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Nucleic Acids as Therapeutic Targets and Agents
Published in David E. Thurston, Ilona Pysz, 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
Published in K. Hüsnü Can Başer, Gerhard Buchbauer, Handbook of Essential Oils, 2020
Darija Gajić, Gerhard Buchbauer
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.
Alternatives to Glycerine in Cosmetics
Published in Eric Jungermann, Norman O.V. Sonntag, Glycerine, 2018
Butylene glycol finds particular use in hair sprays and setting lotions as a humectant. In a compilation of data from the voluntary filing of product formulations with the U.S. FDA in 1981 [10] p. 227, butylene glycol was contained in 165 formulations at concentrations from <0.1 to >50%.
Mechanism-based inactivation of cytochrome P450 3A by evodol
Published in Xenobiotica, 2023
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.
Metabolic activation of aegeline mediated by CYP2C19
Published in Xenobiotica, 2021
Min Tian, Shenzhi Zhou, Wei Li, Jiaru Li, Lan Yang, Ying Peng, Jiang Zheng
Drug induced liver injury (DILI) is a limited factor in preclinical as well as clinical discovery of new drugs, and it is also one of the leading reasons resulting in drug withdrawal. Drug-induced mitochondrial dysfunction, inhibition of hepatic transporters and reactive metabolite formation may account for the adverse reactions (Leung et al. 2012; Norman 2020). A few classical examples are listed to illustrate the mechanisms concerning metabolic activation. The toxicity of nomilin, diosbulbin B, 8-epidiosbulbin E and similar natural products has been proved to result from the furan ring which may be metabolized by CYP3A to a cis-butene-dial intermediate (Li et al. 2020; Zhang et al. 2020; Zhou et al. 2020). Phenol derivatives, such as estragole and icaritin, can be oxidized to quinone methide intermediates to cause liver injury (Minet et al. 2012; Chen et al. 2019). Moreover, other compounds containing potential structures that could be transformed to epoxides, quinone imines or carbocation metabolites deserve attention for the safety in use (Jaeschke et al. 2012; Cartus and Schrenk 2020). In consideration of the vital role of P450 enzymes in the occurrence of hepatotoxicity, it is necessary to pay attention to the drugs or food which may affect the activities of the specific enzymes when co-administered (VandenBrink and Isoherranen 2010; Parkinson et al. 2011).
Agonist of stimulator of interferon genes as antitumor agents: a patent review (2008-2020)
Published in Expert Opinion on Therapeutic Patents, 2021
Nan-Nan Chen, Han Zhang, Qi-Dong You, Xiao-Li Xu
A patent (WO2020006432) filed by Dong Liu et al. disclosed a series of diABZI derivatives with a similar ring-formation and strategy as compound 75. Importantly, compound 84] (Figure 11) had a considerable stimulatory activity toward hSTING with an EC50 value of 0.03 μM in the human THP-1 cells reporter cells assay, as well as an excellent activity in stimulating STING-specific IFN-β generation by ELISA [71] Eternity Bioscience Inc. filed a patent on novel diABZI derivatives that were constructed via a Z-form butene linking two molecular polycyclic compounds, wherein compound [85] 85 contained a morpholine moiety and possessed fine STING agonism with an EC50 value of 0.006 μM in the human THP1 reporter cell assay, as well as significant activity in STING-specific IFN-β secretion. The representative compound 86 that bore a N-methylpiperazine ring had similar biological activity as compound 85 [72]