Experimental Colon Carcinogens and Their Mode of Action
Herman Autrup, Gary M. Williams in Experimental Colon Carcinogenesis, 2019
The proximate carcinogen derived from DMH is MAM, which occurs as the natural product cycasin in the nut of certain species of the cycad tree, in the form of the β-glucoside of methylazoxymethanol.8,9 As described above, the chemical synthesis is complex. The compound itself is rather unstable in aqueous solution or in vivo, but is available commercially as a stable acetate ester, methylazoxymethyl acetate. Tissue esterases split the acetate ester in vivo and make MAM available.9,58,67 MAM and MAM acetate are carcinogens specific for the colon of many species and can cause tumors in the duodenum and in the ear duct of some species such as rats. These compounds, also capable of inducing hepatomegaly, are generally toxic to the liver and kidney. When administered as the acetate ester, it is able to cause cancer after a single dose.
Restoration: Nanotechnology in Tissue Replacement and Prosthetics
Harry F. Tibbals in Medical Nanotechnology and Nanomedicine, 2017
In a sense, classical chemical synthesis induces the self-assembly of chemical bonds by providing conditions such as concentrations, catalyzing templates, and energy to bring molecules into proximity and overcome barriers to reaction—since we do not actually assemble the bonds of the individual molecules. In much the same way, researchers are learning how to induce self-assembly processes at macromolecular levels; these nanoscale self-assembly processes involve fewer chemical covalent and ionic bonds and depend more on weaker intramolecular and conformational forces. Thus, despite describing these processes as “self-assembly,” we have a number of ways to coach them into occurring by mixing components and providing various kinds of templates and energy inputs—just as in molecular synthesis [57-60]. When we think of self-assembly in these terms, it takes a lot of the mystery out of the process—or conversely, it makes us appreciate more the mystery of a chemical reaction, or a soap bubble!
The Chemical Synthesis of Lipid A
Helmut Brade, Steven M. Opal, Stefanie N. Vogel, David C. Morrison in Endotoxin in Health and Disease, 2020
The successful synthetic work during 1982–1987 was of great value in giving the final structural proof for the active entity and opening an entirely new era of endotoxin research (12). The structure proposed for lipid A was chemically constructed de novo as shown in Figure 3 (1,2). It thus became theoretically possible to obtain any related structures as desired. But the synthetic route contained many steps of chemical transformation, and there still remained several important points to be improved in order to make the chemical synthesis a truly efficient and useful tool. The major areas to be improved were (1) selection of protecting groups and their efficient and regioselective introduction onto the carbohydrate or fatty acyl moieties (creation of new protecting procedures was also important), (2) elaboration of efficient and reproducible reaction conditions for glycosyl phosphorylation and the work-up procedure after that step, (3) establishing a method for the purification of the final deprotected products. During the past decade, most of these problems have been greatly resolved by continuous efforts of synthetic chemists. Chemical synthesis has now become a valuable tool in the field.
Linkers in fragment-based drug design: an overview of the literature
Published in Expert Opinion on Drug Discovery, 2023
Dylan Grenier, Solène Audebert, Jordane Preto, Jean-François Guichou, Isabelle Krimm
Protein-templated chemical reactions like DCC and KTGS offer a great opportunity to link fragments in a direct manner. First, 3D structures of the protein or the protein-fragment complexes are not essential for the success of the method. Second, chemical synthesis efforts can be more easily streamlined by focusing on generating libraries of fragments containing the reactive functions that will lead to the final compound. However, DCC and KTGS may be limited as both methods use a large amount of target that need to be stable at 25°C or 37°C. As other limitations, hit identification from complex mixtures is often not straightforward whereas other biocompatible reactions might be needed to increase linker diversity. At last, structural knowledge of the target might be required in order to validate the approach with a first proof of concept, before deciding to invest in the synthesis of fragment libraries. As all published cases were based on already known inhibitors, it will be interesting to keep an eye on future strategies involving protein-templated methods applied to de novo lead design.
An overview of late-stage functionalization in today’s drug discovery
Published in Expert Opinion on Drug Discovery, 2019
Michael Moir, Jonathan J. Danon, Tristan A. Reekie, Michael Kassiou
Chemical synthesis is a key enabler in drug discovery. Whether it is the generation of vast libraries of compounds, manipulation of natural products or developing structure-activity relationships from a lead compound, synthesis is an essential step in the drug discovery process. Late-stage diversification has long been the established approach for generating vast libraries of compounds from a common intermediate. Historically, cross coupling of pre-functionalized fragments with various handles has been the major method for diversification. In turn, problems arising from truncated libraries that have generated flat, uninspired compounds have limited the chemical landscape [1]. Late-stage functionalization of C–H bonds offers a tantalizing prospect of diversification, particularly as it includes sp3-carbon atoms, opening up further chemical space. In order for late-stage diversification to be a useful tool for drug discovery, advances in high-throughput technologies and predictive techniques to accelerate biological testing of generated leads are required [2].
Discovery of N-quinazolinone-4-hydroxy-2-quinolone-3-carboxamides as DNA gyrase B-targeted antibacterial agents
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Wenjie Xue, Yaling Wang, Xu Lian, Xueyao Li, Jing Pang, Johannes Kirchmair, Kebin Wu, Zunsheng Han, Xuefu You, Hongmin Zhang, Jie Xia, Song Wu
In practice, the synthesis of the key intermediate c1, namely 1-ethyl-4-hydroxy-2-quinolone-3-carboxylic acid, was composed of three consecutive steps (cf. Scheme 1): first, isatoic anhydride was ethylated in the presence of N,N-diisopropylethylamine and iodoethane. This reaction introduced the ethyl group to the heterocyclic nitrogen of isatoic anhydride. Second, the ethylated anhydride was treated with diethyl malonate and sodium hydride to afford the intermediate b1. Third, b1 was converted to the acid by hydrolysis under the condition of 12N hydrochloric acid and the refluxing methanol. The key amine intermediates e1–e16 were prepared by conversion of different substituted methyl 2-aminobenzoates d1–d16 into amides under mild condition and with triethylamine as base, followed by annulation with hydrazine hydrate in boiling ethanol. The target molecules f1–f16 were obtained by coupling the above-mentioned acid c1 with the corresponding amines (e1–e16). All synthesised compounds were characterised by melting points, 1H NMR, 13C NMR, and HRMS. The details of the chemical synthesis and structural characterisation are described in the experimental section.
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