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Tromantadine
Published in Anton C. de Groot, Monographs in Contact Allergy, 2021
Tromantadine is a cyclic amine derived from amantadine with activity against Herpes simplex virus. It inhibits absorption of virions to cell surfaces, as well as penetration and uncoating of the virus. It is used in the topical treatment of herpes simplex. In pharmaceutical products, tromantadine is employed as tromantadine hydrochloride (CAS number 41544-24-5, EC number 255-434-5, molecular formula C16H29ClN2O2) (1).
Small Molecules: Process Intensification and Continuous Synthesis
Published in Anthony J. Hickey, Sandro R.P. da Rocha, Pharmaceutical Inhalation Aerosol Technology, 2019
In one relevant example, chemists from Merck conducted a reaction optimization screening on a 1536 plastic microwell plate. They were able to optimize the room temperature cross-coupling of an aryl bromide with a cyclic amine while screening six bases and 16 phosphines. While the reactions were quenched after a short period of time, the analysis of the reaction mixture took place over the next 52 hours, and the products were analyzed by UPLC/MS. This rapid reaction optimization provided up to 98% conversion to product and set the stage for further scale-up.
Epidemiology of Colorectal Cancer
Published in Jim Cassidy, Patrick Johnston, Eric Van Cutsem, Colorectal Cancer, 2006
Heterocyclic amines are generated during the cooking of red meat at high temperatures, and increased consumption of well-done red meat has been associated with increased risk of colorectal neoplasia in some studies (127–128). For the heterocylic amines to be carcinogenic they must be metabolized by enzymes including glutathione-S-transferase (GST), N-acetyltransferase 1 (NAT1), and N-acetyltransferase 2 (NAT2). This has prompted investigation of interactions between variants in phase I and phase II metabolism genes and meat intake with regard to risk of color-ectal neoplasia. Ishibe et al. observed a sixfold increased risk of adenomas among rapid NAT1 acetylators (defined as those carrying the NAT1*10 allele) who were estimated, on the basis of reported meat intake, cooking methods and doneness level, to consume more than 27 ng/day of the hetero-cyclic amine MeIQx, whereas among slow acetylators the increase in risk was twofold (129). While other investigators have also reported patterns in risk suggestive of interactions between particular genetic variants and meat intake [e.g., Welfare et al. for NAT2; Gertig et al. for GSTM1 and GSTT1; Turner et al. for GSTT1 and GSTP1; Cortessis et al. for microsomal epoxide hydrolase (mEH) (59,73,130,131)], the direction of the associations have not always been consistent with the underlying hypotheses (55). Other studies have failed to find any evidence that the relationship between red meat intake and colorectal neoplasia is modified by genotype (76,128, 132,133). In addition to differences between studies in the genes and polymorphisms that have been investigated, and different approaches to statistical analysis and low statistical power, the difficulty of adequately assessing exposure to carcinogens in cooked red meats further complicates this area of research.
1-Oxo-3,4-dihydroisoquinoline-4-carboxamides as novel druglike inhibitors of poly(ADP-ribose) polymerase (PARP) with favourable ADME characteristics
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2021
Alexander Safrygin, Petr Zhmurov, Dmitry Dar’in, Sergey Silonov, Mariia Kasatkina, Yulia Zonis, Maxim Gureev, Mikhail Krasavin
Modifications of the peripheral cyclic amine did not lead to a significant improvement of the PARP1 potency. Diethylamino compound 3ad was not significantly different in potency and selectivity from compound 3 l. Ring-contracted and ring-expanded analogs 3ac and 3ae, respectively, displayed similar profiles to that of compound 3aa. Although compound 3ae possesses the best activity profile among the compounds investigated in this study, we attribute the marginal improvement of potency compared to compound 3aa to the lipophilic efficiency (LE)17 resulting from the introduction of an additional methylene unit. Thus, compound 3aa can be regarded as the lead structure identified in this study. Although its potency is an order of magnitude lower than that of the clinically used Olaparib, compound 3aa possesses lower molecular weight and excellent ADME characteristics (vide infra) and thus can be considered a frontrunner candidate for further preclinical development.
Poly-ADP-ribose polymerases (PARPs) as a therapeutic target in the treatment of selected cancers
Published in Expert Opinion on Therapeutic Targets, 2019
Jarosław Przybycinski, Magdalena Nalewajska, Małgorzata Marchelek-Mysliwiec, Violetta Dziedziejko, Andrzej Pawlik
The majority of PARP inhibitors can be grouped into one of three classes: 1) those containing primary amides and carboxamide, 2) bicyclic lactams, and 3) polycyclic lactams [15]. Despite this general rule, the chemical structures of their molecular scaffolds are variable [12–16]. The first class includes, among others, veliparib and niraparib [15]. Niraparib is a indazole-7-carboxamide derivative that exhibits greater specificity for PARP1/2 than for tankyrases. This specificity was achieved by adding a secondary cyclic amine group that might electrostatically interact with amino acids that are characteristic of PARP1/2 [17]. Veliparib is a benzimidazole-4-carboxamide derivative [12]. Olaparib and talazoparib are both phthalazinone analogues. Olaparib has a bicyclic structure, and due to a diacylpiperazine moiety, it is characterized by increased solubility. A terminal cyclopropyl group ensures high bioavailability [12,17]. Rucaparib is an azepinoindolone analogue, and talazoparib is a polycyclic lactam [12,15]. Talazoparib is the most potent replication fork trapping molecule; thus, it is classified as a second-generation PARP inhibitor [10].
Antifouling activity of portimine, select semisynthetic analogues, and other microalga-derived spirocyclic imines
Published in Biofouling, 2018
Darby G. Brooke, Gunnar Cervin, Olivier Champeau, D. Tim Harwood, Henrik Pavia, Andrew I. Selwood, Johan Svenson, Louis A. Tremblay, Patrick L. Cahill
Semisynthesis subsequently confirmed the importance to AF activity of the cyclic imine moiety of 1. The cyclic imine-reduced analogue of 1, cyclic amine 5, had ∼200-fold lower potency than portimine 1vs C. savignyi. It is, however, worth noting that the activity of 5 still exceeds values determined using this bioassay for some commercial synthetic biocides, such as tolyfluanid (EC99 100 ng ml−1) and chlorothalonil (EC99 300 ng ml−1; Cahill, unpublished data). The potency of 5 also exceeds most other promising natural product AF agents, for example the fungal-derived (+)-sclerotioramine (EC50Balanus amphitrite: 5.6 µg ml−1; Wei et al. 2017) and the Streptomyces-derived butenolide (EC50B. amphitrite: 0.5 ± 0.06 µg ml−1; Xu et al. 2010).