escherichia coli LPS heptose biosynthetic pathway, suggesting that the d-heptopyranose moiety of hygromycin B is also derived from S-7-P. Unlike the other S-7-P isomerases, HygP catalyzes consecutive isomerizations and controls the stereochemistry of both C2 and C3 positions.

STEROID BIOSYNTHESIS IN VITRO BY A VIRILIZING SUPRARENAL TUMOUR

1963 ◽  
Vol 44 (1) ◽  
pp. 1-7 ◽  
Author(s):  
Roversi G. D. ◽  
Polvani F. ◽  
Bompiani A. ◽  
Neher R.
Keyword(s):  
Adrenal Adenoma ◽  
Tumour Tissue ◽  
Side Chain ◽  
Steroid Biosynthesis ◽  
Before And After

ABSTRACT A case of virilizing adrenal adenoma is described. The tumour was incubated with progesterone-4-14C. In the extract the following steroids were identified chromatographically, in order of decreasing quantity and radioactivity: 17α-hydroxyprogesterone, androst-4-ene-3,17-dione, corticosterone (11β,21 -dihydroxy-pregn-4-ene-3,20-dione), cortisol (11β,17,21-trihydroxy-pregn-4-ene-3,20-dione) and 11-deoxycortisol. This indicates either an increase in 17α-hydroxylation and side chain split, or a partial blockage of 21-hydroxylation, or a combination of both in the tumour tissue. The absence of the 3β-hydroxy-dehydrogenase demonstrated histochemically in the tumour and the examination of the urinary 17-ketosteroids before and after removal of the neoplasm, suggested the same abnormal biosynthetic pattern in vivo with regard to the level of the endogenous Δ5-precursors.

scholarly journals Pyridyl-Ala Modified Cyclic Hexapeptides: In-Vitro and In-Vivo Profiling for Oral Bioavailability

2019 ◽  
Vol 26 (3) ◽  
pp. 1383-1397 ◽  
Author(s):  
Thomas Vorherr ◽  
Ian Lewis ◽  
Joerg Berghausen ◽  
Felix Huth ◽  
Michael Schaefer ◽  
...  
Keyword(s):  
Amino Acid ◽  
Oral Bioavailability ◽  
Side Chain ◽  
Pyridyl Nitrogen ◽  
Oral Uptake ◽  
Cyclic Hexapeptides ◽  
Chain Interaction

Abstract We and others have been aiming at modifications to maintain or to enhance solubility while enabling permeability for cyclic hexapeptides. Especially, the 2-pyridyl-Ala modification was investigated, since in this case, the pyridyl-nitrogen is able to form an H-bond to the NH of the same residue. The hypothesis of a backbone side-chain interaction was demonstrated by NMR experiments, and further results obtained on a variety of pyridyl-Ala derivatives, studied systematically in the context of permeability, are presented in this contribution. Thus, this study sheds some more light on the pyridyl-Ala modification, which had been reported earlier. In addition to the in vitro profiling, the extent of oral bioavailability was assessed in rats. In principle, the pyridyl-Ala residue can be considered as an amino acid supporting oral uptake. Graphic Abstract

scholarly journals Synthesis, CYP24A1-Dependent Metabolism and Antiproliferative Potential against Colorectal Cancer Cells of 1,25-Dihydroxyvitamin D2 Derivatives Modified at the Side Chain and the A-Ring

2020 ◽  
Vol 21 (2) ◽  
pp. 642
Author(s):  
Magdalena Milczarek ◽  
Michał Chodyński ◽  
Anita Pietraszek ◽  
Martyna Stachowicz-Suhs ◽  
Kaori Yasuda ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Vitamin D ◽  
Cancer Cells ◽  
Biologically Active ◽  
Side Chain ◽  
Anticancer Properties ◽  
Colorectal Cancer Cells ◽  
Ht 29

Experimental data indicate that low-calcemic vitamin D derivatives (VDDs) exhibit anticancer properties, both in vitro and in vivo. In our search for a vitamin D analog as potential anticancer agent, we investigated the influence of chirality in the side chain of the derivatives of 1,25-dihydroxyergocalciferol (1,25D2) on their activities. In this study, we synthesized modified analogs at the side chain and the A-ring, which differed from one another in their absolute configuration at C-24, namely (24S)- and (24R)-1,25-dihydroxy-19-nor-20a-homo-ergocalciferols (PRI-5105 and PRI-5106, respectively), and evaluated their activity. Unexpectedly, despite introducing double-point modifications, both analogs served as very good substrates for the vitamin D-hydroxylating enzyme. Irrespective of their absolute C-24 configuration, PRI-5105 and PRI-5106 showed relatively low resistance to CYP24A1-dependent metabolic deactivation. Additionally, both VDDs revealed a similar antiproliferative activity against HT-29 colorectal cancer cells which was higher than that of 1,25D3, the major biologically active metabolite of vitamin D. Furthermore, PRI-5105 and PRI-5106 significantly enhanced the cell growth-inhibitory activity of 5-fluorouracil on HT-29 cell line. In conclusion, although the two derivatives showed a relatively high anticancer potential, they exhibited undesired high metabolic conversion.

Side-chain amino acid based cationic polymer induced actin polymerization

2017 ◽  
Vol 5 (6) ◽  
pp. 1218-1226 ◽  
Author(s):  
Binoy Maiti ◽  
Priyanka Dutta ◽  
Soma Seal ◽  
Sunirmal Pal ◽  
Priyadarsi De ◽  
...  
Keyword(s):  
Amino Acid ◽  
Actin Filaments ◽  
Actin Polymerization ◽  
Cationic Polymer ◽  
Side Chain

A side-chain amino acid (alanine) based cationic polymer is able to nucleate, polymerize and stabilize actin filaments in vitro and in vivo.

Inhibitors of Acetylcholinesterase Derived from 7-Methoxytacrine and Their Effects on the Choline Transporter CHT1

2016 ◽  
Vol 43 (1-2) ◽  
pp. 45-58 ◽  
Author(s):  
Zdenka Kristofikova ◽  
Jan Ricny ◽  
Ondrej Soukup ◽  
Jan Korabecny ◽  
Eugenie Nepovimova ◽  
...  
Keyword(s):  
Side Effects ◽  
Amyloid Β ◽  
Acetylcholinesterase Inhibitors ◽  
Side Chain ◽  
Choline Transporter ◽  
Disease Therapy ◽  
Cortical Membranes ◽  
Derivatives Of

Background: Reversible acetylcholinesterase inhibitors are used in Alzheimer disease therapy. However, tacrine and its derivatives have severe side effects. Derivatives of the tacrine analogue 7-methoxytacrine (MEOTA) are less toxic. Methods: We evaluated new derivatives of 7-MEOTA (2 homodimers linked by 2 C4-C5 chains and 5 N-alkylated C4-C8 side chain derivatives) in vitro, using the rat hippocampal choline transporter CHT1. Results: Some derivatives were effective inhibitors of rat acetylcholinesterase and comparable with 7-MEOTA. All derivatives were able to inhibit CHT1, probably via quaternary ammonium, and this interaction could be involved in the enhancement of their detrimental side effects and/or in the attenuation of their promising effects. Under conditions of disrupted lipid rafts, the unfavorable effects of some derivatives were weakened. Only tacrine was probably able to stereospecifically interact with the naturally occurring amyloid-β isoform and to simultaneously stimulate CHT1. Some derivatives, when coincubated with amyloid β, did not influence CHT1. All derivatives also increased the fluidity of the cortical membranes. Conclusion: The N-alkylated derivative of 7-MEOTA bearing from C4 side chains appears to be the most promising compound and should be evaluated in future in vivo research.

scholarly journals Synthesis and Evaluation of Chirally Defined Side Chain Variants of 7-Chloro-4-Aminoquinoline To Overcome Drug Resistance in Malaria Chemotherapy

2016 ◽  
Vol 61 (3) ◽  
Author(s):  
Vasantha Rao Dola ◽  
Awakash Soni ◽  
Pooja Agarwal ◽  
Hafsa Ahmad ◽  
Kanumuri Siva Rama Raju ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Solid State ◽  
Side Chain ◽  
Detailed Structure ◽  
Preclinical Development ◽  
Malaria Parasites ◽  
Sar Studies ◽  
Structure Activity

ABSTRACT A novel 4-aminoquinoline derivative [(S)-7-chloro-N-(4-methyl-1-(4-methylpiperazin-1-yl)pentan-2-yl)-quinolin-4-amine triphosphate] exhibiting curative activity against chloroquine-resistant malaria parasites has been identified for preclinical development as a blood schizonticidal agent. The lead molecule selected after detailed structure-activity relationship (SAR) studies has good solid-state properties and promising activity against in vitro and in vivo experimental malaria models. The in vitro absorption, distribution, metabolism, and excretion (ADME) parameters indicate a favorable drug-like profile.

scholarly journals Androgen profiles during pubertal Leydig cell development in mice

Reproduction ◽  
2010 ◽  
Vol 140 (1) ◽  
pp. 113-121 ◽  
Author(s):  
Xiufeng Wu ◽  
Ramamani Arumugam ◽  
Ningning Zhang ◽  
Mary M Lee
Keyword(s):  
Leydig Cell ◽  
Developmental Changes ◽  
Side Chain ◽  
Adult Rat ◽  
Testosterone Production ◽  
Chain Cleavage ◽  
Cleavage Enzyme ◽  
Species Specific

Postnatal Leydig cell (LC) development in mice has been assumed empirically to resemble that of rats, which have characteristic hormonal profiles at well-defined maturational stages. To characterize the changes in LC function and gene expression in mice, we examined reproductive hormone expression from birth to 180 days, and quantified in vivo and in vitro production of androgens during sexual maturation. Although the overall plasma androgen and LH profiles from birth through puberty were comparable to that of rats, the timing of developmental changes in androgen production and steroidogenic capacity of isolated LCs differed. In mice, onset of androgen biosynthetic capacity, distinguished by an acute rise in androstenedione and testosterone production and an increased expression of the steroidogenic enzymes, cytochrome P450 cholesterol side-chain cleavage enzyme and 17α-hydroxylase, occurred at day 24 (d24) rather than at d21 as reported in rats. Moreover, in contrast to persistently high testosterone production by pubertal and adult rat LCs, testosterone production was maximal at d45 in mice, and then declined in mature LCs. The murine LCs also respond more robustly to LH stimulation, with a greater increment in LH-stimulated testosterone production. Collectively, these data suggest that the mouse LC lineage has a delayed onset, and that it has an accelerated pace of maturation compared with the rat LC lineage. Across comparable maturational stages, LCs exhibit species-specific developmental changes in enzyme expression and capacity for androgen production. Our results demonstrate distinct differences in LC differentiation between mice and rats, and provide informative data for assessing reproductive phenotypes of recombinant mouse models.

Uptake and esterification of plant sterols by rat small intestine

1981 ◽  
Vol 240 (1) ◽  
pp. G50-G55 ◽  
Author(s):  
A. K. Bhattacharyya
Keyword(s):  
Small Intestine ◽  
Tissue Concentration ◽  
Intestinal Content ◽  
Plant Sterols ◽  
Cell Uptake ◽  
Side Chain ◽  
Mucosal Cell ◽  
Rat Small Intestine

The commonly found plant sterols, beta-sitosterol, campesterol, and stigmasterol, differ structurally from cholesterol only in side chains but are absorbed in much smaller amounts than cholesterol. Because intestinal mucosal cell uptake and esterification are important steps in absorption, these were studied in vivo after feeding the sterols and in vitro using everted sacs of rat small intestine. The studies showed that campesterol uptake was significantly higher than that of beta-sitosterol, whereas stigmasterol uptake was extremely low throughout the intestine. The total intestinal content of campesterol was 2.223 mg/g or about 14% of the dose fed as compared with 1.496 mg/g or 7.4% for beta-sitosterol and only 0.392 mg/g or 2.3% for stigmasterol. Intestinal tissue concentration of esterified campesterol was higher than that of beta-sitosterol, whereas that of esterified stigmasterol was extremely low. The results suggest that campesterol absorption would be higher than that of beta-sitosterol; stigmasterol probably would not be absorbed in any significant amount because of its negligible uptake due to its inability to partition out of the mixed micelles. It appears that the structure of the side chain of a sterol is an important determinant for uptake and esterification, and probably absorption, in the small intestine.

3-Nitrotyrosine and related derivatives in proteins: precursors, radical intermediates and impact in function

2020 ◽  
Vol 64 (1) ◽  
pp. 111-133 ◽  
Author(s):  
Nicolás Campolo ◽  
Federico M. Issoglio ◽  
Darío A. Estrin ◽  
Silvina Bartesaghi ◽  
Rafael Radi
Keyword(s):  
Reactive Species ◽  
Side Chain ◽  
Tyrosyl Radical ◽  
Post Translational Modification ◽  
Tyrosine Residues ◽  
Oxidative Products ◽  
Usual Process ◽  
And Function

Abstract Oxidative post-translational modification of proteins by molecular oxygen (O2)- and nitric oxide (•NO)-derived reactive species is a usual process that occurs in mammalian tissues under both physiological and pathological conditions and can exert either regulatory or cytotoxic effects. Although the side chain of several amino acids is prone to experience oxidative modifications, tyrosine residues are one of the preferred targets of one-electron oxidants, given the ability of their phenolic side chain to undergo reversible one-electron oxidation to the relatively stable tyrosyl radical. Naturally occurring as reversible catalytic intermediates at the active site of a variety of enzymes, tyrosyl radicals can also lead to the formation of several stable oxidative products through radical–radical reactions, as is the case of 3-nitrotyrosine (NO2Tyr). The formation of NO2Tyr mainly occurs through the fast reaction between the tyrosyl radical and nitrogen dioxide (•NO2). One of the key endogenous nitrating agents is peroxynitrite (ONOO−), the product of the reaction of superoxide radical (O2•−) with •NO, but ONOO−-independent mechanisms of nitration have been also disclosed. This chemical modification notably affects the physicochemical properties of tyrosine residues and because of this, it can have a remarkable impact on protein structure and function, both in vitro and in vivo. Although low amounts of NO2Tyr are detected under basal conditions, significantly increased levels are found at pathological states related with an overproduction of reactive species, such as cardiovascular and neurodegenerative diseases, inflammation and aging. While NO2Tyr is a well-established stable oxidative stress biomarker and a good predictor of disease progression, its role as a pathogenic mediator has been laboriously defined for just a small number of nitrated proteins and awaits further studies.

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