General Radiobiology Refresher
Loredana G. Marcu, Iuliana Toma-Dasu, Alexandru Dasu, Claes Mercke in Radiotherapy and Clinical Radiobiology of Head and Neck Cancer, 2018
Early experiments performed with short range alpha particles (Munro 1970) have shown that the targets for cell killing were either nuclear or in the immediately perinuclear cytoplasm, leading later to the conclusion that the critical structure for radiation effects in biological systems is the deoxyribonucleic acid (DNA) molecule. This molecule has a complex structure and contains the genetic information in the cells. The backbone of the molecule is a polymer of phosphate and sugar bases on which the genetic information is coded in a unique sequence of four nucleobases: adenine (A), cytosine (C), guanine (G) and thymine (T), which are bound to the sugar-phosphate chain. In living cells, the DNA does not exist as a single molecule, but as a double helix of pairs of molecules bound through hydrogen bonds between nucleobases that pair in a unique way, adenine with thymine and guanine with cytosine. The pairing not only allows the stabilisation of the molecule in the double helix with a diameter of about 2 nm but also the maintenance of two copies of the genetic codes that are used for DNA replication and repair. Depending on the phase of the cell cycle or the repair status, the DNA double helix can be found either as a loose chromatin structure or in more condensed chromosome structures with higher order coiling, which is also associated with increased mechanical stress on the molecule.
Therapeutic Medicinal Mushroom (Ganoderma Lucidum): A Review of Bioactive Compounds and their Applications
Megh R. Goyal, Durgesh Nandini Chauhan in Plant- and Marine-Based Phytochemicals for Human Health, 2018
Huang et al. (1999) designed a study to determine total nucleoside (s) in sporophores of G. lucidum produced in different Asian localities by UV-spectrophotometry. They found that the contents of total nucleosides in sporophore were found to be higher in G. lucidum of Taiwan, Jiangsu, and Guangdong origin than from China and Vietnam. Thin layer chromatography (TLC) identification of adenine, adenosine, uracil, and uridine in sporophore of G. lucidum was also performed.53 In another study, a high-performance liquid chromatography-diode array detector-mass spectrometry (HPLC– DAD-MS) analytical method was employed for detection of nucleosides and nucleobases in G. lucidum fruiting bodies by Gao et al.35 The method qualitatively identified six nucleosides namely adenosine, cytidine, guanosine, inosine, thymidine, uridine, and five nucleobases namely adenine, guanine, hypoxanthine, thymine, and uracil.97, 133
HIV Integrase Inhibitors
Satya Prakash Gupta in Cancer-Causing Viruses and Their Inhibitors, 2014
The 1,3-DKA moiety essential for inhibitory activity of DKAs is biologically not very stable, and the need for its suitable replacement led to the discovery of naphthyridine derivatives. The nitrogen atom of naphthyridine is thought to mimic the carboxylate anion of DKAs, while the enol tautomer of one of the ketones is represented by an isostereic phenolic hydroxyl group in naphthyridine derivatives. Among all of the DKA derivatives, compounds containing nucleobase (pyrimidine and purine) scaffolds were also recognized as potent inhibitors for the 3′-processing and strand transfer mechanisms (Gardelli et al. 2007). Extensive research on these inhibitors resulted in the development of raltegravir (a pyrimidinone carboxamide derivative) and elvitegravir (a naphthyridine carboxamide derivative). QSAR modeling efforts discussed here supported the synthetic efforts (Figure 12.13).
In silico molecular docking and in vitro antioxidant activity studies of novel α-aminophosphonates bearing 6-amino-1,3-dimethyl uracil
Published in Journal of Receptors and Signal Transduction, 2020
Rasool Shaik Nayab, Suresh Maddila, Murthy Potla Krishna, Salam J.J. Titinchi, Basha Shaik Thaslim, Venkataramaiah Chintha, Rajendra Wudayagiri, Venkateswarlu Nagam, Vijaya Tartte, Sampath Chinnam, Naga Raju Chamarthi
The uracil is one of the most prominent structures found in nucleic acid chemistry. Uracil derivatives play a key role as intermediates in the synthesis of purines [5], which constitute the basic nucleus of a number of medicinally active molecules such as caffeine (1), penciclovir (2), theobromine (3), theophylline (4) and uramustine (5) depicted in Figure 1. It is a common and naturally occurring pyrimidine derivative and one of the four nucleobases in the nucleic acid of RNA. In RNA, uracil binds to adenine via two hydrogen bonds. In DNA, the uracil nucleobase is replaced by thymine. Uracils are considered as privileged structures in drug discovery with a wide variety of biological activities [6] such as anti-viral [6], anti-tumour [7], anti-oxidant [8], anti-protozoal [9], anti-microbial [10], anti-angiogenesis [11] and anti-tuberculosis [12] agents. Further, they also possess herbicidal, insecticidal and bactericidal activities [13].
An Expert Overview on Therapies in Non-Transfusion-Dependent Thalassemia: Classical to Cutting Edge in Treatment
Published in Hemoglobin, 2023
Mohammadreza Saeidnia, Pooria Fazeli, Arghavan Farzi, Maryam Atefy Nezhad, Mojtaba Shabani-Borujeni, Mehran Erfani, Gholamhossein Tamaddon, Mehran Karimi
The basis of nuclease-free is peptide nucleic acids (PNAs) [89]. The advantage of nucleobases associated with peptide-like backbone in PNAs is their resistance to nucleases and proteases; moreover, owing to the lack of phosphodiester bond in DNA/PNA structure, it is more stable than DNA/DNA. The complex employs the intrinsic DNA repair machine and triggers high-fidelity DNA repairs by incorporating a short donor DNA template close to the PNA binding site; it should be mentioned that this process does not produce indels. Requiring a delivery transporter is the limitation of this method for acquiring in vivo gene editing solved using nanoparticles. Correcting the IVS-II-654 (C > T) (HBB: c. 316-197 C > T) β-thal mutation in the fetus through DNA/PNA nanoparticles present in utero revealed long-term postnatal improvement [89]. Epigenetic modulation is considered as another genome editing approach that utilizes different mechanisms that cause transcription repression or stimulation via chromatin changes.
The engineering challenges and opportunities when designing potent ionizable materials for the delivery of ribonucleic acids
Published in Expert Opinion on Drug Delivery, 2022
Yan Ming Anson Lau, Janice Pang, Grayson Tilstra, Julien Couture-Senécal, Omar F. Khan
Though not universal features of all ionizable lipids, additional functionalities can be incorporated within their structures. Degradable groups, which are often hydrolysable, offer rapid metabolism and clearance from the body. Ester groups may also improve the potency of the resulting nanoparticle [1]. The position of ester groups also determines the size and chemical structure of the metabolites, which in turn can impact clearance and metabolite-induced inflammatory responses [2]. The degree of the inflammatory response impacts LNP application. Immunogenic materials may be more favorable for vaccines but detrimental when chronically dosing patients for therapeutic protein expression (there is a growing appreciation of the immunogenicity of LNPs and their lipid components; while this topic is outside the scope of this review, we direct the interested reader to a set of primary research and review articles [3–9]). Additionally, a hydrogen bonding group may improve binding to nucleobases (Figure 1). Moreover, changing the hydrogen bonding profile of the ionizable molecule’s headgroup (strong vs. weak donor) has also been shown to impact LNP potency [10].