Red Cells with High Oxygen Affinity Hemoglobins
Ronald L. Nagel in Genetically Abnormal Red Cells, 2019
Heme is the combination of a porphyrin ring and an iron molecule. The porphyrin, in turn, is composed of four pyrrole rings tied together by methenyl (=CH-) bridges. In myoglobin and hemoglobin the porphyrin ring is protoporphyrin IX, defined by the type of substitutions found in the carbons not involved in the bridging. In Figure 3 it can be seen that pyrrols 1 and 4 have methyls and propionic acids as side chains while pyrrols 2 and 3 have methyls and vinyls as side chains. All of these components are arranged in a single plane resulting in a wafer-like structure. The center piece of the structure is a tetracoordinated iron atom, in which the bonds with pyrrole ring 4 and 2 are identical. The same can be said of the bonds between the iron and pyrrole 1 and 3. This structure, weighing 616 daltons, contains a large number of alternating double bonds and consequently delocalized π electrons.
Clinical Pharmacology of the Anti-Tuberculosis Drugs
Peter D O Davies, Stephen B Gordon, Geraint Davies in Clinical Tuberculosis, 2014
PA-824’s chemical cousin, delamanid (OPC-67683), is a nitro-dihydroimidazo-oxazole from Otsuka Pharmaceutical Company (Tokyo, Japan) [160,161]. Delamanid has a similar mechanism to PA-824 but is more potent. The compound has an MIC against M. tuberculosis from 0.006 to 0.024 μg/mL and has shown promising activity in the mouse model [160]. Studies in humans show the drug is well tolerated using doses up to 400 mg [167,168]. A recent study assessed the EBA of delamanid in patients with tuberculosis. Delamanid showed significant extended EBA after 14 days of treatment [167]. Delamanid is undergoing regulatory review. A pyrrole derivative, sudoterb (LL3858) was under development for tuberculosis by Lupin (Mumbai, India) [160,161]. Other pyrrole derivatives are at earlier stages of development [169]. Ethylenediamine (SQ109) was derived from ethambutol but appears to have a unique mechanism of action against the mycobacterial cell wall [160,161]. It has an MIC against M. tuberculosis of 0.11–0.64 μg/mL and appears to be bactericidal [160]. Early PK and animal model data have been published [170,171]. Animal and in vitro studies indicate the drug has synergistic effects with INH and RIF [160]. Phase I studies show the drug is well tolerated using doses up to 300 mg. Like bedaquiline, it is likely that Sequella (Rockville, MD) will pursue an indication for MDR-TB. This drug has entered clinical phase II testing and is licensed for clinical use in Russia [160].
Medicinal Plants of Mongolia
Raymond Cooper, Jeffrey John Deakin in Natural Products of Silk Road Plants, 2020
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).
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.
Related Knowledge Centers
- Aromaticity
- Chlorin
- Chlorophyll
- Heme
- Organic Compound
- Porphyrin
- Ring
- Chemical Formula
- Porphobilinogen
- Porphyrinogen