Nicotinic Acid. Water-insoluble Esters and Amides

Badgett, C. O.; Provost, Raymond C.; Ogg, C L; Woodward, C. F.

doi:10.1021/ja01223a028

Cited by 29 publications

(6 citation statements)

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“…Their characterization and purity are described in detail in the supplemental information online. The analytical data for each compound are in good agreement with literature data (20). DPPC was obtained from Avanti Polar Lipids at Ͼ 99% purity and used without further purification.…”

Section: Methodssupporting

confidence: 83%

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Interaction of long-chain nicotinates with dipalmitoylphosphatidylcholine

Lehmler

Fortis-Santiago

Nauduri

et al. 2005

Journal of Lipid Research

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The interaction of four long-chain nicotinates, compounds that are of interest as potential chemopreventive agents, with dipalmitoylphosphatidylcholine (DPPC) was investigated in monolayers at the air-water interface and in fully hydrated bilayers. For the monolayer studies, the compression isotherms of mixtures of the respective nicotinate with DPPC were recorded at various compositions on a hydrochloric acid subphase (pH 1.9-2.1, 37 ؎ 2 ؇ C). The headgroup of the nicotinates (24-29 Å 2 /molecule) is larger than that of the hydrophobic tail (20 Å 2 /molecule). The pure nicotinates exhibit a temperature-and chain lengthdependent transition from an expanded to a condensed phase. Analysis of the concentration dependence of the average molecular area at constant film pressure and the concentration dependence of the breakpoint of the phase transition from the expanded to the condensed state suggests that all four DPPC-nicotinate mixtures are partially miscible at the air-water interface. Although a complex phase behavior with several phase transitions was observed, differential scanning calorimetry studies of the four mixtures are also indicative of the partial miscibility of DPPC and the respective nicotinate.Overall, the complex phase behavior most likely results from the head-tail mismatch of the nicotinates and the geometric packing constraints in the twocomponent lipid bilayer. Nicotinic acid and its alkyl esters are of considerable biological and pharmacological importance. Besides being the precursor of cofactors to many vital enzymes, nicotinic acid is a drug possessing vasodilating and fibrinolytic properties. Nicotinic acid itself has been proven beneficial against bleomycin-and cyclophosphamide-induced lung injury in animal models (1-5). Dietary supplements of nicotinic acid and dermatologic formulations of its longchain esters are under investigation for the prevention and treatment of skin carcinogenesis (6). Therefore, nicotinic acid esters may be useful as a chemopreventive agent for the prevention of lung cancer.Currently, there is significant interest in the pulmonary administration of several chemopreventive agents, such as steroids and retinoids, directly to the lung because of reduced systemic toxicity (7-11). This route of administration may also be advantageous for the administration of nicotinic acid esters, by using either an aerosol or a perfluorocarbon vehicle (12, 13). Although the interaction of various chemopreventive agents, especially retinoids, with phospholipids has been investigated (14, 15), there is no current knowledge about the factors that determine the interaction (i.e., phase behavior) of nicotinates with biological lipids such as the phospholipids present in pulmonary surfactant. A better understanding of these interactions, however, is a prerequisite for the rational design of nicotinates for pulmonary administration, especially using a perfluorocarbon-based drug delivery system (12, 13). The aim of this study is to understand which molecular characteristics influe...

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Section: Methodssupporting

confidence: 83%

“…In contrast to short-chain nicotinates (Ͻ8 carbon atoms) (13), long-chain nicotinates (Ͼ14 carbon atoms) have a limited solubility in water (20). Therefore, it was typical long-chain hydrocarbon carboxylic acids or alcohols (35).…”

Section: Monolayer Studies Of Pure Nicotinatesmentioning

confidence: 99%

Interaction of long-chain nicotinates with dipalmitoylphosphatidylcholine

Lehmler

Fortis-Santiago

Nauduri

et al. 2005

Journal of Lipid Research

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“…N -Phenyl-3-pyridinecarboxamide (5) : yield 54 mg (27%); mp 118.5−119 (lit. 119−120 °C and 116.8−117.2 °C); IR (gas phase) 3462, 3071, 1712 cm -1 ; IR (KBr) 3351, 3055, 1653 cm -1 ; 1 H NMR (200 MHz, CDCl 3 ) δ 9.03 (d, J = 2.1 Hz, 1H), 8.96 (br s. 1H), 8.65 (dd, J = 4.8, 1.4 Hz, 1H), 8.14 (dt, J = 1.9, 7.9 Hz, 1H), 7.61 (d, J = 7.7, 2H), 7.35−7.27 (m, 3H), 7.14 (dt, J = 0.8, 7.3 Hz, 1H); MS (EI) m / z (rel intensity) 198 (44, M + ), 197 (11, M + − H), 106 (100). Anal.…”

Section: Methodsmentioning

confidence: 99%

Synthesis of 2-Pyridinylbenzoxazole: Mechanism for the Intramolecular Photosubstitution of the Haloarene with the Carbonyl Oxygen of the Amide Bond in Basic Medium

1999

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2-Pyridinylbenzoxazole derivatives have been synthesized by the intramolecular photosubstitution reaction of N-(2-halophenyl)pyridinecarboxamide (1 and 2) with its amide bond in basic medium. In neutral medium both intramolecular photosubstitution and photoreduction reactions occurred. In the photosubstitution reaction a singlet state of the o-haloarene is involved, whereas in the photoreduction a triplet state of the o-haloarene is involved; oxygen inhibited the photoreduction but not the photosubstitution. The relative rate studies showed that a base accelerates the photosubstitution reaction but decelerates the photoreduction. o-Iodoarenecarboxamide is more reactive than o-bromoarenecarboxamide, which in turn is more reacitive than o-chloroarenecarboxamide. UV−vis absorption change in the presence of a base showed that an imidol and/or imidolate anion is involved in the reaction. Several transient species, such as charge-transfer excited states and a cyclohexadienyl anion radical, have been identified from the photolysis of 1 and 2 in basic medium by laser flash photolysis. In neutral medium dibromide anion radical and a phenyl σ radical were identified in addition to the above intermediates. On the basis of the photokinetic and laser flash photolysis studies, an intramolecular photosubstitution of N-(o-halophenyl)pyridinecarboxamide with its amide bond occurs via an intramolecular SN(ET)Ar* mechanism to afford 2-pyridinylbenzoxazole derivative, and the photoreduction proceeds via a free radical mechanism to give N-phenylpyridinecarboxamide.

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“…NJf '-Bis(l-decylnipecotoyl)-2-methylpiperazine (7b) was prepared by a modification of the procedure reported by Badgett et al 20…”

Section: Methodsmentioning

confidence: 99%

Design and Synthesis of Piperidine-3-carboxamides as Human Platelet Aggregation Inhibitors

Zheng¹,

Salgia²,

Thompson³

et al. 1995

J. Med. Chem.

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A detailed structure-activity analysis was carried out using eight 1-alkyl(aralkyl)nipecotamides (type 5), 33 bis-nipecotamidoalkanes and aralkanes (type 6), and 7 N,N'-bis(nipecotoyl)-piperazines (type 7) as inhibitors of human platelet aggregation. Steric factors played an important role in determining the activity of type 5 compounds possessing an an appropriate degree of hydrophobic character. Types 6 and 7 compounds were more potent than the corresponding type 5 molecules. Hydrophobic character appeared to influence the activity of type 6 compounds. A 3-substituent on the piperidine ring was necessary for antiplatelet activity; the substituent should be preferably an amide with its C attached directly to the ring. 3,5-Disubstitution and 2-substitution led to a decline in activity. Optimal activity was attained when the two nipecotoyl ring N atoms were connected by an aralkyl group, and separated by approximately 7 A. It is suggested that van der Waals forces and pi interactions may govern the inhibitor-platelet interaction. The most potent type 6 inhibitor was alpha,alpha'-bis[3-(N-ethyl-N-butylcarbamoyl)piperidino]-p-xylene (6i). The most potent type 5 compound was 1-decyl-3-(N,N-diethylcarbamoyl)piperidine (5a). Any substitution on the piperazine ring of type 7 compounds led to a decline in activity, the most active analog being N,N'-bis(1-decylnipecotoyl)piperazine (7a). It is suggested that nipecotamides interact with anionic platelet sites located 7 A from each other and connected by a hydrophobic well.

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Nicotinic Acid. Water-insoluble Esters and Amides

Cited by 29 publications

References 0 publications

Interaction of long-chain nicotinates with dipalmitoylphosphatidylcholine

Interaction of long-chain nicotinates with dipalmitoylphosphatidylcholine

Synthesis of 2-Pyridinylbenzoxazole: Mechanism for the Intramolecular Photosubstitution of the Haloarene with the Carbonyl Oxygen of the Amide Bond in Basic Medium

Design and Synthesis of Piperidine-3-carboxamides as Human Platelet Aggregation Inhibitors

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