Carbonyl Toxification Hypothesis of Biological Aging
Alvaro Macieira-Coelho in Molecular Basis of Aging, 2017
Among these, carbonyl compounds (biomolecules that contain a carbon-oxygen double bond, or carbonyl group, mainly aldehydes and ketones) are active intermediates, particularly when they are conjugated with a secondary functional group (e.g., α,β-unsaturated aldehydes). Carbonyl compounds have the potential to react with a variety of biomolecules such as proteins and nucleic acids.28 Carbonyls conjugated with some additional functional groups in the vicinity of the primary aldehyde group are termed di-, multicarbonyl compounds (DMcarbonyls) in this review. Such DMcarbonyls include 2-ketoaldehydes, hydroxylenals, enals, dienals, trienals, osones, and various reductones that are all very reactive and toxic to almost all cellular and extracellular biomolecules.29,30 Two of the most intensively studied DMcarbonyls are malondialdehyde31 and 4-hydroxylnonenals.30 A large body of knowledge about their biological occurrence, mechanism of formation, reactivity, and biotoxicity has been obtained mainly through studies of lipid peroxidation.
Molecular Properties of Radiotracer Receptors
Lelio G. Colombetti in Principles of Radiopharmacology, 1979
A convenient tissue to study the effect of acetylcholine and its congeneric series is clam hearts, where the effect of acetylcholine is to reduce contractions. The effect of altering the molecular structure on the relative potency is shown in Table 1. As the table shows, any alteration in the acetylcholine structure results in a drastic decrease in the relative potency. When the ester bond was replaced by a methylene group, the relative potency dropped to 8%. The position of the carbonyl group is also important. If the carbonyl group is moved closer to the nitrogen group, a reduction in potency is noted. It is also noted that a 5-carbon chain is optimal for the receptor species. Changes in the alkyl group attached to the nitrogen also affected the potency of the chemical. The monomethylamine showed a drastic decrease in potency, and the unsubstituted monomethylamine was practically inert.
Free Radical Damage and Lipid Peroxidation
Robert G. Meeks, Steadman D. Harrison, Richard J. Bull in Hepatotoxicology, 2020
Thus, once lipid peroxidation is initiated, the process can be propagated via autocatalysis, which is dependent not only on oxygen, but on metal catalyzed decomposition of transiently appearing lipid hydroperoxides. Eventual decomposition of the peroxidized fatty acids gives rise to a variety of stable end products. Endoperoxide decomposition yields malonic dialdehyde (Figure 4), easily detected in the widely used thiobarbituric acid (TBA) test (Recknagel et al., 1982). A variety of other carbonyl compounds also appear (Esterbauer, 1985), some of which are toxic (Benedetti et al., 1980, and see below). Peroxidative decomposition of lipids also yields ethane, from omega-3 fatty acids, e.g., linolenic acid; and pentane, from omega-6 fatty acids, e.g., linoleic acid (Sevanian and Hochstein, 1985; Horton and Fairhurst, 1987). Gas chromatographic detection of these short-chain hydrocarbons in exhaled air of experimental animals has proven to be a powerful noninvasive technique for monitoring lipid peroxidation in vivo (Wendel, 1987).
A 2018–2019 patent review of metallo beta-lactamase inhibitors
Published in Expert Opinion on Therapeutic Patents, 2020
Nakita Reddy, Mbongeni Shungube, Per I Arvidsson, Sooraj Baijnath, Hendrik G Kruger, Thavendran Govender, Tricia Naicker
The patent filed by Wu et al. [55] claims the synthesis of cyclic boronic acid derivatives that possess efficacy as inhibitors of both SBLs and MBLs, as well as Ambler class C beta-lactamases. The synthesis of 16 examples were reported with variation on the amide carbonyl group as depicted by the R-group shown in Figure 9. However, only the biological activity of compounds 44 and 45 were reported which showed moderate activity against VIM-2. A crystal structure of example 44 bound to VIM-2 was reported by Krajnc et al. [56], depicting the bicyclic borate inhibiting the MBL via a tetrahedral boron bound to the enzyme and thus forming a tricyclic borate. The broth microdilution technique was employed by Wu et al. [55], to determine the MIC’s of the inhibitors in the presence of a fixed amount of ceftazidime or cefotaxime. In addition, the IC50 was also determined for each compound. The beta-lactamases included in this study were SHV-5 (SBL), CTXM-15 (ESBL), KPC-2 (SBL) VIM-2 (MBL), P99+ (CLASS C) and OXA-23 (SBL). All the enzymes tested against compounds 44 and 45 produced a biochemical IC50 of <0.10 µM. Compounds 44 and 45 showed similar results for VIM-2, P99+ and OXA-23, producing a MIC within the range of 2–16 mg/L. However, for SHV-5, CTXM-15, and KPC-2, compound 44 produced a much lower MIC of <1 mg/L, indicating suitability as an inhibitor for SBLs.
Ethanol-assisted kneading of apigenin with arginine for enhanced dissolution rate of apigenin: development of rapidly disintegrating tablets
Published in Pharmaceutical Development and Technology, 2021
Fatma A. Kassem, Abdelaziz E. Abdelaziz, Gamal M. El Maghraby
The FTIR spectra were collected for apigenin, arginine, and their co-processed mixtures. Figure 1 shows representative spectra of these materials. The FTIR spectrum of unprocessed apigenin shows specific absorption bands corresponding to its functional groups. These include the broad absorption band at 3334 cm−1 for phenolic O–H stretching vibration, an absorption band at 3096 cm−1 reflecting the C–H aromatic stretching. The ketonic carbonyl group was shown at 1656 cm−1 with aromatic C = C stretching vibrations being noticed at 1611 cm−1 and 1500 cm−1. The absorption band of phenolic OH bending appeared at 1358 cm−1 with the phenolic C–O stretching showing at 1299 cm−1, 1272 cm−1 and 1245 cm−1. The absorption band at 1181 cm−1 is due to C–O–C stretching (Figure 1). This spectral pattern and its assignment correlate with the published work on apigenin (Mariappan et al. 2012; Altamimi et al. 2018).
Steroid sulfatase inhibitors: the current landscape
Published in Expert Opinion on Therapeutic Patents, 2021
Hanan S. Anbar, Zahraa Isa, Jana J. Elounais, Mariam A. Jameel, Joudi H. Zib, Aya M. Samer, Aya F. Jawad, Mohammed I. El-Gamal
Piptolinic acid D (21), pinicolic acid B (22), and ganoderol A (23) are natural lanostane triterpene compounds isolated from natural sources and reported as STS inhibitors. Compounds 21 and 22 are isolated from Fomitopsis pinicola Karst. (strain 442, voucher number: FompinE00442) [115] while compound 23 is isolated from Ganoderma lucidum Karst. (voucher number: 680,898). They were tested against STS enzyme and showed modest activity. The three compounds were tested at 20 µM concentration and exerted inhibition percentage values of 74%, 72%, and 62%, respectively. Their IC50 values in cell-free STS assay are 10.5, 12.4, and 15.7 µM, respectively. Reduction of the ketone group attached to ring A of compound 23 to secondary alcohol or oxidation of the terminal alcoholic group into aldehyde led to weaker inhibitory effect against STS (39% and 31% inhibition at 20 µM, respectively). Reduction of the ketone group attached to ring A in general in all the compounds led to weaker activity, so this carbonyl group seems essential for activity[116]. Further lead optimization and development of more potent semi-synthetic analogs of these three compounds maybe required to optimize the potency against STS.