Nucleic Acids as Therapeutic Targets and Agents
David E. Thurston, Ilona Pysz in Chemistry and Pharmacology of Anticancer Drugs, 2021
Busulfan’s mechanism of action includes the formation of G-G and G-A intrastrand DNA cross-links formed through an SN2 reaction in which the nucleophilic guanine N7- or adenine N3-positions attack the carbons adjacent to the mesylate leaving groups. For example, 1,4-di(7-guanyl)butane has been identified as a product of the reaction between busulfan and DNA, suggesting that the agent acts as an interstrand cross-linking agent in a similar manner to the nitrogen mustards. This type of DNA damage cannot be easily repaired by tumor cells and leads to apoptosis. SAR studies have revealed that unsaturated analogs of known stereochemistry, such as the corresponding butyne and trans-butene derivatives, are inactive, whereas cis-butene derivatives retain activity. The activities of the saturated busulfan and cis-butene analogs depend on their structural flexibility and three-dimensional shape, respectively, which allows them to form cyclic derivatives by 1,4-bisalkylation of suitable nucleophilic groups on DNA bases. Interestingly, studies of the structure of urinary metabolites suggest that cysteine residues in certain proteins are also alkylated, which may explain some of the side effects caused by this agent.
Influence of Air on Essential Oil Constituents
K. Hüsnü Can Başer, Gerhard Buchbauer in Handbook of Essential Oils, 2020
In order to further investigate terpenoid oxidation during handling and storage, the first computational study of this kind (Bäcktorp et al., 2006) was conducted in 2006. The main goal was to obtain mechanistic understanding on possible reaction mechanisms of transforming a harmless compound such a linalool into a skin sensitizer. The theoretical framework was established by systematic investigation of smaller unsaturated systems like propene, 2-methyl-2-butene and finally 2-methyl-2-pentene. All the intermediates and products derived from this model concept system were used for comparison with the actual linalool oxidation patterns. The study (Bäcktorp et al., 2006) discussed the addition of O2 to linalool in terms of an ene-type mechanism, the radical mechanism, and the direct reaction pathway. All of the three considered the linalool-O2 biradical intermediate formation (Figure 29.2) as a branching point for further oxidation. Given that hydroperoxides were confirmed to be the strongest sensitizers of the oxidation products, these compounds were the main focus of the study.
Phosphonic Acids And Phosphonates As Antimetabolites
Richard L. Hilderbrand in The Role of Phosphonates in Living Systems, 2018
The initial synthesis5 generated the material in racemic form via a route analogous to that used2 for (20) but starting with 4-bromo-l-butene. It was later6 generated in chiral form using a Wittig phosphonylation of the aldehyde derived from D–mannitol diacetonide cleavage. This latter process has now been improved to provide higher yields31 and to allow specific introduction of tritium at the 1- and 2-positions via catalytic reduction of the vinylic phosphonate intermediate.9 A further chiral synthesis has been reported7 beginning with optically active malic acid; this route readily provides both enantiomers and a variety of useful intermediates. A further synthesis of racemic material involves sodium borohydride reduction of the immediate precursor to (13), the isosteric phosphonic acid analogue of dihydroxyacetone phosphate.8 This route is of particular interest as it allows specific introduction of a tritium label at the 3-position. A route vaguely related to those involving D- mannitol diacetonide6–7–31 has also been reported by Paulsen and Bartsch.116,117
Exposure to 1,3-Butadiene in the U.S. Population: National Health and Nutrition Examination Survey 2011–2016
Published in Biomarkers, 2021
Alma Nieto, Luyu Zhang, Deepak Bhandari, Wanzhe Zhu, Benjamin C. Blount, Víctor R. De Jesús
Human studies indicate that inhalational absorption of 2 ppm 1,3-butadiene for 20 minutes varied from 18% to 74% (Lin et al. 2001). In the liver, cytochrome P450 oxidises 1,3-butadiene to highly reactive butadiene monoepoxide (BMO). Enzymatic hydrolysis of BMO by epoxide hydrolase enzyme leads to 1,2-dihydroxy-3-butene (butadiene-diol). Conjugation with glutathione produces mercapturic acids that are excreted in urine (Csanady et al. 1992, Richardson et al. 1998, 1999). Urinary biomarkers used to evaluate 1,3-butadiene exposure include N-acetyl-S-(3,4-dihydroxybutyl)-L-cysteine (34HBMA) and the isomeric mixture of N-acetyl-S-(1-hydroxymethyl-2-propenyl)-L-cysteine (1HMPeMA), N-acetyl-S-(2-hydroxy-3-butenyl)-L-cysteine (2HBeMA), and N-acetyl-S-(4-hydroxy-2-buten-1-yl)-L-cysteine (4HBeMA). The chemical structures of 1,3-butadiene and its urinary metabolites are depicted in Scheme 1. Hydrolysis of BMO leads to the formation of butadiene-diol which subsequently reacts with glutathione to form 34HBMA, while 1HMPeMA, 2HBeMA and 4HBeMA are formed by direct conjugation of BMO with glutathione (Csanady et al. 1992, Bechtold et al. 1994, Richardson et al. 1998, 1999, Urban et al. 2003).
Design, synthesis and characterization of enzyme-analogue-built polymer catalysts as artificial hydrolases
Published in Artificial Cells, Nanomedicine, and Biotechnology, 2019
Divya Mathew, Benny Thomas, Karakkattu Subrahmanian Devaky
In 2001, Ohkubo et al. reported the dependence of substrate-stereospecific properties of esterase MIPs on the alkyl chain length and the content of the crosslinker [59,60]. Esterase mimics containing L-histidine and trimethylammonium groups were imprinted with a racemic transition state analogue of phenyl 1-benzyloxycarbonyl-3-methylpentylphosphonate for the hydrolysis of p-nitrophenyl N-benzyloxycarbonyl- L/D-leucinate using crosslinking with varying alkyl chain length (Figure 24). They used N,N0-ethylene (C2), butylene (C4), hexamethylene (C6), and decamethylene (C10)-bisacrylamide as the crosslinking agents (Figure 25). Reduced catalytic activity was observed with increasing length of alkyl chain of the crosslinker from C2 to C4. Greater stereoselectivity was observed with 20 mol% C4-crosslinked esterase MIP compared to C2-crosslinked esterase MIP. Further increase of the crosslinker content resulted in a decrease of the catalytic activities; plenty of crosslinker causes the decrease of the “fluctuations” of the cavity. Thus, substrate-stereospecific properties of crosslinked esterase MIPs could be improved by changing the length and the content of the crosslinker. They reported the effect of styrene comonomer in enhancing the stereoselectivities of the esterase MIPs through better cooperativity with the hydrophobic substrate. Maximal stereoselectivity was obtained for 11 mol% N,N’-C4-bisacrylamide crosslinked MIP, which was copolymerized with hydrophobic styrene monomer.
Mechanism-based inactivation of cytochrome P450 3A by evodol
Published in Xenobiotica, 2023
Jie Zhao, Jingyu He, Jie Xu
Evodol is a naturally occurring component coming from the fruits of Evodia rutaecarpa (Juss.) Benth that has been widely prescribed for the treatment of gastrointestinal diseases in China (Wang et al. 2010; Yu et al. 2013; Qin et al. 2021). Evodol has been demonstrated to have larvicidal activity against Asian tiger mosquitoes (Liu et al. 2012). In addition, evodol showed inhibition on NO production in the lipopolysaccharide-activated RAW264.7 cell line (Yang et al. 2013). From the perspective of structure, evodol comprises a furan ring, which raises a great of concerns with regard to the safety of evodol. Previous researches demonstrated that furan is a structural alert that can be biotransformed into corresponding cis-butene-1, 4-dial (BDA) intermediate (Chen et al. 1997; Lu and Peterson 2010; Lin et al. 2014; Phillips et al. 2014; Yu et al. 2014). This intermediate is electrophilic in nature and can covalently bind to protein, resulting in protein dysfunction (Lu et al. 2009; Lu and Peterson 2010; Peterson 2013; Lin et al. 2016), such as diosbulbin B (Hu et al. 2018) and 8-epidiosbulbin E acetate (Lin et al. 2015). Apart from the toxicological implications, another concern caused by the furan-containing compound is the mechanism-based inactivation of P450 enzymes. The BDA intermediate can covalently bind to P450 enzymes in an irreversible manner, leading to mechanism-based inactivation of P450 enzymes. In this regard, rutaevin (Liu et al. 2020) and limonin (Iwata et al. 2005) serve as examples.
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