Nicotinic Acid Derivatives Research Articles

Lipoprotein(a) - Structure, Epidemiology, Function and Diagnostics of a Cardiovascular Risk Marker

Decades after its first description by Berg 1963 lipoprotein(a) (Lp(a)) is an established risk marker of cardio- vascular diseases which is independent from other risk markers. The main difference of Lp(a) compared to LDL is the apo(a) residue which is covalently bound to apoB. Apo(a) is a glycoprotein which underlies a large genetic polymor- phism. The latter is caused by a variation of the kringle-IV-type-2 repeats of the protein which is characterized by a large structural homology to plasminogen. The Lp(a) plasma concentration in the population is highly skewed and determined to more than 90 % by genetic factors. In healthy subjects the Lp(a)-concentration is correlated to its synthesis and not to its metabolism. Plasma concentrations of Lp(a) are affected by different diseases (e.g. diseases of liver and kidney), hor- monal factors (e.g. sexual steroids, glucocorticoids, thyroid hormones), individual and environmental factors (e.g. age, cigarette smoking) as well as pharmaceuticals (e.g. derivatives of nicotinic acid) and therapeutic procedures (lipid aphere- sis). However, even though a large number of studies on Lp(a) were performed up to now many details of its physiologi- cal function and regulation of plasma concentration are not yet understood. In addition, studies showed contradictory re- sults because there were large differences of the included patients, use of not sufficiently validated tests as well as analysis of frozen samples. Aim of our review was to describe function and physiological regulation of Lp(a) as well as factors in- fluencing its plasma concentration.

A PIP-family protein is required for biosynthesis of tobacco alkaloids

Plants in the Nicotiana genus produce nicotine and related pyridine alkaloids as a part of their chemical defense against insect herbivores. These alkaloids are formed by condensation of a derivative of nicotinic acid, but the enzyme(s) involved in the final condensation step remains elusive. In Nicotiana tabacum, an orphan reductase A622 and its close homolog A622L are coordinately expressed in the root, upregulated by methyl jasmonate treatment, and controlled by the NIC regulatory loci specific to the biosynthesis of tobacco alkaloids. Conditional suppression of A622 and A622L by RNA interference inhibited cell growth, severely decreased the formation of all tobacco alkaloids, and concomitantly induced an accumulation of nicotinic acid beta-N-glucoside, a probable detoxification metabolite of nicotinic acid, in both hairy roots and methyl jasmonate-elicited cultured cells of tobacco. N-methylpyrrolinium cation, a precursor of the pyrrolidine moiety of nicotine, also accumulated in the A622(L)-knockdown hairy roots. We propose that the tobacco A622-like reductases of the PIP family are involved in either the formation of a nicotinic acid-derived precursor or the final condensation reaction of tobacco alkaloids.

Synthesis of α-amyrin derivatives and their in vivo antihyperglycemic activity

Ficus racemosa belongs to the family of Moraceae and is commonly known as ‘Gular’ in north India. Bio-activity guided isolation work on the fruits of F. racemosa resulted in the identification of antidiabetic active principle, α-amyrin acetate 7. Compound 7 lowered the blood glucose levels by 18.4 and 17.0% at 5 and 24 h, respectively, in sucrose challenged streptozotocin induced diabetic rat (STZ-S) model at the dose of 100 mg/kg body weight. Fifteen novel derivatives viz, 9– 21, 24, 25 of α-amyrin 8 were prepared and their antihyperglycemic activity profile was assessed. The p-chlorobenzoic acid derivative 9 and nicotinic acid derivative 14 showed potent antihyperglycemic activity at 100 mg/kg body weight.

ChemInform Abstract: One‐Pot Three‐Component Reaction of 3‐(Polyfluoroacyl)chromones with Active Methylene Compounds and Ammonium Acetate: Regioselective Synthesis of Novel RF‐Containing Nicotinic Acid Derivatives.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Stereoselective hetero-Diels–Alder reaction of 3-(polyfluoroacyl)chromones with enol ethers. Novel synthesis of 2-R F-containing nicotinic acid derivatives

3-(Polyfluoroacyl)chromones undergo heterodiene cycloaddition to 3,4-dihydro-2 H-pyran, 2,3-dihydrofuran and ethyl vinyl ether under mild conditions, producing novel fused pyrans with high stereoselectivity and in good yields. Some of these pyrans were transformed into 2-R F-containing pyridines on treatment with ammonium acetate in ethanol.

Synthesis of sterically hindered 3-(azolyl)pyridines

Sterically hindered 2,4-disubstituted 3-(1,2,4-oxadiazol-3-yl)-, 3-(imidazol-2-yl)- and 3-(thiazol-2yl)pyridines were synthesized from the corresponding nicotinonitriles via amidoximes, amidines and thioamides, respectively. N-Alkyl- and N-arylamidines were prepared directly from nicotinonitriles using microwave technology. The series of 3-(azolyl)pyridines form a combinatorial library of heterocyclic derivatives of nicotinic acid and were examined by prognostic software PASS.

Efficient Synthesis of 2-(Trifluoromethyl)nicotinic Acid Derivatives from Simple Fluorinated Precursors

Novel routes to 2-trifluoromethyl-nicotinic acid derivatives have been developed involving synthesis of the pyridine ring. These pyridyl compounds serve as key intermediates in the manufacture of the recently discovered COMT inhibitor, 3-(5-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-3-yl)-2-(trifluoromethyl)pyridine 1-oxide.

One-pot three-component reaction of 3-(polyfluoroacyl)chromones with active methylene compounds and ammonium acetate: regioselective synthesis of novel R F-containing nicotinic acid derivatives

Reactions of 3-(polyfluoroacyl)chromones with acetoacetamide and ethyl acetoacetate in the presence of ammonium acetate proceed at the C-2 atom of the chromone system with pyrone ring-opening and subsequent cyclization to 5-salicyloyl-2-methyl-6-(trifluoromethyl)nicotinamides, ethyl 5-salicyloyl-2-methyl-6-(trifluoromethyl)nicotinates, and ethyl 5-hydroxy-2-methyl-5-(polyfluoroalkyl)-5 H-chromeno[4,3- b]pyridine-3-carboxylates. Similar reaction with β-aminocrotononitrile gave 5-hydroxy-2-methyl-5-(polyfluoroalkyl)-5 H-chromeno[4,3- b]pyridine-3-carbonitriles.

Application of Densitometry for the Evaluation of the Separation Effect of Nicotinic Acid Derivatives. Part III. Nicotinic Acid and its Derivatives

Nicotinic acid (1) and its derivatives, namely nicotinamide (8), 3‐pyridinecarbaldehyde (11), 3‐pyridinecarbonitrile (12), 3‐pyridylmethanol (13), and methyl 3‐pirydyl ketone (14) were investigated by NP‐TLC, and RP‐HPTLC. The RF values were obtained from the densitometric analysis. The separation factors ΔRF, RF α, and selectivity α were calculated from the RF values. The comparison and characteristic of chromatographic bands of the examined compounds were presented on the basis of calculated resolutions: RS(c), RS(b), RS(h), and RS(a). The resolutions of substances were determined by visual method (RS(c)) and densitometric method (RS(b), RS(h), and RS(a)). It was affirmed that the densitometric method is correct and the standard method to determine the above mentioned parameters. Furthermore, the R S parameter determined by the visual method for two adjacent substances is always larger than determined by the densitometric method. It was affirmed, that the best separation of the studied compounds was obtained by the RP‐HPTLC technique on RP18WF254 plates, and by use of dioxane‐water in a volume composition of 20∶80. However, 3‐pyridinecarbaldehyde (11) from 3‐pryridinecarbonitrile (12) cannot be separated by the RP‐HPTLC technique. It was also affirmed, that adsorption thin‐layer chromatography (NP‐TLC) in the system of a silica gel 60F254 and the acetone‐n‐hexane mobile phase in a volume composition of 80∶20 provided the optimum conditions for the complete separation of 3‐pyridinecarbaldehyde (11) from 3‐pryridinecarbonitrile (12).

Synthetic Routes to Three Novel Scaffolds for Potential Glycosidase Inhibitors

AbstractEfficient syntheses of three novel scaffolds for potential β‐glycosidase inhibitors were developed: The first consists of a 2,7‐dioxabicyclo[2.2.1]heptane derivative, which was prepared by an intramolecular ketalisation. The second scaffold consists of a hydroxylated cyclopentylamine, which could be synthesised stereoselectively from 2‐azabicyclo[2.2.1]hept‐5‐en‐3‐one. The third scaffold, a 4,5‐dihydroxynicotinic acid, was accessible through a sequence of substituent directed ortho‐lithiations. Selected compounds were tested as inhibitors for a number of glycosidases. Three nicotinic acid derivatives were found to be selective β‐glucosidase inhibitors.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)

Lewis Acid Promoted Direct Substitution of 2‐Methoxy‐3‐cyanopyridines by Organo Cuprates. Part 3. Facile Preparation of Nicotinamide and Nicotinic Acid Derivatives.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Application of Densitometry for the Evaluation of the Separation Effect of Nicotinic Acid Derivatives. Part II. Nicotinic Acid and its Esters

The nicotinic acid (1) and its esters, namely methyl nicotinate (2), ethyl nicotinate (3), isopropyl nicotinate (4), butyl nicotinate (5), hexyl nicotinate (6), and benzyl nicotinate (7) were investigated by NP‐TLC, and RP‐HPTLC. The RF values were obtained from the densitometric analysis. The separation factors ΔRF, RF α and selectivity α were calculated from the RF values. The comparison and characteristic of chromatographic bands of the examined compounds were presented on the basis of calculated resolutions: RS(c), RS(b), RS(h), and RS(a). The resolutions of substances were determined by visual method (RS(c)) and densitometric method (RS(b), RS(h), and RS(a)). It was affirmed that the densitometric method is correct and is the standard method to determine the above mentioned parameters. Furthermore, the R S parameter determined by the visual method for two adjacent substances is always larger than determined by the densitometric method. It was affirmed, that the best separation of the studied compounds was obtained by the RP‐HPTLC technique on RP18WF254 plates, and by use of dioxane‐water in a volume composition of 50:50. However, butyl nicotinate from benzyl nicotinate cannot be separated by RP‐HPTLC. Good separations of isopropyl nicotinate from ethyl nicotinate, as well as ethyl nicotinate from methyl nicotinate, were also not obtained by RP‐HPTLC. It was affirmed, that adsorption thin‐layer chromatography (NP‐TLC) in the system of a neutral aluminum oxide 60F254 and the acetone‐n‐hexane mobile phase in a volume composition of 20:80 provided the optimum conditions for the complete separation of butyl nicotinate from benzyl nicotinate. These chromatographic conditions also allow better separations of methyl nicotinate from ethyl nicotinate, as well as ethyl nicotinate from isopropyl nicotinate, in relation to the separations of these compounds by RP‐HPTLC.

Application of Densitometry for the Evaluation of the Separation Effect of Nicotinic Acid Derivatives. Part I. Nicotinic Acid and its Amides

Nicotinic acid (1) and its amides, namely nicotinamide (8), N‐methylnicotinamide (9) and N,N‐diethylnicotynamide (10) were investigated by NP‐TLC, and RP‐HPTLC. The RF values were obtained from the densitometric analysis. The separation factors ΔRF, RF α and selectivity α were calculated from the RF values. The resolution RS values obtained by use of the chromatogram were verified by use of densitometric analysis. It was affirmed, that RS values can be correctly marked exclusively on the basis of the densitograms. The RS values larger than 1.5 calculated on the basis of the densitograms were obtained for the pair of compounds (10)/(9) and (8)/(1) on RP18WF254 plates, and by use of methanol+water in a volume composition of 30:70, and dioxane+water in volume compositions of 20:80 and 10:90 as mobile phases. However, these conditions did not provide for the complete separation of N‐methylnicotinamide (9) from nicotinamide (8). Adsorption thin‐layer chromatography (NP‐TLC) in the system of a neutral aluminum oxide 60F254 and acetone+n‐hexane mobile phase in a volume composition of 50:50 provided the optimum conditions for the separation of all the studied compounds.

Catalytic three-phase diastereoselective hydrogenation of o-toluic and 2-methyl nicotinic acid derivatives: In situ FTIR/ATR investigation

Catalytic diastereoselective hydrogenation of o-toluic and 2-methyl nicotinic acids covalently bound to various chiral auxiliaries was carried out in a three-phase slurry reactor and followed in real time by means of in situ Fourier transform infrared/attenuated total reflection (FTIR/ATR) spectroscopy. The measurements show that the catalytic hydrogenation of o-toluic acid derivatives undergoes direct transformation to corresponding cyclohexanoic compounds. On the contrary, the presence of the nitrogen atom in the nicotinyl ring affects deeply the mechanism of hydrogenation by favoring the accumulation of tetrahydropyridine intermediate in the liquid phase, which is probably caused by modifying the adsorption mode on the metallic surface. It was demonstrated that data provided by examining corresponding IR stack plots by employing a chemometric, self-modeling curve resolution algorithm are more reliable than data derived from off-line GC analysis.

Lewis acid-promoted direct substitution of 2-methoxy-3-cyanopyridines by organo cuprates. Part 3: Facile preparation of nicotinamide and nicotinic acid derivatives

2-Methoxy-3-cyano-4,6-diarylpyridines were subjected to Lewis acid-promoted nucleophilic displacement reactions with various organo cuprates to afford the corresponding 2,4,6-trisubstituted nicotinonitriles. Subsequent hydrolysis of compounds 10 and 11 afforded the corresponding 2,4,6-trisubstituted nicotinic acid 22 and nicotinamide 23 derivatives, respectively. The mechanism of the displacement reaction has been studied experimentally and by molecular modeling calculations.

Effects on insulin secretion and insulin action of a 48-h reduction of plasma free fatty acids with acipimox in nondiabetic subjects genetically predisposed to type 2 diabetes.

Elevated plasma FFA cause beta-cell lipotoxicity and impair insulin secretion in nondiabetic subjects predisposed to type 2 diabetes mellitus [T2DM; i.e., with a strong family history of T2DM (FH+)] but not in nondiabetic subjects without a family history of T2DM. To determine whether lowering plasma FFA with acipimox, an antilipolytic nicotinic acid derivative, may enhance insulin secretion, nine FH+ volunteers were admitted twice and received in random order either acipimox or placebo (double-blind) for 48 h. Plasma glucose/insulin/C-peptide concentrations were measured from 0800 to 2400. On day 3, insulin secretion rates (ISRs) were assessed during a +125 mg/dl hyperglycemic clamp. Acipimox reduced 48-h plasma FFA by 36% (P < 0.001) and increased the plasma C-peptide relative to the plasma glucose concentration or DeltaC-peptide/Deltaglucose AUC (+177%, P = 0.02), an index of improved beta-cell function. Acipimox improved insulin sensitivity (M/I) 26.1 +/- 5% (P < 0.04). First- (+19 +/- 6%, P = 0.1) and second-phase (+31 +/- 6%, P = 0.05) ISRs during the hyperglycemic clamp also improved. This was particularly evident when examined relative to the prevailing insulin resistance [1/(M/I)], as both first- and second-phase ISR markedly increased by 29 +/- 7 (P < 0.05) and 41 +/- 8% (P = 0.02). There was an inverse correlation between fasting FFA and first-phase ISR (r2 = 0.31, P < 0.02) and acute (2-4 min) glucose-induced insulin release after acipimox (r2 =0.52, P < 0.04). In this proof-of-concept study in FH+ individuals predisposed to T2DM, a 48-h reduction of plasma FFA improves day-long meal and glucose-stimulated insulin secretion. These results provide additional evidence for the important role that plasma FFA play regarding insulin secretion in FH+ subjects predisposed to T2DM.

The power to reduce: pyridine nucleotides – small molecules with a multitude of functions

The pyridine nucleotides NAD and NADP play vital roles in metabolic conversions as signal transducers and in cellular defence systems. Both coenzymes participate as electron carriers in energy transduction and biosynthetic processes. Their oxidized forms, NAD+ and NADP+, have been identified as important elements of regulatory pathways. In particular, NAD+ serves as a substrate for ADP-ribosylation reactions and for the Sir2 family of NAD+-dependent protein deacetylases as well as a precursor of the calcium mobilizing molecule cADPr (cyclic ADP-ribose). The conversions of NADP+ into the 2'-phosphorylated form of cADPr or to its nicotinic acid derivative, NAADP, also result in the formation of potent intracellular calcium-signalling agents. Perhaps, the most critical function of NADP is in the maintenance of a pool of reducing equivalents which is essential to counteract oxidative damage and for other detoxifying reactions. It is well known that the NADPH/NADP+ ratio is usually kept high, in favour of the reduced form. Research within the past few years has revealed important insights into how the NADPH pool is generated and maintained in different subcellular compartments. Moreover, tremendous progress in the molecular characterization of NAD kinases has established these enzymes as vital factors for cell survival. In the present review, we summarize recent advances in the understanding of the biosynthesis and signalling functions of NAD(P) and highlight the new insights into the molecular mechanisms of NADPH generation and their roles in cell physiology.

Unusual Sterically Controlled Regioselective Lithiation of 3-Bromo-5-(4,4‘-dimethyl)oxazolinylpyridine. Straightforward Access to Highly Substituted Nicotinic Acid Derivatives

[Structure: see text] Lithiation of 5-bromonicotinic acid protected as secondary or tertiary amide as well as (4,4'-dimethyl)oxazoline with lithium amides is reported. The unusual C-2 and C-4 regioselective lithiation of 3-bromo-5-(4,4'-dimethyl)oxazolinylpyridine using LTMP versus LDA was observed, providing a new route to substituted nicotinic acid scaffolds. The methodology was applied to the synthesis of novel C-4 and C-6 arylated 5-bromonicotinic acids.

Microwave‐Assisted Flexible Synthesis of 7‐Azaindoles.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Efficient Route to 6‐CF3‐Substituted Nicotinic Acid Derivatives.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.