Several natural products with a coumarinic moiety have been reported to have multiple biological activities. It is to be expected that, in a similar way to isomeric flavonoids, coumarins might affect the formation and scavenging of reactive oxygen species (ROS) and influence processes involving free radical-mediated injury. Coumarin can reduce tissue edema and inflammation. Moreover coumarin and its 7-hydroxy-derivative inhibit prostaglandin biosynthesis, which involves fatty acid hydroperoxy intermediates. Natural products like esculetin, fraxetin, daphnetin and other related coumarin derivatives are recognised as inhibitors not only of the lipoxygenase and cycloxygenase enzymic systems, but also of the neutrophil-dependent superoxide anion generation. Due to the unquestionable importance of coumarin derivatives considerable efforts have been made by several investigators, to prepare new compounds bearing single substituents, or more complicated systems, including heterocyclic rings mainly at 3-, 4- and/or 7-positions. In this review we shall deal with naturally occurring or synthetically derived coumarin derivatives, which possess anti-inflammatory as well as antioxidant activities.
Tumor hypoxia is a characteristic of cancer cell growth and invasion, promoting angiogenesis, which facilitates metastasis. Oxygen delivery remains impaired because tumor vessels are anarchic and leaky, contributing to tumor cell dissemination. Counteracting hypoxia by normalizing tumor vessels in order to improve drug and radio therapy efficacy and avoid cancer stem-like cell selection is a highly challenging issue. We show here that inositol trispyrophosphate (ITPP) treatment stably increases oxygen tension and blood flow in melanoma and breast cancer syngeneic models. It suppresses hypoxia-inducible factors (HIFs) and proangiogenic/glycolysis genes and proteins cascade. It selectively activates the tumor suppressor phosphatase and tensin homolog (PTEN) in vitro and in vivo at the endothelial cell (EC) level thus inhibiting PI3K and reducing tumor AKT phosphorylation. These mechanisms normalize tumor vessels by EC reorganization, maturation, pericytes attraction, and lowering progenitor cells recruitment in the tumor. It strongly reduces vascular leakage, tumor growth, drug resistance, and metastasis. ITPP treatment avoids cancer stem-like cell selection, multidrug resistance (MDR) activation and efficiently enhances chemotherapeutic drugs activity. These data show that counteracting tumor hypoxia by stably restoring healthy vasculature is achieved by ITPP treatment, which opens new therapeutic options overcoming hypoxia-related limitations of antiangiogenesis-restricted therapies. By achieving long-term vessels normalization, ITPP should provide the adjuvant treatment required in order to overcome the subtle definition of therapeutic windows for in vivo treatments aimed by the current strategies against angiogenesis-dependent tumors.Electronic supplementary materialThe online version of this article (doi:10.1007/s00109-013-0992-6) contains supplementary material, which is available to authorized users.
Reaction of compound 3 with nitrile oxide 4a affords compounds 5a and 6 in 73% and 3% yield respectively, while reaction of 3 with 4b affords only compound 5b (85%). Reactions of compound 8 with the nitrile oxides 4a,b result in compounds 9a,b. The compound 10, prepared from 1 and O‐methylhydroxylamine, reacts with nitrile oxide 4b to give the oxadiazole derivative 12. The above referred coumarins are screened for antiinflammatory activity in vivo using the carrageenin rat paw edema and in vitro through their antiproteolytic activity and their ability to inhibit β‐glucuronidase and 12‐Lipoxygenase.
A series of novel 3-(coumarin-4-yl)tetrahydroisoxazoles 5a,b, 7, 9 and 3-(coumarin-4-yl)dihydropyrazoles 13a-d, 14, 15a,b were synthesized from coumarin-4-carboxaldehyde 1 via the intermediate N-methyl nitrone 3 and N-phenyl or N-methyl hydrazones 11a,b. These coumarin derivatives were isolated, characterized and evaluated in vitro for their ability to inhibit trypsin, β-glucuronidase, soybean lipoxygenase and to interact with the stable radical 1,1-diphenyl-2-picrylhydrazyl. The compounds were tested in vivo as antiinflammatory agents in the rat carrageenin paw edema assay. Compound 15a seems to be a lead molecule to be modified in order to improve the lipoxygenase inhibition. The results are discussed in terms of structural characteristics.J. Heterocyclic Chem., 38, 717 (2001).Coumarins have been reported to have multiple biological activities [1]. It is to be expected that coumarins might affect the formation and scavenging of reactive substances derived from oxygen (Reactive Oxygen Species, ROS) and influence processes involving free radical-mediated injury, as can some other plant phenolics and flavonoids [2,3]. There is evidence that the naturally occuring prototypical compound, coumarin can reduce tissue oedema and inflammation [4]. Coumarin and 7-hydroxycoumarin inhibit prostaglandin biosynthesis, which involves fatty acid hydroperoxy intermediates [5]. Various coumarin related derivatives are recognised as inhibitors not only of the lipoxygenase and cyclooxygenase pathways of arachidonate metabolism [6,7,8], but also of neutrophile dependent superoxide anion generation [9].In connection to our previous work on the synthesis of coumarin derivatives [10][11][12][13][14] In continuation to these studies we tried to design and synthesize novel coumarins like the new 4-(3'-tetrahydroisoxazolyl)-and 4-(3'-dihydropyrazolyl)coumarin derivatives and to define structure features for active compounds and to discuss our results in terms of structure-activity relationships. The reactions studied and the products (new compounds) obtained are depicted in schemes 1-2.We prepared previously 4-(3'-isoxazolinyl)coumarins through 1,3-cycloaddition reactions of 2-oxo-2H-[1]benzopyran-4-carbonitrile N-oxide with different dipolarophiles [16]. In this work we try to extend those 1,3-cycloaddition reactions by preparing the new dipoles 3 and 12a,b and studying their reactions with dipolarophiles 4a,b, 6, 8.Treatment of ethanol solution of aldehyde 1 with Nmethyl hydroxylamine hydrochloride 2 and sodium acetate under reflux (Scheme 1) gave as a precipitate, after ice/water work up, the new nitrone 3 (54% yield). Reactions of compound 3 with maleimides 4a,b resulted to new isoxazolidines 5a (47%), 5b (83%) respectively as the sole 1,3-cycloadducts. The chemical shifts for 5-H (5.02, d, J = 7.6 Hz), 3-H (4.82, d, J = 2.5 Hz), 4-H (3.94, dd, J 1 = 2.5 Hz, J 2 = 7.6 Hz) of 5a and 5-H (4.92, d, J = 7.4 Hz), 3-H (4.66, d, J = 2.7 Hz), 4-H (3.79, dd, J 1 = 2.7 Hz, J = 7.4 Hz) of 5b resemble well with the proposed structures in analogy...
Amidoximes are compounds bearing both a hydroxyimino and an amino group at the same carbon atom which makes them versatile building blocks for the synthesis of various heterocycles. Their importance in chemistry along with their rich biology, make amidoximes an attractive target for medicinal chemists, biochemists and biologists. Amidoximes and simple O-substituted derivatives possess very important biological activities functioning as antituberculotic, antibacterial, bacteriostatic, insecticidal, elminthicidal, antiviral, herbicidal, fungicidal, antineoplastic, antiarrythmic, antihypertensive, antihistaminic, anxiolytic-antidepressant, anti-inflammatory/antioxidant, antiaggregatory (NO donors) or plant growth regulatory agents. A number of amidoximes has already been used as drugs, or currently being in clinical trials. Their numerous pharmaceutical applications have been recently enriched, due to the fact that some mechanistic pathways, concerning their conversion to amidines, as well as their ability to release NO were clarified, giving a new insight to their mode of action and allowing the design of new therapeutic agents. The main subject of the present review paper is to highlight aspects concerning chemical and biological questions on this interesting class of compounds. Some new synthetic methodologies as well as improvements of previously reported general reactions involving amidoximes, acylated amidoximes, and amidines are presented. The biological applications of amidoximes over the end of 2006 are also extensively reviewed.
A major determinant of maximal exercise capacity is the delivery of oxygen to exercising muscles. myo-Inositol trispyrophosphate (ITPP) is a recently identified membrane-permeant molecule that causes allosteric regulation of Hb oxygen binding affinity. In normal mice, i.p. administration of ITPP (0.5-3 g/kg) caused a dose-related increase in the oxygen tension at which Hb is 50% saturated (p50), with a maximal increase of 31%. In parallel experiments, ITPP caused a dose-related increase in maximal exercise capacity, with a maximal increase of 57 ؎ 13% (P ؍ 0.002). In transgenic mice with severe heart failure caused by cardiacspecific overexpression of G␣q, i.p. ITPP increased exercise capacity, with a maximal increase of 63 ؎ 7% (P ؍ 0.005). Oral administration of ITPP in drinking water increased Hb p50 and maximal exercise capacity (؉34 ؎ 10%; P < 0.002) in normal and failing mice. Consistent with increased tissue oxygen availability, ITPP decreased hypoxia inducible factor-1␣ mRNA expression in myocardium. It had no effect on myocardial contractility in isolated mouse cardiac myocytes and did not affect arterial blood pressure in vivo in mice. Thus, ITPP decreases the oxygen binding affinity of Hb, increases tissue oxygen delivery, and increases maximal exercise capacity in normal mice and mice with severe heart failure. ITPP is thus an attractive candidate for the therapy of patients with reduced exercise capacity caused by heart failure.hypoxia ͉ oxygen delivery
A general strategy for the total synthesis of the antitumor agent apoptolidin (1) is proposed, and the chemical synthesis of the defined key building blocks (4, 5, 6, 8, and 9) in their enantiomerically pure forms is described. The projected total synthesis calls for a dithiane coupling reaction to construct the C(20)-C(21) bond, a Stille coupling reaction to form the C(11)-C(12) bond, and a Yamaguchi macrolactonization to assemble the macrolide ring, as well as two glycosidation reactions to fuse the carbohydrate units onto the molecule. First and second generation syntheses to the required fragments for apoptolidin (1) are described.
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