Photoreactivity of biologically active compounds. XVII. Influence of solvent interactions on spectroscopic properties and photostability of primaquine

The influence of solvent interactions on absorption properties, fluorescence properties (emission spectra and quantum yields) and relative photochemical degradation rates of primaquine has been investigated, in order to evaluate photochemical reaction mechanisms and chemical properties of the compound. The first absorption band (n - pi*) of primaquine is only slightly dependent on properties of the solvent, which can be ascribed to a strong, intramolecular hydrogen bond between the quinoline N and amine group in the ground state (S0). Amphiprotic solvents with predominant acidic properties (water and methanol) will to some extent stabilize the molecule and initiate hypsochromic shifts of the absorption band by protic interactions, while the other solvents (amphiprotic, basic and neutral) influence the absorption spectrum by general solvent effects only. The excited singlet (S1*) state of primaquine interacts more efficiently with the surrounding solvents than the S0 state, as evaluated by the Stokes shifts. The pKa value of the quinoline N is likely to increase in the S1* state, which is important for the observed protic interactions with amphiprotic solvents of predominant acidity. Specific solvent effects are highly important for the efficiency of the fluorescence (fluorescence quantum yields; phi f). The fluorescence is quenched by amphiprotic solvents, likely due to a rupture of the intramolecular bond and protonation of the quinolone N, and enhanced by polar, non-protic (basic) solvents, probably by stabilization of the delta intramolecular hydrogen bond. The observed photochemical degradation rates of primaquine in amphiprotic media are positively correlated with phi f, indicating that the photochemical degradation of primaquine is dependent on intramolecular hydrogen bonding and non protonated lone-pair electrons at the quinoline N. The intramolecular ring-formation with a subsequent increased lipophilic character and (lack of) interactions with the surroundings, are important factors for biological behavior as well as pharmaceutical properties of primaquine. Knowledge about solvent interactions with primaquine in the S0 and S1* states is essential for the proceeding evaluation of photostability and phototoxicity of the drug.     

Determination of aqueous stability and degradation products of series of coumarin dimers

The stability in aqueous solution of five classes of coumarin dimers (I–V, compounds 1–29) was studied by HPLC–MS/MS at various pH values. The relationship between chemical structure and stability is discussed. It was found that dimeric compounds with strong electron withdrawing groups (EWGs) on the α-carbon to the bridging C-atom are stable at all pH values, whereas other derivatives undergo retro-Michael addition at rates which are also affected by the substituents on the aromatic rings. In some cases formation of stable isomers or oxidation products was observed. In order to evaluate their developability and potential for progression to in vivo studies, representative compounds were tested in an in vitro microsomal stability assay.     

Isoxazoles V: chemical stability of diisoxazolylnaphthoquinone in aqueous solution

The hydrolytic degradation of 2-(3,4-dimethyl-5-isoxazolylamine)-N-(3,4-dimethyl-5-isoxazolyl )-1,4- naphthoquinone-4-imine (1) was investigated over a wide range of pH values and at different temperatures. The degradation rates were determined by reversed-phase HPLC and were observed to follow pseudo-first-order kinetics with respect to the concentration of 1. The pH-rate profile was linear with slopes -1 and +1 in acid and alkaline pH, respectively, becoming pH independent in the region of maximum stability from pH 4.5 to 10.0. Neither primary salt effects nor buffer catalysis was observed due to the buffer species employed.     

Comparative stability of cephalosporins in aqueous solution: kinetics and mechanisms of degradation.

The acidic, neutral, and alkaline degradations of six therapeutically useful cephalosporins (cephalothin, cephaloridine, cephaloglycin, cephalexin, cephradine, and cefazolin), 7-amino-cephalosporanic acid, 7-aminodeacetoxycephalosporanic acid, and some 7-substituted derivatives were followed by high-pressure liquid chromatographic, UV spectrometric, iodometric, and hydroxamic acid assays. The pH-rate profiles were determined at 35 degrees and mu = 0.5. The acidic degradation pathway for the 3-acetoxymethyl and 3-pyridinylmethyl derivatives was the specific hydrogen-ion-catalyzed hydrolysis of the beta-lactam bonds. The beta-lactam hydrolyses of these antibiotics exhibited half-lives of about 25 hr at pH 1.0 and 35 degrees. The acetyl functions of 3-acetoxymethylcephalosporins were hydrolyzed eight times faster than their beta-lactam moieties to yield the corresponding deacetyl intermediates, which were rapidly converted to the lactones. Deacetoxycephalosporins were fairly acid stable; e.g., cephalexin and cephradine were about 25 times more stable than cephalothin, cephaloridine, and cephaloglycin and about 180 times more stable than ampicillin at pH 1.0. In the neutral degradation of 3-acetoxymethyl compounds, the competitive reactions of the direct water attack and intramolecular catalysis by the side-chain amido upon the beta-lactams were proposed. The pH-rate profiles near pH 8 for cephaloglycin, cephalexin, and cephradine could be explained by the intramolecular-nucleophilic attack of the side-chain alpha-amino group upon the beta-lactam carbonyls to produce diketopiperazine-type compounds. The reactivity of the cephalosporins in the hydroxideion-catalyzed degradation was influenced significantly by the C-3 methylene substituents.     

Nature of the main contaminant in the drug primaquine diphosphate: SFC and SFC-MS methods of analysis

The drug primaquine diphosphate is used for causative treatment of malaria. Using HPLC-MS and GC-MS, this research group was previously able to show that the main contaminant of primaquine is the positional isomer quinocide [I. Brondz, D. Mantzilas, U. Klein, D. Ekeberg, E. Hvattum, M.N. Lebedeva, F.S. Mikhailitsyn, G.D. Soulimanov, J. Roe, J. Chromatogr. B: Anal. Technol. Biomed. Life Sci. 800 (2004) 211-223; I. Brondz, U. Klein, D. Ekeberg, D. Mantzilas, E. Hvattum, H. Schultz, F. S. Mikhailitsyn, Asian J. Chem. 17 (2005) 1678-1688]. Primaquine and quinocide are highly toxic substances which can have a number of side effects upon use in medical treatment. A standard for quinocide is not typically commercially available. In the present work, supercritical fluid chromatography-mass spectrometry (SFC-MS) with two different columns was used to achieve a shorter analysis time for the separation between the positional isomers quinocide and primaquine in primaquine diphosphate and to elucidate additional information about differences in their MS fragmentation. Unlike using HPLC-MS, it was possible to achieve the differential fragmentation of positional isomers at branching points using the SFC-MS technique. The desired short analysis time was achieved using SFC equipped with a Discovery HS F5 column and the differential fragmentation of positional isomers during SFC-MS provides information on the differences in the structure of these substances. Using a Chiralpak AD-H chiral column, it was possible to resolve the enantiomers in primaquine and separate quinocide from those enantiomers.     

Oxidation and degradation products of papaverine. Part II[1]: investigations on the photochemical degradation of papaverine solutions

The structure of the final degradation product formed in papaverine solutions in either water or chloroform was found to be a 2, 3, 9, 10-tetramethoxy-12-oxo-12H-indolo [2, 1-a] isoquinolinylium salt (a dibenzo [b, g] pyrrocolonium derivative). Its formation from papaverine oxidation products that is papaverinol, papaveraldine, and papaverine-N-oxide chloroform solutions under the influence of UV light, was investigated and possible reaction pathways are discussed.     

Physiologically active substances from marine sponges V: Isolation of physiologically active compounds from the sponge Verongia archeri.

Methanolic extracts of hard and soft varieties of the sponge Verongia archeri were found to contain similar compounds. An isolation procedure and the structures of 2-(3',5'-dibromo-4'-hydroxyphenyl)-acetamide, 1-(3',5'-dibromo-1',6'-dihydroxy-4'-methoxycyclohexa-2',4'-diene)acetonitrile, and 2-oxo-5,7-dibromo-6-methoxy-9-hydroxy-8,9-dihydrocoumarin from one variety are described.     

Photoreactivity of biologically active compounds. XVIII. Photostability of ofloxacin in the solid state and in a tablet formulation

The photostability of ofloxacin in the solid state has been investigated. The change in colour of uncoated and film coated ofloxacin tablets and compressed ofloxacin was studied as a function of irradiance level and total exposure energy. The degradation of ofloxacin in the various preparations was quantified by HPLC and the antimicrobial activity was determined for selected tablets. The structure of two main degradation products from ofloxacin in the solid state has been postulated from LC-MS analysis. Both products have an absorption cut-off below 400 nm and cannot explain the observed change in tablet colour. There was no apparent relationship between the change in colour and the loss of active substance or antibacterial activity for the preparations investigated. The change in colour was easily detectable at rather low exposure levels. Apparently, there was a difference in light sensitivity between the two film-coated tablet batches investigated. The results obtained were partly dependent on the conditions within the radiation chamber (e.g., exposure time and irradiance level), which emphasizes the importance of testing the samples under various conditions unless the results are unequivocal. The tablets were sensitive to visible light although ofloxacin only has a neglectible absorption above 400 nm. The film coated ofloxacin tablets did, however, absorb above 400 nm with a cut-off at approximately 520 nm. A change in tablet coating to include a component that filters visible light in addition to UV radiation might provide a solution to the discolouration problem and prevent batch to batch variations with respect to light sensitivity.     

Insects: an underrepresented resource for the discovery of biologically active natural products

Nature has been the source of life-changing and -saving medications for centuries. Aspirin, penicillin and morphine are prime examples of Nature׳s gifts to medicine. These discoveries catalyzed the field of natural product drug discovery which has mostly focused on plants. However, insects have more than twice the number of species and entomotherapy has been in practice for as long as and often in conjunction with medicinal plants and is an important alternative to modern medicine in many parts of the world. Herein, an overview of current traditional medicinal applications of insects and characterization of isolated biologically active molecules starting from approximately 2010 is presented. Insect natural products reviewed were isolated from ants, bees, wasps, beetles, cockroaches, termites, flies, true bugs, moths and more. Biological activities of these natural products from insects include antimicrobial, antifungal, antiviral, anticancer, antioxidant, anti-inflammatory and immunomodulatory effects.     

胰岛素聚氰基丙烯酸正丁酯纳米粒在油介质中的稳定性及其对糖尿病大鼠的降血糖作用

目的通过对胰岛素聚氰基丙烯酸正丁酯纳米粒(IPN)在油介质(含有0.5%吐温-20和5%维生素E的豆油)中的稳定性及其口服后对链脲霉素引起的糖尿病大鼠降血糖作用的研究，希望得到一种稳定而有效的胰岛素纳米粒口服制剂。方法依据IPN中的胰岛素含量，IPN的平均粒径和粒子跨度，及其体外释药来评估其稳定性。将IPN分散在含有0.5% 吐温-20，pH 2.0的水溶液中作为对照。结果研究表明，不论样品是在(25±2) ℃条件下避光放置1年，还是在体外与3种消化道酶37 ℃酶解30 min，油介质中的IPN都比水介质中IPN稳定性好。依据单剂量po给药后，在0-144 h血糖降低的百分数与时间曲线上面积(AAC)可知，po IPN的油溶液(50 u·kg^-1)相对于sc胰岛素(2 u·kg^-1)的生物利用度为22.4%，明显高于po IPN水溶液的相对生物利用度(15.5%)。结论分散在油介质中的IPN具有较好的稳定性和相对较高的生物利用度，因此，含有0.5%吐温-20和5%维生素E的豆油有望成为口服胰岛素聚氰基丙烯酸正丁酯纳米粒的有效而稳定的分散介质。     

固定化脂质体色谱研究二至丸及其组成药物的经肠吸收成分

目的:应用固定化脂质体色谱(ILC)分析中药复方二至丸及其组成药物的经肠吸收成分及质量控制。方法:分别观察不同溶剂提取时提取液在ILC色谱柱上的色谱保留与分离,同时对在ILC色谱柱上保留的槲皮素及芹菜素进行了定量分析。结果:从ILC色谱柱保留峰的数目和峰面积两方面观察,墨旱莲的75%乙醇提取优于水提取。二至丸75%乙醇提取液中槲皮素的含量为9.6μg.g-1,芹菜素的含量为2.7μg.g-1。墨旱莲提取液中槲皮素的含量为2.8μg.g-1,芹菜素的含量为3.8μg.g-1。女贞子提取液中槲皮素的含量为9.1μg.g-1,而芹菜素用ILC未检测到。结论:槲皮素和芹菜素是二至丸中主要的可在ILC色谱上保留的成分,其中槲皮素来源于两个组成药物女贞子和墨旱莲,芹菜素仅来源于墨旱莲。槲皮素和芹菜素可能是二至丸的经肠吸收活性成分。固定化脂质体色谱有望成为中药及其复方肠吸收成分的初筛选和定量评价方法之一。     

Effect of cyclodextrins on anthracycline stability in acidic aqueous media

The effect of cyclodextrins on the stability of six anthracyclines in acidic medium at 50°C has been investigated using a stability-indicating high pressure liquid Chromatographic method. The influences of various parameters, such as the structure of cyclodextrins (-cyclodextrin, -cyclodextrin, dimethyl--cyclodextrin and -cyclodextrin) and anthracyclines, cyclodextrin concentration, the pH and the presence of a co-solvent, are investigated. Lineweaver-Burk plots were used to calculate the stability constants of the various inclusion complexes as well as the rate constants for degradation of the anthracycline guest molecules in the complexes with the host cyclodextrins. Anthracyclines complexate only with -cyclodextrin to a substantial extent. On complexation the stability of the guest molecule increases, however, the degradation pattern does not alter. The influence of the pH on the degradation of the included molecule is identical to that of the free drug. Addition of co-solvents, such as acetonitrile, causes decomposition of the complex.     

Synthesis of cinca alkaloids and related compounds. X: preparation of biologically active derivatives of indolopyridonaphthyridine (author's transl)]

Synthesis of Vinca Alkaloids and Related Compounds, X: Preparation of Biologically Active Derivatives of Indolopyridonaphthyridine The reaction of enamine derivatives of type 1 with α-substituted acrylic esters and with α-chloro-acrylonitrile furnishes a pentacyclic system. Some of the new compounds show significant vasodilator activity.