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Nasal Cavity Carcinogens: Possible Routes of Metabolic Activation
Published in D. V. M. Gerd Reznik, Sherman F. Stinson, Nasal Tumors in Animals and Man, 2017
Stephen S. Hecht, Andre Castonguay, Dietrich Hoffmann
Several aromatic amines with methyl or methoxy groups ortho to the amine functionality are more carcinogenic than the corresponding unsubstituted compounds or than those with meta and para substitutents. For example, o-toluidine is more carcinogenic than aniline, and o-anisidine is a fairly potent bladder carcinogen in rats.85,86 In contrast, p-anisidine and p-toluidine are only weakly carcinogenic or inactive.85,87 Since p-cresidine has a methoxy group ortho to the amino group, its mechanism of activation may in some way be similar to those of o-toluidine and o-anisidine. However, no metabolic studies have been reported on p-cresidine.
Organic Chemicals
Published in William J. Rea, Kalpana D. Patel, Reversibility of Chronic Disease and Hypersensitivity, Volume 4, 2017
William J. Rea, Kalpana D. Patel
Direct carcinogens are alkyl imine (ethylene imino-), alkylene epoxides (1,2,3,4-butadiene epoxide), small-ring lactenes (β-propiolactone), propane sultone, sulfate esters (dimethyl sulfate, methyl methanesulfonate, 1,4-butacaine dimethanesulfonate [Myleran]), mustards (bis[2-chloroethyl] sulfide mustard gas, Yperite), bis(2-chloroethyl)amine (nor-nitrogen mustard RKH, nitrogen mustard RKCH3), cyclophosphamide (cytoxin), 2-naphthylamine mustard (chlornaphazine), triethylenemelamine chloride, methyl iodide, dimethylcarbamyl chloride, PAHs (anthracene, benzopyrene), aromatic amines (aniline, toluidine, o-anisidine, p-cresidine, phenacetin). Quinolones and aza are nitranologues of carcinogenic aromatic urethane, ethionine, formaldehyde, hexamethyl phosphoramide, carbamates, and halogenated hydrocarbons. Inorganics include uranium, polonium, radium, radon gas, titanium, nickel chromium under special conditions, cobalt, lead, manganese, beryllium, selenium, and arsenic.
An update on cutaneous complications of permanent tattooing
Published in Expert Review of Clinical Immunology, 2019
Tattoo inks are a mix of organic or inorganic pigments dispersed in water as well as additives to obtain ready-to-use tattooing products [14–17]. There is a high diversity of pigments used in tattoo inks. According to a recent US study, 44 different pigments were identified. They contain azo, diketopyrrolopyrrole, quinacridone, anthraquinone, dioxazine, or quinophthalone dyes. Metallic pigments are mainly iron, barium, zinc, copper, molybdenum, and titanium. Tattoo inks may contain several pigments [16]. Additives include binders (which bind the pigments particles to each other and the tattooing needle for easier injections into the skin), solvents and surfactants, preservative, and thickening agents [15]. Manufacturers in Europe have reinforced their inks following the resolution (ResAP(2008)1) on requirements and criteria for the safety of tattoos and permanent make-up (PMU) adopted by the council of Europe [18]. Lack of harmonized analytical methods, of guidelines for risk assessment and of guidelines for good manufacturing practice are still an issue for manufacturers [19]. In 2017, the European Chemicals Agency (ECHA) was asked by the European Commission to assess the chemical-related risks associated with the inks, the need for Union-wide action, and the relevant socio-economic impacts. In 2019, ECHA’s Committee for socio-economic analysis has adopted a restriction proposal on hazardous substances in tattoo inks and permanent make-up. The proposal has been forwarded to the European Commission for a draft regulation and possible amendment of Annex XVII to REACH [20]. Regarding cancer, in vivo tattooed mice models are currently showing no or only a weak cocarcinogenic effect, which is reassuring [21,22]. In the first model, immunocompetent hairless mice were tattooed with a black ink known to contain benzo(a)pyrene and then exposed to UV radiation (UVR). The development of UVR-induced squamous cell carcinoma was delayed on the tattooed areas compared to nontattooed areas [21]. In the second model, somewhat similar, immunocompetent hairless mice were tattoo with a red tattoo ink banned because of it contains 2-anisidine, a potential carcinogen. In this case, the time to the onset of the first and second tumor was identical in the red-tattooed group compared with the control group and only the third tumor appeared slightly faster in the red-tattooed group than in the controls [22]. In this late case, there seem indeed to be a cocarcinogenic effect that remains weak. The results give also insights regarding cases of keratoacanthomas on red tattoos as presented later in the article.
Design, synthesis and biological evaluation of 2-((4-sulfamoylphenyl)amino)-pyrrolo[2,3-d]pyrimidine derivatives as CDK inhibitors
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2023
Bo Yang, Yanni Quan, Wuli Zhao, Yingjie Ji, Xiaotang Yang, Jianrui Li, Yi Li, Xiujun Liu, Ying Wang, Yanping Li
In previous study, we found that CDK4 inhibitory activity of compound 1 is obviously weaker than highly selectively CDK4 inhibitor ribociclib, but compound 1 exhibited higher in vitro anti-proliferative activity compared to ribociclib. CDK kinase screening indicated that compound 1 possessed of the most potent inhibition on CDK9 than other CDK kinase. It led us to speculate that inhibition of CDK9 contributes much to the efficacy of compound 1 against PDAC cell growth. Thus, we firstly screened the CDK9 enzymatic activity inhibitory rate of new derivatives at concentration of 50 nM in a biochemical assay. As shown in Table 1, most of new sulphonamide derivatives possessed of significantly inhibitory activity (>80%) on CDK9. Moreover, these CDK9 inhibitors exhibited higher anti-proliferative activity in MIA PaCa-2 cells than non-CDK9 inhibitors, such as pyrrolo[2,3-d]pyrimidine derivatives with 2-aminopyridine side chain (2i and 2j) or 6-anilinocarbonyl side chain (10a and 10b). Low CDK9 inhibitory potency of compound 2i (27%) and 2j (25%) is consistent with the report that pyridin-2-amino moiety is key determinant of high selectivity to CDK4/625. In previous study CDK4/6 inhibition effect was less impaired when dimethylamino group of ribociclib was replaced with o-anisidine. However, such a change from 1 to 10a caused the loss of CDK9 inhibition activity. In general, terminal of C2-substituent of pyrrolo[2,3-d]pyrimidine skeleton reach out of cavity and expose to solvent region. Therefore, we assume that there is a size limitation for cavity outlet of CDK9. Steric hindrance of 3,5-dimethylpyrimidin-2-amino group stopped small molecule into deeper spacious cavity to accommodate planar anisidine fragment. Removal of two methyl substituents on pyrimidine from 10a could improve flexibility of small molecule within protein cavity. Thus, some CDK9 inhibitory activity was recovered in 10b (54%). These four inactive compounds on CDK9 also lack of the activity against PDAC cell growth. This result, at least to some extent, confirmed the anticancer activity of this class of 2-((4-sulfamoylphenyl)amino)-pyrrolo[2,3-d]pyrimidine derivatives is related to CDK9 inhibition activity. Admittedly, the anticancer activity of these compounds is not strictly dependent on CDK9 inhibition from the data in Table 1. Therefore, several active compounds (IC50 < 10 µM) were further investigated in multiple CDK (1, 2, 4, 7, 9) assays. As a result, all these compounds were identified as CDK9 inhibitors but not CDK7 inhibitors. Meanwhile, they presented the differential effect on CDK1, 2, and 4. Comparing to 1, compounds 5b, 5c, and 5e exhibited higher selectivity preference for both CDK4 and 9. However, the most potent compound 2g in PDAC cell culture behaves as a pan-CDK inhibitor which has strong inhibition on CDK1, 2, 4, and 9. Considering that ribociclib is a highly selective CDK4 inhibitor with low potency on CDK9, we estimated that inhibiting CDK9 enzyme activity played more important role to the anticancer performance of these derivatives in PDAC cells compared to other CDK subtypes.