Bile acids (BAs) are key signaling steroidal molecules that regulate glucose, lipid, and energy homeostasis via interactions with the farnesoid X receptor (FXR) and G-protein bile acid receptor 1 (GPBAR1). Extensive medicinal chemistry modifications of the BA scaffold led to the discovery of potent selective or dual FXR and GPBAR1 agonists. Herein, we discovered 7-ethylidene-lithocholic acid (7-ELCA) as a novel combined FXR antagonist/GPBAR1 agonist (IC50 = 15 μM/EC50 = 26 nM) with no off-target activation in a library of 7-alkyl substituted derivatives of BAs. 7-ELCA significantly suppressed the effect of the FXR agonist obeticholic acid in BSEP and SHP regulation in human hepatocytes. Importantly, 7-ELCA significantly stimulated the production of glucagon-like peptide-1 (GLP-1), an incretin with insulinotropic effect in postprandial glucose utilization, in intestinal enteroendocrine cells. We can suggest that 7-ELCA may be a prospective approach to the treatment of type II diabetes as the dual modulation of GPBAR1 and FXR has been supposed to be effective in the synergistic regulation of glucose homeostasis in the intestine.
- Publikační typ
- časopisecké články MeSH
Three series of isomeric pyrrolo- and furo-fused 7-deazapurine ribonucleosides were synthesized and screened for cytostatic and antiviral activity. The synthesis was based on heterocyclizations of hetaryl-azidopyrimidines to form the tricyclic heterocyclic bases, followed by glycosylation and final derivatizations through cross-coupling reactions or nucleophilic substitutions. The pyrrolo[2',3':4,5]pyrrolo[2,3- d]pyrimidine and furo[2',3':4,5]pyrrolo[2,3- d]pyrimidine ribonucleosides were found to be potent cytostatics, whereas the isomeric pyrrolo[3',2',4,5]pyrrolo[2,3- d]pyrimidine nucleosides were inactive. The most active were the methyl, methoxy, and methylsulfanyl derivatives exerting submicromolar cytostatic effects and good selectivity toward cancer cells. We have shown that the nucleosides are activated by intracellular phosphorylation and the nucleotides get incorporated to both RNA and DNA, where they cause DNA damage. They represent a new type of promising candidates for preclinical development toward antitumor agents.
- MeSH
- antivirové látky chemická syntéza chemie farmakologie MeSH
- furany chemie MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- protinádorové látky chemická syntéza chemie farmakologie MeSH
- puriny chemie MeSH
- pyrroly chemie MeSH
- ribonukleosidy chemická syntéza chemie farmakologie MeSH
- techniky syntetické chemie MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Two molecules of mistaken identity are addressed. Uncovering these assignment errors led us to formulate more general guidelines about additional misassignments in cases of published bis-imines derived from 1,2-phenylenediamine and hydroxybenzaldehydes having no substituent in ortho-positions. The main purpose of this article is to highlight this repetitive assignment error in the literature and thus increase the likelihood of correct assignments in future papers.
- MeSH
- DNA chemie MeSH
- G-kvadruplexy * MeSH
- Publikační typ
- časopisecké články MeSH
- komentáře MeSH
- práce podpořená grantem MeSH
An efficient method for the synthesis of N(9)-[3-fluoro-2-(phosphonomethoxy)propyl] (FPMP) derivatives of purine bases has been developed. Both (R)- and (S)-enantiomers of the N(6)-substituted FPMP derivatives of adenine and 2,6-diaminopurine were prepared and their anti-human immunodeficiency virus (HIV) and anti-Moloney murine sarcoma virus (MSV) activity was evaluated. Whereas none of the 6-substituted FPMPA derivatives showed any antiviral activity, several FPMPDAP derivatives had a moderate antiretroviral activity. Moreover, the data obtained from the study of the substrate activity of the active derivatives towards N(6)-methyl-AMP aminohydrolase support the notion that the studied N(6)-substituted FPMPDAP derivatives act as prodrugs of the antiretroviral FPMPG analogues.
- MeSH
- 2-aminopurin analogy a deriváty chemická syntéza chemie farmakologie MeSH
- adenin analogy a deriváty chemická syntéza chemie farmakologie MeSH
- antivirové látky chemická syntéza chemie farmakologie MeSH
- buňky 3T3 MeSH
- HIV-1 účinky léků MeSH
- HIV-2 účinky léků MeSH
- krystalografie rentgenová MeSH
- kultivované buňky MeSH
- kyseliny fosforité chemická syntéza chemie farmakologie MeSH
- lidé MeSH
- Moloneyho virus myšího sarkomu účinky léků MeSH
- myši inbrední C3H MeSH
- myši MeSH
- puriny chemická syntéza chemie farmakologie MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- vztahy mezi strukturou a aktivitou MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
A novel approach to the synthesis of (purin-6-yl)acetates was developed based on Pd-catalyzed cross-coupling reactions of 6-chloropurines with a Reformatsky reagent. Their reduction with NaBH4 and treatment with MnO2 gave 6-(2-hydroxyethyl)purines, while reactions with amines in presence of NaCN afforded 6-(carbamoylmethyl)purines. Mesylation of the 6-(2-hydroxyethyl)purines followed by nucleophilic substitutions gave rise to several 6-(2-substituted ethyl)purines. This methodology was successfully applied to the synthesis of substituted purine bases and nucleosides for cytostatic and antiviral activity screening. None of the compounds exerted significant activity.
Three types of brassinosteroid analogues with perfluoroalkylated side chains were synthesized by using alkene cross-metathesis of a brassinosteroid derivative bearing a terminal alkene moiety with different (perfluoroalkyl)propenes. The presence of the double bonds in the cross-metathesis products allowed a facile one-step double dihydroxylation to provide intermediates that after Baeyer-Villiger oxidation afforded the target compounds. Biological activity of the prepared analogues was tested in GABA(A) receptor, cytotoxic, and brassinolide activity, which reached in some cases the same range as their nonfluorinated analogues.
- MeSH
- alkeny chemie MeSH
- biotest MeSH
- cholestanoly farmakologie MeSH
- krysa rodu rattus MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- objevování léků MeSH
- potkani Wistar MeSH
- protinádorové látky farmakologie chemická syntéza chemie metabolismus MeSH
- receptory GABA-A metabolismus MeSH
- steroidy heterocyklické farmakologie MeSH
- steroidy chemická syntéza chemie metabolismus farmakologie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- lidé MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- práce podpořená grantem MeSH
Novel direct C-H borylations of 7-deazapurines to position 8 by B2pin2 under Ir catalysis were followed by Suzuki cross-couplings with aryl halides and other functional group transformations to give diverse 8-substituted 7-deazaadenines.
Synthesis of novel purine bases and nucleosides bearing unsubstituted or substituted cyclopropyl rings in position 6 is reported. Unsubstituted 6-cyclopropylpurines were efficiently prepared by cross-coupling reactions of 6-chloropurines with cyclopropylzinc chloride. 6-Vinylpurines underwent Cu-mediated cyclopropanations with ethyl diazoacetate to give 6-[(ethoxycarbonyl)cyclopropyl]purines that were further transformed to carboxylic acids, amides and alcohols. 6-Cyclopropylpurine ribonucleoside exerted a significant cytostatic effect while all substituted derivatives were inactive.
A new modular methodology of preparation of 5-substituted thiophene-2-yl C-nucleosides was developed. A Friedel-Crafts-type of C-glycosidation of 2-bromothiophene with toluoyl-protected methylglycoside 2 gave the desired protected 1beta-(5-bromothiophen-2-yl)-1,2-dideoxyribofuranose 4a in 60%. The key intermediate 4a was then subjected to a series of palladium-catalyzed cross-coupling reactions. The cross-coupling reactions with alkyl organometallics gave beta-(5-alkylthiophen-2-yl)-2-deoxyribonucleosides 4 and 7 in moderate yields accompanied by side-products of reduction. On the other hand, cross-couplings with arylstannanes proceeded smoothly to give a series of beta-(5-arylthiophen-2-yl)-2-deoxyribonucleosides 4 in good yields. Deprotection of toluoylated nucleosides by NaOMe in MeOH and silylated nucleosides by Et 3N.3HF gave a series of free C-nucleosides 6. Alternatively, other types of 5-arylthiophene C-nucleosides 6 were prepared in one step by the aqueous-phase cross-coupling reactions of unprotected 1beta-(5-bromothiophen-2-yl)-1,2-dideoxyribofuranose with boronic acids. Title 5-arylthiophene C-nucleosides 6 exhibit interesting fluorescent properties with emission maxima varying from 339 to 396 nm depending on the aryl group attached.
