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1.
Future Med Chem ; 12(21): 1891-1910, 2020 11.
Article in English | MEDLINE | ID: mdl-33124467

ABSTRACT

Aim: Quinic acid (QA) is a cyclic polyol exhibiting anticancer properties on several cancers. However, potential role of QA derivatives against glioblastoma is not well established. Methodology & results: Sixteen novel QA derivatives and QA-16 encapsulated poly (lactic-co-glycolic acid) nanoparticles (QA-16-NPs) were screened for their anti-glioblastoma effect using standard cell and molecular biology methods. Presence of a tertiary hydroxy and silylether groups in the lead compound were identified for the antitumor activity. QA-16 have 90% inhibition with the IC50 of 10.66 µM and 28.22 µM for LN229 and SNB19, respectively. The induction of apoptosis is faster with the increased fold change of caspase 3/7 and reactive oxygen species. Conclusion: QA-16 and QA-16-NPs shows similar cytotoxicity effect, providing the opportunity to use QA-16 as a potential chemotherapeutic agent.


Subject(s)
Antineoplastic Agents/pharmacology , Drug Design , Glioblastoma/drug therapy , Quinic Acid/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Apoptosis/drug effects , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Glioblastoma/metabolism , Glioblastoma/pathology , Humans , Quinic Acid/chemical synthesis , Quinic Acid/chemistry , Structure-Activity Relationship , Tumor Cells, Cultured
2.
J Agric Food Chem ; 68(39): 10489-10516, 2020 Sep 30.
Article in English | MEDLINE | ID: mdl-32846084

ABSTRACT

Caffeoylquinic acids (CQAs) are a broad class of secondary metabolites that have been found in edible and medicinal plants from various families. It has been 100 years since the discovery of chlorogenic acid in 1920. In recent years, a number of naturally derived CQAs have been isolated and structurally elucidated. Accumulated evidence demonstrate that CQAs have a wide range of biological activities, such as antioxidation, antibacterial, antiparasitic, neuroprotective, anti-inflammatory, anticancer, antiviral, and antidiabetic effects. Up to date, some meaningful progresses on the biosynthesis and total synthesis of CQAs have also been made. Therefore, it is necessary to comprehensively summarize the structure, biological activity, biosynthesis, and chemical synthesis of CQAs. This review provides extensive coverage of naturally occurring CQAs discovered from 1990 until 2020. Modern isolation techniques, chemical data (including structure, biosynthesis, and total synthesis), and bioactivity are summarized. This would be helpful for further research of CQAs as potential pharmaceutical agents.


Subject(s)
Quinic Acid/analogs & derivatives , Animals , Antioxidants/chemical synthesis , Antioxidants/chemistry , Antioxidants/pharmacology , Humans , Molecular Structure , Quinic Acid/chemical synthesis , Quinic Acid/chemistry , Quinic Acid/pharmacology
3.
Molecules ; 24(5)2019 Mar 09.
Article in English | MEDLINE | ID: mdl-30857274

ABSTRACT

A series of novel caffeoylquinic acid derivatives of chlorogenic acid have been designed and synthesized. Biological evaluation indicated that several synthesized derivatives exhibited moderate to good lipid-lowering effects on oleic acid-elicited lipid accumulation in HepG2 liver cells. Particularly, derivatives 3d, 3g, 4c and 4d exhibited more potential lipid-lowering effect than the positive control simvastatin and chlorogenic acid. Further studies on the mechanism of 3d, 3g, 4c and 4d revealed that the lipid-lowering effects were related to their regulation of TG levels and merit further investigation.


Subject(s)
Hypolipidemic Agents/chemical synthesis , Hypolipidemic Agents/pharmacology , Oleic Acid/pharmacology , Quinic Acid/analogs & derivatives , Chlorogenic Acid/pharmacology , Hep G2 Cells , Humans , Hypolipidemic Agents/chemistry , Lipid Metabolism/drug effects , Quinic Acid/chemical synthesis , Quinic Acid/chemistry , Quinic Acid/pharmacology , Simvastatin/pharmacology
4.
Bioorg Med Chem ; 26(14): 4201-4208, 2018 08 07.
Article in English | MEDLINE | ID: mdl-30030001

ABSTRACT

Dicaffeoylquinic acid (DCQA), which contain 2 caffeic acids and a quinic acid, is 6 isomeric compounds (1,3-, 1,4-, 1,5-, 3,4-, 3,5-, and 4,5-DCQA). In this study, the mechanism underlying the inhibitory effect of DCQA isomers on melanogenesis in B16F1 murine melanoma cells stimulated by melanocyte stimulating hormone (α-MSH) was evaluated. DCQA isomers showed inhibitory effects on melanogenesis in α-MSH-stimulated B16F1 cells. Furthermore, the anti-melanogenesis activities of 1,5-DCQA and 4,5-DCQA were 61% and 84%, respectively, which were greater than that of arbutin (35%). For cell-free tyrosinase, 3,4-DCQA and 4,5-DCQA indicated high inhibitory effects, similar to the activity to arbutin (35%) at 25 µM. DCQA isomers inhibited the melanogenic enzymes including tyrosinase and dopachrome tautomerase (DCT) on α-MSH-stimulated B16F1 cells. Interestingly, 4,5-DCQA, the most potent inhibitor of melanogenesis among the six DCQA isomers, significantly downregulated the expression of microphthalmia-associated transcription factor (MITF), tyrosinase-related protein 1 (TRP1) containing tyrosinase, and DCT. In particular, the inhibitory mechanism of 4,5-DCQA on MITF expression was elucidated, revealing that 4,5-DCQA inhibits the phosphorylation of cAMP response element-binding protein (CREB) by attenuating cAMP generation during melanogenesis. A molecular docking study was conducted to elucidate the inhibitory mechanism of 4,5-DCQA on cAMP production. DCQA isomers dock to the residues of adenylyl cyclase with a distance of <3 Å, except for 1,3-DCQA. Especially, 4,5-DCQA showed Full Fitness of -1304.68 kcal/mol and △G of -8.33 kcal/mol, as well as H-bonding with adenylyl cyclase at ILE953 and LYS930 residues. In conclusion, DCQA isomers have different effects on melanogenesis depending on their structure. Especially, 4,5-DCQA has depigmentation activity through the inhibitory effect on cellular tyrosinase directly and binding effect on adenylyl cyclase, resulting in the downregulation of MITF protein, thereby reducing the expression of melanogenic enzymes.


Subject(s)
Enzyme Inhibitors/pharmacology , Melanins/antagonists & inhibitors , Monophenol Monooxygenase/antagonists & inhibitors , Quinic Acid/analogs & derivatives , Animals , Cell Survival/drug effects , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Humans , Melanins/chemistry , Melanins/metabolism , Melanocytes/chemistry , Melanocytes/drug effects , Melanocytes/metabolism , Mice , Molecular Docking Simulation , Molecular Structure , Monophenol Monooxygenase/metabolism , Quinic Acid/chemical synthesis , Quinic Acid/chemistry , Quinic Acid/pharmacology , Stereoisomerism , Structure-Activity Relationship , Tumor Cells, Cultured
5.
Bioorg Med Chem Lett ; 28(7): 1194-1197, 2018 04 15.
Article in English | MEDLINE | ID: mdl-29525218

ABSTRACT

Considerable attention has been paid to protein tyrosine phosphatase 1B (PTP1B) inhibitors as a potential therapy for diabetes, obesity, and cancer. Ten caffeoylquinic acid derivatives (1-10) from leaves of Artemisia princeps Pamp. (Asteraceae) were identified as natural PTP1B inhibitors. Among them, chlorogenic acid (3) showed the most potent inhibitory activity (IC50 11.1 µM). Compound 3 was demonstrated to be a noncompetitive inhibitor by a kinetic analysis. Molecular docking simulation suggested that compound 3 bound to the allosteric site of PTP1B. Furthermore, compound 3 showed remarkable selectivity against four homologous PTPs. According to these findings, compound 3 might be potentially valuable for further drug development.


Subject(s)
Artemisia/chemistry , Protein Tyrosine Phosphatase, Non-Receptor Type 1/antagonists & inhibitors , Quinic Acid/analogs & derivatives , Dose-Response Relationship, Drug , Humans , Molecular Docking Simulation , Molecular Structure , Protein Tyrosine Phosphatase, Non-Receptor Type 1/metabolism , Quinic Acid/chemical synthesis , Quinic Acid/chemistry , Quinic Acid/pharmacology , Structure-Activity Relationship
6.
J Med Chem ; 61(4): 1609-1621, 2018 02 22.
Article in English | MEDLINE | ID: mdl-29406740

ABSTRACT

The plant metabolite 3,4,5-tri-O-galloylquinic acid methyl ester (TGAME, compound 6) was synthesized, and its potential effect on calcium oxalate monohydrate (COM) crystal binding to the surface of Madin-Darby canine kidney cells type I (MDCKI) and crystal growth in a Drosophila melanogaster Malpighian tubule (MT) model were investigated. Membrane, cytosolic, and total annexin A1 (AxA1), α-enolase, and heat shock protein 90 (HSP90) amounts were examined by Western blot analysis after subcellular fractionation, then confirmed by immunofluorescence staining of cultured cells. Pretreatment of MDCKI cells with TGAME for up to 6 h significantly diminished COM crystal binding in a concentration-dependent manner. TGAME significantly inhibited AxA1 surface expression by immunofluorescence microscopy, whereas intracellular AxA1 increased. Western blot analysis confirmed AxA1 expression changes in the membrane and cytosolic fractions of compound-treated cells, whereas whole cell AxA1 remained unchanged. TGAME also significantly decreased the size, number, and growth of calcium oxalate (CaOx) crystals induced in a Drosophila melanogaster MT model and possessed a potent antioxidant activity in a DPPH assay.


Subject(s)
Annexin A1/drug effects , Calcium Oxalate/chemistry , Cell Adhesion/drug effects , Gallic Acid/analogs & derivatives , Quinic Acid/analogs & derivatives , Animals , Annexin A1/metabolism , Antioxidants , Cell Line , Crystallization , Dogs , Drosophila melanogaster , Gallic Acid/chemical synthesis , Gallic Acid/chemistry , Gallic Acid/pharmacology , Madin Darby Canine Kidney Cells/drug effects , Madin Darby Canine Kidney Cells/metabolism , Malpighian Tubules/chemistry , Quinic Acid/chemical synthesis , Quinic Acid/chemistry , Quinic Acid/pharmacology , Subcellular Fractions/chemistry , Subcellular Fractions/metabolism
7.
Org Biomol Chem ; 14(8): 2487-97, 2016 Feb 28.
Article in English | MEDLINE | ID: mdl-26815337

ABSTRACT

New dicinnamoyl (caffeoyl, feruloyl, ortho and para-coumaroyl) 4-deoxyquinic acid and esters were synthesized by using a new 4-deoxy quinic acid triol intermediate. The optimisation of both coupling and deprotection steps allowed the preparation in good yields of the target products either as the carboxylic acid or the methyl ester form. Eight new compounds were evaluated for their ability to influence the feeding behaviour of the pea aphid Acyrthosiphon pisum. Artificial diet bioassays showed that two compounds are toxic (mortality and growth inhibition) at lower concentrations than the reference 3,5-dicaffeoyl quinic acid.


Subject(s)
Aphids/drug effects , Cinnamates/chemical synthesis , Cinnamates/toxicity , Esters/chemistry , Esters/toxicity , Insecticides/chemical synthesis , Insecticides/toxicity , Quinic Acid/analogs & derivatives , Quinic Acid/chemical synthesis , Quinic Acid/toxicity , Animals , Aphids/growth & development , Cinnamates/chemistry , Dose-Response Relationship, Drug , Esters/chemical synthesis , Feeding Behavior/drug effects , Insecticides/chemistry , Molecular Structure , Quinic Acid/chemistry
8.
Chem Biol Drug Des ; 86(3): 344-50, 2015 Sep.
Article in English | MEDLINE | ID: mdl-25528858

ABSTRACT

Different series of N-alkylated diamines and their derivatives condensed to quinic acid were synthesized and tested for antibacterial properties against Staphylococcus aureus, Staphylococcus epidermidis, Pseudomonas aeruginosa, and Mycobacterium tuberculosis. The lipophilic chain and carbohydrate moiety modulate the antibacterial activity and the compounds showed a structure-activity relationship. Overall, 11 compounds displayed better activity than chloramphenicol against Gram-positive and Gram-negative bacteria. Monoalkylated amines 2a-h displayed an activity similar to that of ethambutol against Mycobacterium tuberculosis.


Subject(s)
Amides/chemical synthesis , Amides/pharmacology , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Diamines/chemical synthesis , Diamines/pharmacology , Quinic Acid/analogs & derivatives , Alkylation , Gram-Negative Bacteria/drug effects , Gram-Positive Bacteria/drug effects , Microbial Sensitivity Tests , Quinic Acid/chemical synthesis , Quinic Acid/chemistry , Quinic Acid/pharmacology , Structure-Activity Relationship , Surface-Active Agents/pharmacology
9.
Bioconjug Chem ; 24(12): 2036-44, 2013 Dec 18.
Article in English | MEDLINE | ID: mdl-24256337

ABSTRACT

Mycophenolic acid (MPA) is a commonly used immunosuppressive drug for human islet transplantation. However, it is toxic to transplanted islets, causing primary nonfunction. We recently synthesized a quinic acid derivative, 1,3,4,5-tetrahydroxy-N-propylcyclohexanecarboxamide (KZ41), which has anti-inflammatory and anti-apoptotic effects. We hypothesized that the conjugate (E)-2,3,5-trihydroxy-5-(propylcarbamoyl) cyclohexyl 6-(4-ethoxy-6-methoxy-7-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4-methylhex-4-enoate (JP-3-110), which is composed of KZ41 and MPA through esterification, can suppress the immune rejection while inducing less toxicity. Early characterization showed that the solubility of JP-3-110 was significantly higher than that of MPA, though JP-3-110 was still poorly water-soluble. The ester bond connecting KZ41 and MPA is stable for a limited duration (<4 weeks). Pharmacological studies demonstrated that JP-3-110 induced significantly less activated caspase 3 and apoptotic cell death of human islets than MPA, while maintaining an equally potent immunosuppressive effect. A similar immunosuppressive effect of JP-3-110 and MPA in humanized NOD.Cg-Prkdc(scid)Il2rg(tm1Wjl)/SzJ (NOD scid gamma, NSG) mice with adoptively transferred human immunity was observed. Taken together, our results demonstrated that JP-3-110 can be a safer immunosuppressive agent for human islet transplantation.


Subject(s)
Apoptosis/drug effects , Benzofurans/chemical synthesis , Benzofurans/pharmacology , Immunosuppressive Agents/chemical synthesis , Immunosuppressive Agents/pharmacology , Islets of Langerhans Transplantation/methods , Mycophenolic Acid/analogs & derivatives , Quinic Acid/analogs & derivatives , Animals , B-Lymphocytes/drug effects , B-Lymphocytes/immunology , Cell Line, Tumor , Chemistry Techniques, Synthetic , Humans , Islets of Langerhans/drug effects , Islets of Langerhans/immunology , Islets of Langerhans/metabolism , Mice , Mycophenolic Acid/chemical synthesis , Mycophenolic Acid/pharmacology , NF-kappa B/metabolism , Quinic Acid/chemical synthesis , Quinic Acid/pharmacology , Rats , T-Lymphocytes/drug effects , T-Lymphocytes/immunology , Treatment Outcome
10.
ACS Chem Biol ; 8(3): 568-77, 2013 Mar 15.
Article in English | MEDLINE | ID: mdl-23198883

ABSTRACT

The structural changes caused by the substitution of the aromatic moiety in (2S)-2-benzyl-3-dehydroquinic acids and its epimers in C2 by electron-withdrawing or electron-donating groups in type II dehydroquinase enzyme from M. tuberculosis and H. pylori has been investigated by structural and computational studies. Both compounds are reversible competitive inhibitors of this enzyme, which is essential in these pathogenic bacteria. The crystal structures of M. tuberculosis and H. pylori in complex with (2S)-2-(4-methoxy)benzyl- and (2S)-2-perfluorobenzyl-3-dehydroquinic acids have been solved at 2.0, 2.3, 2.0, and 1.9 Å, respectively. The crystal structure of M. tuberculosis in complex with (2R)-2-(benzothiophen-5-yl)methyl-3-dehydroquinic acid is also reported at 1.55 Å. These crystal structures reveal key differences in the conformation of the flexible loop of the two enzymes, a difference that depends on the presence of electron-withdrawing or electron-donating groups in the aromatic moiety of the inhibitors. This loop closes over the active site after substrate binding, and its flexibility is essential for the function of the enzyme. These differences have also been investigated by molecular dynamics simulations in an effort to understand the significant inhibition potency differences observed between some of these compounds and also to obtain more information about the possible movements of the loop. These computational studies have also allowed us to identify key structural factors of the H. pylori loop that could explain its reduced flexibility in comparison to the M. tuberculosis loop, specifically by the formation of a key salt bridge between the side chains of residues Asp18 and Arg20.


Subject(s)
Enzyme Inhibitors/pharmacology , Hydro-Lyases/antagonists & inhibitors , Quinic Acid/analogs & derivatives , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Helicobacter pylori/enzymology , Hydro-Lyases/metabolism , Models, Molecular , Molecular Dynamics Simulation , Molecular Structure , Mycobacterium tuberculosis/enzymology , Quinic Acid/chemical synthesis , Quinic Acid/chemistry , Quinic Acid/pharmacology
11.
Org Biomol Chem ; 10(27): 5266-77, 2012 Jul 21.
Article in English | MEDLINE | ID: mdl-22678124

ABSTRACT

We report on a diastereoselective synthesis of six derivatives of caffeoyl- and feruloyl-muco-quinic acids. All the muco-quinic acid derivatives were obtained in excellent yield in five steps starting from quinic acid, caffeic acid and ferulic acid. Allyl ether protection of trans-hydroxy cinnamic acids was here introduced to chlorogenic acids synthesis. We show that muco-quinic acid derivatives, which are formally diastereoisomers of chlorogenic acids, can be readily distinguished by their tandem mass spectra.


Subject(s)
Caffeic Acids/chemistry , Coumaric Acids/chemistry , Quinic Acid/chemical synthesis , Methylation , Models, Molecular , Molecular Structure , Stereoisomerism
12.
Chem Pharm Bull (Tokyo) ; 59(4): 502-7, 2011.
Article in English | MEDLINE | ID: mdl-21467684

ABSTRACT

Caffeoylquinic acid (CQA) is one of the phenylpropanoids which have various bioactivities such as antioxidant, antibacterial, anticancer, antihistamic, and other biological effects. We previously reported that 3,5-di-O-caffeoylquinic acid inhibited amyloid ß(1-42)-induced cellular toxicity on human neuroblastoma SH-SY5Y cells and increased the mRNA expression level of glycolytic enzymes and the intracellular ATP level. To investigate structure-activity relationship on the accelerating activity on ATP production, we synthesized 1,4,5-tri-O-caffeoylquinic acid, 4,5-di-O-caffeoylquinic acid, 3,4,5-tri-O-caffeoylquinic acid, and other derivatives. Additionally, we evaluated intracellular ATP level in SH-SY5Y treated with each CQA derivative. As a result, 3,4,5-tri-O-caffeoylquinic acid showed the highest accelerating activity on ATP production among tested compounds. It was suggested that caffeoyl groups bound to quinic acid are important for activity and the more caffeoyl groups are bound to quinic acid, the higher accelerating activity on ATP production exhibits.


Subject(s)
Adenosine Triphosphate/metabolism , Quinic Acid/analogs & derivatives , Amyloid beta-Peptides/antagonists & inhibitors , Amyloid beta-Peptides/metabolism , Cell Line, Tumor , Humans , Peptide Fragments/antagonists & inhibitors , Peptide Fragments/metabolism , Quinic Acid/chemical synthesis , Quinic Acid/chemistry , Quinic Acid/pharmacology , Structure-Activity Relationship
13.
J Agric Food Chem ; 59(10): 5671-6, 2011 May 25.
Article in English | MEDLINE | ID: mdl-21417257

ABSTRACT

Feruloylquinic acids are a major class of biologically active phenolic antioxidants in coffee beans, but their metabolic fate is poorly understood. The present study investigated the phase II metabolism of feruloylquinic acids with selected human sulfotransferases (SULT1A1 and SULT1E1) and uridine 5'-diphosphoglucuronosyltransferases (UGT1A1 and UGT1A9). For unequivocal metabolite identification, the chemical synthesis of two potential human metabolites of 5-O-feruloylquinic acid, the 4'-sulfated and 4'-O-glucuronidated conjugates, has been performed for the first time. Following incubation with human SULT1A1 or SULT1E1, formation of 5-O-feruloylquinic acid 4'-O-sulfate was confirmed by matching its HPLC and MS data with those of the authentic standard. On the other hand, no glucuronide conjugates were detected after incubation with human uridine 5'-diphosphoglucuronosyltransferases. These results suggest that sulfation can take place on the ferulic acid moiety of feruloylquinic acids and may be a major metabolic pathway for feruloylquinic acids in humans.


Subject(s)
Arylsulfotransferase/metabolism , Glucuronides/chemical synthesis , Glucuronosyltransferase/metabolism , Quinic Acid/analogs & derivatives , Sulfotransferases/metabolism , Coumaric Acids/metabolism , Glucuronides/metabolism , Humans , Quinic Acid/chemical synthesis , Quinic Acid/metabolism , Recombinant Proteins/metabolism , UDP-Glucuronosyltransferase 1A9
14.
Bioorg Med Chem ; 18(19): 7009-14, 2010 Oct 01.
Article in English | MEDLINE | ID: mdl-20813534

ABSTRACT

New derivatives of caffeic acid and quinic acid were synthesized and their anti-fungal and inhibitory activities on fungal 1,3-ß-glucan synthase were determined in comparison with those of the corresponding chlorogenic acid derivatives. All the chlorogenic, quinic and caffeic acid derivatives that were coupled with an H(2)N-orn-4-(octyloxy) aniline group (1, 1b and 1c) displayed potent activities in both anti-fungal and inhibition of 1,3-glucan synthase assays. Compounds 1 and 1c inhibited the fungal membrane enzyme with the potency comparable to that of a known 1,3-ß-D-glucan synthase inhibitor, aculeacin A. The results revealed that the anti-fungal activity of the chlorogenic acid derivative with a free amino group was at least partly due to inhibition of the fungal 1,3-ß-glucan synthase. These results suggest that further investigation on caffeic acid derivatives may lead to the discovery of novel anti-fungal agents with drug-like properties.


Subject(s)
Antifungal Agents/pharmacology , Caffeic Acids/pharmacology , Candida albicans/drug effects , Enzyme Inhibitors/pharmacology , Glucosyltransferases/antagonists & inhibitors , Quinic Acid/pharmacology , Antifungal Agents/chemical synthesis , Antifungal Agents/chemistry , Caffeic Acids/chemical synthesis , Caffeic Acids/chemistry , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Glucosyltransferases/metabolism , Microbial Sensitivity Tests , Molecular Structure , Quinic Acid/chemical synthesis , Quinic Acid/chemistry , Stereoisomerism , Structure-Activity Relationship
15.
Rapid Commun Mass Spectrom ; 24(11): 1575-82, 2010 Jun 15.
Article in English | MEDLINE | ID: mdl-20486253

ABSTRACT

All four regioisomers of feruloyl quinic acid and isoferuloyl quinic acid were synthesized and a liquid chromatography/tandem mass spectrometry (LC/MS/MS) method developed that resolves all eight regioisomers. All eight regioisomers can be readily distinguished by their MS/MS spectra in the negative ion mode, illustrating the power of tandem mass spectrometry to elucidate the structures of regioisomeric compounds. Compound identification is possible, either by direct comparison of spectral fingerprints or by rational probing of diagnostic fragment ions, thus allowing the identification of these important classes of natural products and potential human metabolites.


Subject(s)
Chromatography, Liquid/methods , Mass Spectrometry/methods , Quinic Acid/chemistry , Humans , Isomerism , Molecular Structure , Quinic Acid/chemical synthesis
16.
Bioorg Med Chem ; 18(2): 863-9, 2010 Jan 15.
Article in English | MEDLINE | ID: mdl-20004585

ABSTRACT

In our continued research on chlorogenic acid analogues and derivatives with improved bioactivity, we have synthesized some caffeoyl 5,6-anhydroquinic acid derivatives. The 1,7 acetonides of chlorogenic acid (15), and of the mono-caffeoyl 5,6-anhydroquinic acids (7-8) showed appreciable anti-HIV activity. The 3,4-dicaffeoyl 5,6-anhydroquinic acid (12) exhibited an anti-HIV activity twice as that of 3,5-dicaffeoylquinic acid (22). The caffeoyl 5,6-anhydroquinic acid derivatives displayed potent anti-oxidant activities. The mono-caffeoyl 5,6-anhydroquinic acids (10-11) were more than twice stronger than chlorogenic acid (21) on SOD-like activity.


Subject(s)
Anti-HIV Agents/chemical synthesis , Anti-HIV Agents/pharmacology , Antioxidants/chemical synthesis , Antioxidants/pharmacology , Caffeic Acids/chemical synthesis , Caffeic Acids/pharmacology , HIV-1/drug effects , Quinic Acid/analogs & derivatives , Animals , Anti-HIV Agents/chemistry , Antioxidants/chemistry , Caffeic Acids/chemistry , Cell Line, Tumor , Drug Evaluation, Preclinical , Microbial Sensitivity Tests , Molecular Structure , Quinic Acid/chemical synthesis , Quinic Acid/chemistry , Quinic Acid/pharmacology , Stereoisomerism , Structure-Activity Relationship
17.
Bioorg Med Chem Lett ; 19(18): 5458-60, 2009 Sep 15.
Article in English | MEDLINE | ID: mdl-19674895

ABSTRACT

Quinic acid (QA) esters found in hot water extracts of Uncaria tomentosa (a.k.a. cat's claw) exert anti-inflammatory activity through mechanisms involving inhibition of the pro-inflammatory transcription factor nuclear factor kappa B (NF-kappaB). Herein, we describe the synthesis and biological testing of novel QA derivatives. Inhibition of NF-kappaB was assessed using A549 (Type II alveolar epithelial-like) cells that stably express a secreted alkaline phosphatase (SEAP) reporter driven by an NF-kappaB response element. A549-NF-kappaB cells were stimulated with TNF-alpha (10 ng/mL) in the presence or absence of QA derivative for 18 hours followed by measurement of SEAP activity. Amide substitution at the carboxylic acid position yielded potent inhibitors of NF-kappaB. A variety of modifications to the amide substitution were tolerated with the N-propyl amide derivative being the most potent. Further examination of the SAR demonstrated that acetylation of the hydroxyl groups reduced NF-kappaB inhibitory activity. QA amide derivatives lacked anti-oxidant activity and were found to be neither anti-proliferative nor cytotoxic at concentrations up to 100 microM. In conclusion, we have discovered a novel series of non-toxic QA amides that potently inhibit NF-kappaB, despite their lack of anti-oxidant activity. Mechanistic studies and pre-clinical efficacy studies in various inflammatory animal models are on-going.


Subject(s)
Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/pharmacology , NF-kappa B/antagonists & inhibitors , NF-kappa B/metabolism , Quinic Acid/chemistry , Quinic Acid/pharmacology , Alkaline Phosphatase/metabolism , Anti-Inflammatory Agents/chemical synthesis , Cell Line , Epithelial Cells/drug effects , Epithelial Cells/metabolism , Humans , Pulmonary Alveoli/cytology , Quinic Acid/chemical synthesis , Uncaria/chemistry
18.
Org Biomol Chem ; 6(6): 986-7, 2008 Mar 21.
Article in English | MEDLINE | ID: mdl-18327321

ABSTRACT

A novel synthesis of 5-O-feruloylquinic acid, a polyphenolic compound found in coffee beans, and its methyl ester derivative has been optimized. The sequence involves 6 steps and is compatible with the preparation of potential human metabolites of these compounds. The key reaction is a Knoevenagel condensation of 4-hydroxy-3-methoxy-benzaldehyde and a malonate ester of quinic acid.


Subject(s)
Benzaldehydes/chemistry , Coumaric Acids/chemical synthesis , Quinic Acid/chemistry , Coumaric Acids/chemistry , Molecular Structure , Quinic Acid/analogs & derivatives , Quinic Acid/chemical synthesis
19.
J Org Chem ; 71(14): 5396-9, 2006 Jul 07.
Article in English | MEDLINE | ID: mdl-16808536

ABSTRACT

We have developed simple methods that provide a rapid entry into the synthesis of a series of quinate and shikimate analogues, including (-)-methyl 4-epi-shikimate and the 4,5-epoxy analogues of the parent acids. Epoxy derivatives of quinic and shikimic acids were converted into methyl scyllo-quinate and (+)-methyl 3-epi-shikimate, respectively, by processes involving a regio- and stereoselective epoxide ring opening. The strategies described take place through short, high-yield reaction sequences.


Subject(s)
Epoxy Compounds/chemical synthesis , Quinic Acid/analogs & derivatives , Quinic Acid/chemical synthesis , Shikimic Acid/analogs & derivatives , Shikimic Acid/chemical synthesis , Epoxy Compounds/chemistry , Molecular Conformation , Quinic Acid/chemistry , Shikimic Acid/chemistry , Stereoisomerism
20.
Org Lett ; 8(10): 2035-7, 2006 May 11.
Article in English | MEDLINE | ID: mdl-16671775

ABSTRACT

[reaction: see text] An expedient, enantioselective synthesis of a key precursor to (-)-quinic acid has been achieved from an ephedrine-derived morpholine-dione. The salient features of this approach are a highly diastereoselective conversion of the dione to a dialkenyl morpholinone and a subsequent ring-closing metathesis reaction. Removal of the ephedrine portion generates an enantiomerically enriched hydroxycyclohexene carboxamide that is readily converted to the quinic acid precursor.


Subject(s)
Quinic Acid/chemical synthesis , Alkylation , Molecular Structure , Quinic Acid/chemistry , Shikimic Acid/chemical synthesis , Shikimic Acid/chemistry , Stereoisomerism
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