Synthesis and evaluation of novel pyrazolidinone analogs of PGE(2) as EP2 and EP4 receptors agonists

ArticleinBioorganic & medicinal chemistry letters 17(23):6572-5 · January 2008with10 Reads
DOI: 10.1016/j.bmcl.2007.09.074 · Source: PubMed
Replacement of the hydroxy cyclopentanone ring in PGE(2) with chemically more stable heterocyclic rings and substitution of the unsaturated alpha-alkenyl chain with a metabolically more stable phenethyl chain led to the development of potent and selective analogs of PGE(2). Compound 10f showed the highest potency and selectivity for EP(4) the receptor.
    • "Robust PGE 2 -type analogues have also been prepared through substitution of the native ring system with heterocycles. Thus, γ-lactam (Table 3, entries 6 and 9) (Elworthy et al., 2004; Cameron et al., 2006; Kambe et al., 2012) and pyrazolidinone (Zhao et al., 2007) systems have been used to improve chemical and metabolic stability and to produce analogues with higher EP receptor subtype selectivity. Stable analogues of PGE 3 , the COX-2/PGE synthase-derived product of ω−3 EPA biotransformation, could have value in anticancer drug development. "
    [Show abstract] [Hide abstract] ABSTRACT: Lipids have the potential for development as anticancer agents. Endogenous membrane lipids, such as ceramides and certain saturated fatty acids, have been found to modulate the viability of tumor cells. In addition, many tumors over-express cyclooxygenase, lipoxygenase or cytochrome P450 enzymes that mediate the biotransformation of ω-6 polyunsaturated fatty acids (PUFAs) to potent eicosanoid regulators of tumor cell proliferation and cell death. In contrast, several analogous products from the biotransformation of ω-3 PUFAs impair particular tumorigenic pathways. For example, the ω-3 17,18-epoxide of eicosapentaenoic acid activates anti-proliferative and proapoptotic signaling cascades in tumor cells and the lipoxygenase-derived resolvins are effective inhibitors of inflammatory pathways that may drive tumor expansion. However, the development of potential anti-cancer drugs based on these molecules is complex, with in vivo stability a major issue. Nevertheless, recent successes with the antitumor alkyl phospholipids, which are synthetic analogues of naturally-occurring membrane phospholipid esters, have provided the impetus for development of further molecules. The alkyl phospholipids have been tested against a range of cancers and show considerable activity against skin cancers and certain leukemias. Very recently, it has been shown that combination strategies, in which alkyl phospholipids are used in conjunction with established anticancer agents, are promising new therapeutic approaches. In future, the evaluation of new lipid-based molecules in single-agent and combination treatments may also be assessed. This could provide a range of important treatment options in the management of advanced and metastatic cancer. Copyright © 2015. Published by Elsevier Inc.
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  • [Show abstract] [Hide abstract] ABSTRACT: This chapter discusses agonists for EP2, EP4, FP, DP, EP1, EP3, and EP4. Prostaglandins (PGs) are a class of naturally occurring hormone-like substances. PGs are derived from 20-carbon essential fatty acid lipids and as a result possess a highly oxygenated C20 backbone. They are produced in response to various stimuli in cells throughout the body and are synthesized, released and then act primarily in the vicinity of their formation. The prostanoid family of receptors includes G protein-coupled receptors with seven transmembrane domains which are ∼20–30% homologous within the family. The structures, properties and function of PG receptors have been extensively reviewed. In the early 1980s a non-definitive but “working hypothesis” classification was proposed for DP, EP, FP, IP and TP receptors according to the binding affinities, potencies and selectivities of endogenous PGD2, PGE2, PGF2α, PGI2 and TxA2. Additional pharmacological studies and molecular biology techniques later corroborated this classification and also assisted in subdivision of the Prostaglandin E (EP)-receptor into EP1, EP2, EP3 and EP4. Further use of molecular biology led to development of single receptor cell-based assays and advanced the understanding of PG pharmacology, thus promoting a revival in PG biological utilities.
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