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Long-Acting VIP Analogs
Published in Sami I. Said, Proinflammatory and Antiinflammatory Peptides, 2020
The development of other types of cyclic analogs with internal lactam bridges was described in Section II. It had been the goal of these efforts to enhance potency as well as stability against enzymatic degradation by creating conformational restrictions of these molecules in order to obtain highly active and long-acting analogs (62). It has been pointed out that the formation of a lactam bridge between Lys21 and Asp25 in one analog, namely, Ac-[Lys12,Ahx17,Asp25,Val26,Thr28]-VIP cyclo(Lys21—>Asp25) [13 in Table 3], was most successful. When this analog was tested as a bronchodilator in guinea pigs in vivo, it was also found to be quite potent, with an ED50 of 1.2 mg in comparison to the parent linear analog 3 (ED50 = 6.3 mg). It was important to find, in addition to increased potency, also a prolonged duration of action: a halftime of activity of 90 min was determined for the cyclic compound 13, as compared to only 5 min observed for the parent linear peptide 3.
Benzene Hematotoxicity
Published in Muzaffer Aksoy, Benzene Carcinogenicity, 2017
Benzene (C6H6) is the parent hydrocarbon of the aromatic group, the resonant cyclic compound consisting of only carbon and hydrogen.1,2 In 1825, Faraday was able to isolate benzene from coal tar naptha which was used as a rubber solvent.3 Kekule was the first to determine the arrangement of six carbon atoms and the closed ring of the benzene nucleus in 1866. The term "benzene" is used in England and in the U.S. while benzol is favored in Germany. In France, benzene is called "benzine". Benzene is produced mainly in petrochemical operations, but small quantities may be obtained as a by-product of operations in the steel industry. Benzene stems not only from industrial sources. All crude oils contain small amounts of benzene, and vegetation emits benzene.2 It is also found in tap and unprocessed water and in animal sources. Tobacco smoke contains benzene in insignificant amounts.4-6 The discovery of aniline dye gave reason for industry to develop the distillation of coal tar to obtain benzene, homologs, and phenols.3 Benzene is used as a solvent for rubber, gum, dyes, resins, fats, and alkaloids, besides being used in the manufacture of drugs, dyes, and explosives. In the last decade, the development of the chemical industry, especially in the field of plastics, firmly established the necessity of using large quantities of benzene as the starting material for chemical synthesis. Benzene is often used to clean machinery as well as grease from hands, and has even been used as a domestic agent. Additional uses of benzene are still being discovered; the possible use of benzene to replace lead as the "antiknock" component in motor oils is an example. However, public exposure to benzene in petroleum (ranging between 1 to 5%) has caused increased concern regarding benzene as a significant environmental pollutant.4-10 All data concerning benzene occurrence and uses are discussed extensively in Chapter 1.
Application of the Mannich reaction in the structural modification of natural products
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2023
Miao-Xia Pu, Hong-Yan Guo, Zhe-Shan Quan, Xiaoting Li, Qing-Kun Shen
Liu et al.70 synthesised a series of Mannich base derivatives with apigenin as the lead compound, introduced different primary or secondary amines at the C-8 position through the Mannich reaction, and evaluated their antibacterial activities against Staphylococcus aureus, Bacillus subtilis, Escherichia coli, and Pseudomonas aeruginosa (Table 3). All compounds exhibited stronger antibacterial activity than the lead compound ampicillin, with minimum inhibitory concentration (MIC) values ranging 1.95–62.5 µg/mL. Among them, compounds 52 and 53 (Figure 4) exhibited significant inhibitory activity against S. aureus and B. subtilis, with MIC values of 1.95 and 3.91 µg/mL, respectively, which were comparable to that of the positive control tetracycline (MIC = 1.95 and 3.91 µg/mL), but lower than that of ampicillin (MIC = 31.25 µg/mL). Moreover, SAR analysis showed that the six-membered cyclic compound 52, containing two heteroatoms, was better at improving the antibacterial activity of apigenin.
Transcriptional Profiling of Daily Patterns of mRNA Expression in the C57BL/6J Mouse Cornea
Published in Current Eye Research, 2019
Xinwei Jiao, Mingjuan Wu, Dingli Lu, Jianqin Gu, Zhijie Li
During the day, metabolic processes, peptide metabolic processes, and amide biosynthetic processes are uniquely enriched for biological processes (Figure 5a and Supplemental Table 5); mitochondria and organelle parts for cellular components (Figure 5b and Supplemental Table 6); and structural constituents of ribosomes, RNA binding, and organic cyclic compound binding for molecular function (Figure 5c and Supplemental Table 7). However, during the night, positive regulation of biological processes, positive regulation of cellular processes, and positive regulation of nitrogen compound metabolic processes are commonly enriched for biological processes (Figure 5a); intracellular organelles and cytoplasmic parts for cellular components (Figure 5b); protein binding, enzyme binding, and binding for molecular function (Figure 5c).
Bioactive cyclic molecules and drug design
Published in Expert Opinion on Drug Discovery, 2018
Research in the latter part of the 20th century identified many classes of natural products with a majority being classified into one of four major groups from their structures and biosynthetic mechanisms. These were the terpenoids, alkaloids, polyketides, and non-ribosomal peptides (the NRPs). Although there is not enough space to show many clinically important cyclic peptides, one immunosuppressive agent should be commented on, cyclosporin (aka ciclosporin) shown in Figure 56. The structure of the compound was first reported as an iodo derivative (X-ray) in 1976 [15] and more than 30 variations have been isolated from submerged cultures of T. inflatum all synthesized by the same three enzymes with their genes being organized in a large secondary metabolite cluster. Cyclosporins have been isolated from at least 17 different fungal taxa[16], and all have the necessary ‘flexability’ to cross cell membranes and to interact with peptidyl prolyl cis/trans isomerase. Since the molecule contains D-alanine as well as two other non-proteinogenic amino acids, a D-alanine racemase is part of the genetic cluster, but will also racemize serine, Abu and leucine. The final assembly utilizes a large (15K aminoacid) NRPS complex known as CySyn, which starts with the D-Ala precursor and then follows along with the other 10 aminoacids, followed by cyclization. D-Ala in the cyclic compound is probably a method of stopping proteolytic cleavage of the active molecule.