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Medicinal Plants of Mongolia
Published in Raymond Cooper, Jeffrey John Deakin, Natural Products of Silk Road Plants, 2020
Narantuya Samdan, Odonchimeg Batsukh
More than 660 PAs and PA N-oxides have been identified in over 6,000 plants, and about half of these compounds exhibit hepato-toxicity (Radominska-Pandya, 2010). While certain PAs may themselves show little toxicity, the compounds can undergo change in the liver of humans and animals to become highly toxic, alkylating pyrroles, which have (i) a double-bond in position 1,2 of the necine, (ii) a non-substituted alpha – position next to the nitrogen atom, and (iii) di-esterification of the OH-groups of the necine (monoesters are less toxic) (Hartmann and Witte, 1995; Rizk, 1991).
Drug-Induced Abnormalities of Liver Heme Biosynthesis
Published in Robert G. Meeks, Steadman D. Harrison, Richard J. Bull, Hepatotoxicology, 2020
It can, therefore, be concluded that production of a N-alkyl porphyrin with inhibitory properties towards ferrochelatase is of more common occurrence than originally suspected. Following the discovery of N-methyl protoporphyrin after DDC treatment, similar porphyrins also inhibitory towards ferrochelatase have been isolated after treatment with other dihydropyridines, griseofulvin, sydnones, and dihydroquinolines. In most cases metabolic transfer by cytochrome P450 of a small fragment of the foreign chemical to one pyrrole nitrogen of heme has been demonstrated, a fragment small enough to allow interaction of the modified porphyrin with the active site of ferrochelatase, as will now be discussed.
Red Cells with High Oxygen Affinity Hemoglobins
Published in Ronald L. Nagel, Genetically Abnormal Red Cells, 2019
How does the iron of the heme interact with the globin? As pointed out previously, four valencies are consumed by coordination with the four pyrrole rings. The fifth coordination occurs with a histidine residue in the eighth position of the F helix (His F8), also called the “proximal histidine”. The sixth coordination is occupied by the oxygen molecule when the heme is oxygenated. In oxymyoglobin the -O-O- axis is at 59° from the heme plane, while in deoxymyoglobin there is a water molecule instead. This arrangement completes the favored structure for ferrous or ferric iron — octahedral coordination. Nevertheless, this structure is further complicated by the presence of an interacting histidine, the E7 “distal histidine”, on the far site of the oxygen. This residue is too far to coordinate directly with the iron, but the nitrogen of this histidine does interact with the oxygen or the water, further modifying the properties of this ligand binding. The globin interacts with the other side chains of the pyrrole rings as we will discuss during the analysis of the conformational changes associated with oxygen binding in hemoglobin. That this whole arrangement is indispensable for the proper state of the iron in the ferrous state will be discussed again when we analyze the M hemoglobins, consisting of mutations of the proximal and distal histidines.
TGR5 agonists for diabetes treatment: a patent review and clinical advancements (2012-present)
Published in Expert Opinion on Therapeutic Patents, 2022
Rachana S. Bhimanwar, Amit Mittal
Janssen Pharmaceutica filed a patent application describing a bicyclic pyrrole scaffold-based series (general structure 11 in Figure 10) as a TGR5 modulator [38]. Compared with other designed compounds, representative compounds 11a-11d exhibited better TGR5 agonistic potency. A variety of substituted pyrrole derivatives were synthesized. The substitutions included chlorophenyl, methyl phenyl, and ethyl phenyl at the R-1 position of the Pyrrole ring. Representative compound 11a (4-chlorophenyl pyrrole derivative) exhibited lowest EC50 values of 0.069 µM as compared to compound 11b (4-methylphenyl pyrrole derivative) and 11 c (4-ethyl phenyl pyrrole derivative). The EC50 value for compound 11b and 11 c was found to be 0.179 µM and 0.219 µM respectively in a β-Arrestin assay. In OGTT experiments conducted in DIO mice, Compound 11a lowered plasma glucose levels with a delta AUC of 79% at the dose of 3 mg/kg. Furthermore, compounds 11b and 11 c decreased glucose levels by 27% and 59%, respectively.
Diurnal hepatic CYP3A11 contributes to chronotoxicity of the pyrrolizidine alkaloid retrorsine in mice
Published in Xenobiotica, 2021
Li Guo, Li Zhang, Haiman Xu, Pei Yu, Zhigang Wang, Danyi Lu, Min Chen, Baojian Wu
In this study, we observed dosing time-dependent toxicity of the pyrrolizidine alkaloid RTS in mice (Figures 3 and 4). RTS toxicity was more severe in the dark phase (ZT14 and ZT18) than in the light phase (ZT2 and ZT6) (Figure 3). This chronotoxicity was associated with a difference in systemic exposure of a pyrrolic ester (rapidly forms the pyrrole-GSH conjugate and pyrrole-protein adducts) caused by dosing time-dependent metabolism (Figure 5). Furthermore, circadian metabolism and chronotoxicity of RTS were probably due to the diurnal expression of hepatic CYP3A11, a major enzyme responsible for RTS hepatoxicity (Figures 6 and 7). This was supported by the facts that 1) CYP3A11 inhibitor ketoconazole decreased the production of pyrrole-GSH conjugate and abrogated diurnal rhythm in RTS metabolism (Figure 7), and 2) E4bp4 (a circadian regulator for Cyp3a11) ablation abolished the rhythm of CYP3A11 expression and abrogated the dosing time-dependency of RTS toxicity (Figure 8).
Synthesis of novel pyrroles and fused pyrroles as antifungal and antibacterial agents
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2021
Rania Helmy Abd El-Hameed, Amira Ibrahim Sayed, Shima Mahmoud Ali, Mohamed A. Mosa, Zainab M. Khoder, Samar Said Fatahala
Pyrroles and its fused derivatives, are an important class of naturally22,23 and synthetically24–26 occurring compounds with a wide-range of biological activities; antibacterial27–29, antifungal30–33, antiviral34–39, anticancer40,41 and anti-inflammatory42,43. Pyrrolnitin and fludioxonil, are two naturally secreted pyrroles, reported to bear a broad spectrum antifungal activities44–46. 7-deazapurine, naturally secreted pyrrolopyrimidines antibiotics, toyocamycin, tubercidin and sangivamycin, commonly have antibacterial, antifungal, anticancer, antiviral and anti-inflammatory activities22,47. Due to structural resemblance to purine, 7-deazapurines interfered with various cellular processes; toyocamycin united with tRNA, pyrrolopyrimidine inhibits tRNA aminoacylation. Sangivamycin has lately been revealed to inhibit protein kinases22, as revealed in Figure 2.