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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
The carbinolamine moiety is described here in the context of the experimental anticancer agent trimelamol (Figure 5.37) which contains three carbinolamine moieties. This agent, which was investigated in the 1990s but not progressed beyond Phase II, was developed from the clinically active hexamethylmelamine and the closely related pentamethylmelamine (Figure 5.37) which do not contain carbinolamine groups themselves but gain them during oxidative metabolism. Trimelamol was designed to have the carbinolamine moieties already in place. Phase II clinical trials carried out in the early 1990s showed that trimelamol is active in refractory ovarian cancer and is less emetic and neurotoxic than pentamethylmelamine. Structures of hexamethylmelamine, pentamethylmelamine, and trimelamol. Trimelamol can lose three water molecules to form the DNA-reactive tri-iminium form
Introduction to Bioresponsive Polymers
Published in Deepa H. Patel, Bioresponsive Polymers, 2020
Deepa H. Patel, Drashti Pathak, Neelang Trivedi
Another system utilizes the unique carbohydrate-binding properties of lectin for the fabrication of a glucose-sensitive system. Lectins are multi-valent proteins and numerous glucose-responsive materials are obtained from this glucose-biding property of lectins. The response of these systems was specific for glucose and mannose, while other sugars caused no response. Con A is a lectin possessing four binding sites and has been used frequently in insulin-modulated drug delivery. In this type of system, the insulin moiety is chemically modified by introducing a functional group (or glucose molecule) and then attached to a carrier or support through specific interactions which can only be interrupted by the glucose itself. The glycosylated insulin-Con A complex exploits the competitive binding behavior of Con A with glucose and glycosylated insulin. The free glucose molecule causes the displacement of glycosylated Con A-insulin conjugates within the surrounding tissues and are bioactive. Additional studies reported the synthesis of monosubstituted conjugates of glucosyl-terminal PEG and insulin. The G-PEG-insulin conjugates were covalently bound to Con A that was attached to a PEG-poly(vinyl pyrrolidine-co-acrylic acid) backbone, and as the concentration of glucose increased competitive binding of glucose to Con A led to displacement and release of G-PEG insulin conjugates [135].
Excitotoxicity and Nitric Oxide
Published in Richard A. Jonas, Jane W. Newburger, Joseph J. Volpe, John W. Kirklin, Brain Injury and Pediatric Cardiac Surgery, 2019
To understand the actions of the NO moiety one has to review some chemistry. As you will see, the bottom line is that an old friend, nitroglycerin, can actually be used to prevent damage mediated by excessive activation of the NMDA receptor. First, we need to review the properties of the redox site of the NMDA receptor because that is actually one of the sites where the NO group can react (see Figure 16.1). This site modulates the activity of the NMDA receptor and limits calcium influx. If a disulfide bond is formed at this site, an oxidation reaction is produced. This limits the influx of calcium by decreasing the opening frequency of the NMDA receptor-associated channel. This can protect neurons from Ca2+ mediated damage.
New quinoline and isatin derivatives as apoptotic VEGFR-2 inhibitors: design, synthesis, anti-proliferative activity, docking, ADMET, toxicity, and MD simulation studies
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Eslam B. Elkaeed, Mohammed S. Taghour, Hazem A. Mahdy, Wagdy M. Eldehna, Nehal M. El-Deeb, Ahmed M. Kenawy, Bshra A. Alsfouk, Mohammed A. Dahab, Ahmed M. Metwaly, Ibrahim H. Eissa, Mohamed A. El-Zahabi
Utilising ligand-based drug design, especially the molecular hybridisation strategy that entails the connection of two or more groups with significant biological capabilities25, Two series of VEGFR-2 were design new hybrids of quinoline-thiazolidine-2,4-dione (compounds 7, 8, and 9) and isatin-thiazolidine-2,4-dione(compounds 13 and 14). As shown in Figure 2, the heteroaromatic system was designed to be quinoline or isatin moieties. The liker group was the thiazolidine-2,4-dione moiety as a ring equivalent for 2,4-dimethyl-1H-pyrrole of sunitinib with increased the advantage of being a good centre for hydrogen bonding interactions and enhancement of water solubility of the synthesised compounds. The pharmacophore moiety was kept to be an amide group in all the designed compounds. The terminal hydrophobic moiety was kept to be different substituted aromatic structures.
Development of topical thymoquinone loaded polymer–lipid hybrid vesicular gel: in-vitro and ex-vivo evaluation
Published in Journal of Liposome Research, 2022
Sagar Trivedi, Kamlesh Wadher, Milind Umekar
The release mechanism and the release profiles were compared employing various different mathematical equations. The release data of the drug moiety from the prepared formulation was evaluated with the help of a linear regression analysis model. The correlation coefficients (R2) values of zero order kinetics (0.757), First order kinetics (0.947), Higuchi kinetics (0.9673), Hixon crowell (0.9755) and Kosermeyer–Peppas model (0.9828) showed that the release of TH from formulations best-fitted to Kosermeyer–Peppas with highest R2 value The results point to sustained release characteristics with a diffusion pattern of drug release, where formulation acts as a reservoir system for continuous delivery of the drug. These controlled-release patterns of entrapped drugs reflect the high stability of the formulations. These findings confirmed that the drug was released from the formulation in a diffusion-controlled manner, and they are in agreement with results obtained and reported by previous research studies (Alsarra 2009; Lee et al.2009).
Dual antitubercular drug loaded liposomes for macrophage targeting: development, characterisation, ex vivo and in vivo assessment
Published in Journal of Microencapsulation, 2021
Priya Shrivastava, Laxmikant Gautam, Rajeev Sharma, Devyani Dube, Sonal Vyas, Suresh P. Vyas
These clinical problems could be addressed by ingenious designing and development of novel strategic drug delivery modules. Novel drug delivery modules are seen as potential options in the treatment of drug-resistant tuberculosis. They can effectively circumvent and address the limitations associated with conventional antitubercular therapy. Several bioactive carrier systems with enormous potential for bioactive effective delivery have been previously developed and reported. They include liposomes, vesosomes, microparticles, polymeric implants, and polymeric microspheres (Dutt and Khuller 2001, Vyas et al. 2004, Sharma et al. 2020). Antitubercular bioactive(s) entrapped or encapsulated in drug delivery modules have exhibited higher bioavailability. These bioactive carrier systems when coupled to a targeting moiety resulted in significantly enhanced drug efficacy due to target-specific drug delivery and accumulation as a consequence with optimum therapeutic index (Bhardwaj et al. 2013, Hamed et al. 2019, Mehta et al. 2019).