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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
Developed in the 1960s, the nitrosourea family of anticancer agents alkylate DNA, leading to the formation of both mono-adducts and interstrand cross-links at a number of different sites. The study of a large number of nitrosourea analogs over many years has established the structural unit for optimal activity as the 2-chloroethyl-N-nitrosoureido moiety, and the likely mechanism of both mono-alkylation and cross-linking is shown in Figure 5.27. Although these molecules possess chloroethyl fragments, their activity is not associated with aziridinium ion formation as in the mustards because the corresponding nitrogen atom is part of a urea structure, and so the electron pair on the nitrogen is not available to participate in a cyclization reaction. Instead, it is thought that the alkylation of nucleic acids proceeds via a chloroethyl carbonium ion intermediate. An alkyl isocyanate fragment is also formed, and potentially carbamoylates the amino groups of proteins. Mechanism of action of the nitrosoureas showing the formation of mono- and bis-alkylated (i.e., cross-linked) adducts.
Adrenergic Antagonists
Published in Sahab Uddin, Rashid Mamunur, Advances in Neuropharmacology, 2020
It is an α-adrenoceptor antagonist with a non-selective nature. Being a haloalkyl amine compound, it produces irreversible antagonism. Phenoxybenzamine undergoes a spontaneous chemical transformation to yield an intermediate active electrophilic carbonium ion (Brunton et al., 2011; Katzung, 2009). This electrophilic carbonium ion makes a stable covalent bond with the α receptors causing a non-competitive antagonism thus blocks GPCR mechanism by blocking Gαq protein. Blockade of Gαq happens to reduce IP3 level which inhibits accessibility of free calcium required for the activation of protein kinase necessary for vasoconstriction (Fig. 4.2). Subsequently cardiac output tends to elevate producing an abatement of peripheral resistance. Moreover, relaxation of smooth muscles in the region of neck, prostate, and urinary bladder. Hence used in treating BPH (Caine et al., 1981; Caine et al., 1978; Majid et al., 1971). It also finds its usage in treating secondary shock and pheochromocytoma (Russell et al., 1998). According to Ghostine et al. (1984), it can be used in treating causalgia. It can cause postural hypotension along with reflex tachycardia which can produce cardiac arrhythmias. Reports demonstrates incomplete absorption when this drug is administered via oral route with a gradual onset of action. The impact of the medication lasts for about 3–4 days and is eliminated via urine in a 24-h time limit (Brunton et al., 2011; Seideman, 1982).
Experimental Colon Carcinogens and Their Mode of Action
Published in Herman Autrup, Gary M. Williams, Experimental Colon Carcinogenesis, 2019
John H. Weisburger, Emerich S. Fiala
Methylazoxymethanol is unstable at temperatures above 0°C, and at 37°C has a halflife of approximately 8.5 to 12 hr in solutions of physiological pH. The products of the spontaneous decomposition include formaldehyde and the unstable methyl diazonium ion and, hence, an electrophilic methyl carbonium ion which can methylate macromolecules such as nucleic acids.
Quercetin and naringenin abate diethylnitrosamine/acetylaminofluorene-induced hepatocarcinogenesis in Wistar rats: the roles of oxidative stress, inflammation and cell apoptosis
Published in Drug and Chemical Toxicology, 2022
Osama M. Ahmed, Adel A. Ahmed, Hanaa I. Fahim, Mohamed Y. Zaky
DEN-initiated and 2AAF-promoted hepatocarcinogenesis is most consistent and useful for cancer studies (Taha et al. 2008). Thus, the model of hepatocellular carcinoma induced by DEN as initiator and 2AAF as promoter was chosen in the present study to evaluate the preventive effects of quercetin and naringenin and to suggest their probable mechanisms of action. DEN administration increases the permeability of mitochondrial pores enhancing the production of H2O2 and inducing oxidative stress (Oliveira et al. 2013). The reasons for pathological effects of DEN in the liver are owing to the degraded products which are carbonium ion and the diazoalkane. These reactive metabolites react directly with the most vital compounds of the liver such as DNA or proteins forming adducts of DNA and protein (Wu et al. 2009).
Bioactivation of herbal constituents: mechanisms and toxicological relevance
Published in Drug Metabolism Reviews, 2019
The chemical reactivity of pyrrolic esters (or dehydro-PAs) is mainly attributed to the electrophilic sites at C7 and C9 positions of the necine base, which upon hydrolysis leads to conversion of the pyrrolic ester to the corresponding carbonium ion(s). The highly regioselective reaction of nucleophiles with dehydro-PAs at the C9 position is presumably due to less steric hindrance at the C9 vs C7 position, leading to formation of C9-substituted DHP-DNA adducts, DHP-dA-3, DHP-dA-4, DHP-dG-3 and DHP-dG-4 (Zhao et al. 2012) (Figure 10). Similar regioselectivity was observed in that 9-GSH-DHP was found to be the predominant GSH conjugate in vitro and in vivo (Chen et al. 2016). DHP [(±)-6,7-dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizine], an esterase-catalyzed hydrolysis product of the pyrrolic ester, is also reactive and able to form DNA adducts in vitro and in vivo (Yang et al. 2001). In contrast, reaction of DHP with 2′-deoxyguanosine (dG) and 2′-deoxyadenosine (dA) mainly produced DHP-dA-1, DHP-dA-2, DHP-dG-1 and DHP-dG-2, with the binding site at the C7-position of the necine base, suggesting that the carbonium ion at C7 position is more reactive than the one at C9 position of the necine base (Fu et al. 2010; Zhao et al. 2012). Regardless, there has been substantial evidence that DHP-DNA adducts are mediators of PA-induced tumorigenicity with a good correlation between levels of DNA adducts and the tumorigenic potency in animals (Fu 2017).
Capecitabine lipid nanoparticles for anti-colon cancer activity in 1,2-dimethylhydrazine-induced colon cancer: preparation, cytotoxic, pharmacokinetic, and pathological evaluation
Published in Drug Development and Industrial Pharmacy, 2018
Narendar Dudhipala, Goverdhan Puchchakayala
In this study, DMH was used to induce colon cancer in rats. This rat model has a similar pathology with that of the human disease, during the development of colon cancer. The metabolism of DMH in the liver quantitatively predominates over organ-specific metabolism, when injected intraperitoneally. It undergoes the dehydrogenation and is converted to an active carbonium ion through several processes, to be excreted in the bile, where it mediates its carcinogenic activities on the mucosa while passing through the digestive tract. Carbonium ions methylate DNA bases, induce point mutations, micronuclei and sister chromatid exchanges leading to colon-specific carcinogenesis. It is believed that alkylation of specific sites in DNA leads to promutagenic events which may result in tumor initiation [41].