Mutagenic Consequences Of Chemical Reaction with DNA
Philip L. Grover in Chemical Carcinogens and DNA, 2019
It is not possible to consider chemical mutagenesis separately from DNA repair, because of the dual importance of repair in removing potentially mutagenic lesions from the DNA, and in converting such lesions into mutations. As a starting point, the author will try to describe our current knowledge of how DNA damage is accurately repaired by E. coli. Primarily, ultraviolet light (UV) induced damage will be discussed, and the responses of the bacterium to the whole spectrum of chemical carcinogens can then be considered as variations on a basic theme. UV is by far the most comprehensively investigated DNA damaging agent, and E. coli its most studied victim. As a reference agent, UV has several advantages, including easy administration, accurate dosimetry, and virtually instant treatment for kinetic studies. Moreover, the principal lesion is well characterized. Pyrimidine dimers are formed in which adjacent pyrimi-dines on the same DNA strand are joined by a cyclobutane type ring.38 Formation of the cyclobutane structure saturates the 5,6-double bond in the pyrimidine ring, causing it to become nonplanar.
Aliphatic and Aromatic Hydrocarbons
Frank A. Barile in Barile’s Clinical Toxicology, 2019
Hydrocarbons (HCs) are composed of carbon and hydrogen molecules whose carbon–carbon (C–C) bonds are composed of either all single (saturated) bonds or combinations of single and multiple (unsaturated) bonds. Aliphatic HCs, the term usually pertaining to fats or oils, applies to straight, open chains of carbon atoms, rather than ring structures, the simplest of which are the saturated HCs (alkanes). In addition, alkanes exist as unbranched straight chains or branched (for butane or longer chains), depending on the structural isomerism. Multiple C–C bonds result when hydrogens are removed from the alkanes, yielding unsaturated HCs such as alkenes (double C–C bonds) and alkynes (triple C–C bonds). Alicyclic HCs are saturated ring structures consisting of three or more carbon atoms. Unlike the aromatic chemicals (see next subsection), cyclopropane, cyclobutane, cyclopentane, and cyclohexane, for example, have three-, four-, five-, and six-membered rings, respectively, but do not exhibit double bonds within the rings.
DNA Repair During Aging
Alvaro Macieira-Coelho in Molecular Basis of Aging, 2017
One type of dimer results from covalent linkage between two neighboring pyrimidine bases and forms a cyclobutane ring. The DNA photolyase directly opens the ring in a light-dependent process.48 This photolyase was found in bacteria, plants and animals — with the highest significance probably in plants. Interestingly, this enzyme was found in internal organs which never get in contact with exogenous UV. Possibly it is used to remove damages caused by endogenous UV that is produced together with visible light inside the cells.49
Identification of highly selective type II kinase inhibitors with chiral peptidomimetic tails
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Seo-Jung Han, Jae Eun Jung, Do Hee Oh, Minsup Kim, Jae-Min Kim, Kyung-Sook Chung, Hee-Soo Han, Jeong-Hun Lee, Kyung-Tae Lee, Hee Jin Jeong, In Ho Park, Eunkyeong Jeon, Jeon-Soo Shin, Dongkeun Hwang, Art E. Cho, Duck-Hyung Lee, Taebo Sim
With the exciting initial data in hand, selectivities between Lck and c-Src were investigated on derivatives 7 containing the β-turn mimetic scaffolds (Table 2). Kinase-inhibitory activities of derivatives 7 against Lck and c-Src were assessed by in vitro kinase assay. Interestingly, 7c possessing alternative stereochemistry compared to 7a showed significantly (>10-fold) diminished selectivity. Changing i + 2 functional groups to cyclopropane (7d and 7e), cyclobutane (7f), and even glycine (7g and 7h) exhibited high selectivities. However, we observed diminished selectivity with benzyl substitution at i + 2 position (7i). High selectivity was kept with piperidine scaffold at i + 1 (7j). In contrast to the pyrrolidine and the piperidine groups, addition of the azetidine at i + 1 (7k) resulted in over 10-fold lower selectivity. The selectivities were not decreased by replacement of iso-butyl with valine at i + 3 (7l, 7m, 7n, and 7o). Substituents at i significantly affected selectivities (7p, 7q, 7r, 7s, and 7t). High selectivities were observed with iso-butyl and cyclohexyl substitution at i (over 10-fold selectivities, 7q and 7s). Compared to 7a, The selectivities of 7v and 7w on Lck and c-Src were highly diminished10f.
An updated patent review of small-molecule ROS1 kinase inhibitors (2015–2021)
Published in Expert Opinion on Therapeutic Patents, 2022
Meng Liu, Jintian Dai, Mudan Wei, Qingshan Pan, Wufu Zhu
Compounds disclosed in the patent CN112110938A had made new attempts in structural modification. In addition to introducing cyclopropanyl, cyclobutane and n-pentyl groups on the macrocycle skeleton, halogen, alkynyl and alkynes groups were also introduced into the pyrimidine ring of the nucleus. Among all these 20 compounds, compounds 8 (two cyclopropane groups were introduced into the backbone) and 9 (cyclopropane and pyrrolidinyl groups were introduced) exhibited the best inhibitory activity with the IC50 against ROS1 kinase valued of 0.26/5.60 nM, respectively. Meanwhile, they also demonstrated strong inhibitory activity toward TRKA kinase with IC50 of only 0.63/0.47 nM. In addition, these compounds have emerged obvious advantages in pharmacokinetics compared with the control TPX-0005, which is undergoing phase II clinical trials. In the liver microsome stability experiments, the two compounds exhibited better metabolic stability, higher permeability, and smaller efflux. Pharmacokinetic studies in rats also illustrated that these compounds had better absorption and higher bioavailability [55].
Insights and controversies on sunscreen safety
Published in Critical Reviews in Toxicology, 2020
Juliana P. Paiva, Raiane R. Diniz, Alvaro C. Leitão, Lucio M. Cabral, Rodrigo S. Fortunato, Bianca A. M. C. Santos, Marcelo de Pádula
The most frequent DNA lesions generated directly by UV radiation are the pyrimidine cyclobutane dimmers (CPDs) and the 6-4-pyrimidine-pyrimidone photoproducts (6-4PPs). These lesions are responsible for promoting structural alterations to the DNA helix, which can lead to the inhibition of replication and transcription. CPDs are formed after a covalent bond between two adjacent pyrimidine bases generating a cyclobutane ring formed from the saturation of the double bond between carbons 5 and 6 of the neighbor pyrimidine nitrogen bases (Friedberg et al. 2006). These bonds have a high mutagenic potential and need to be corrected by DNA repair mechanisms (Mancebo et al. 2014). The 6-4PPs are characterized by a covalent bond between the 5′ end of carbon 6 from a base to the 3′ end of carbon 4 from its adjacent base (Friedberg et al. 2006). These two lesions appear to induce differential biological effects in the cell exposed to UV. Scientific evidence suggests that 6-4PPs participate more effectively in UV-induced apoptosis, whereas CPDs appear to be more important in arresting progression cell cycle (Lo et al. 2005). The conversion of 6-4PPs into their Dewar valence isomers, other type of lesion, results from the intramolecular electrocyclization of the pyrimidone ring after the photon absorption (Perdiz et al. 2000; Douki 2016). The formation of a Dewar isomer requires at least two photons: the first induces the 6-4PP and the second, arisen from UVA, is required for the isomerization of the initial 6-4PP.
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