Anti-tumor metabolites

Coriolin (689), a metabolite of the Basidiomycete Coriolus consors, has attracted widespread interest because of its unusual anti-tumor activity and highly functionalized triquinane structure. Accordingly, a number of syntheses of689 have appeared on the scene. One of the earliest, due to Tatsuta, et al., begins with epoxide 690, whose preparation had been earlier realized in connection with their work on hirsutine (see Scheme LXIII). Deoxygenation of 690, hydrolysis, and cis-hydroxy-lation provided keto triol 691 (Scheme LXXII) The derived acetonide was transformed via 692 into tetraol 693 which could be selectively acetylated and dehydrated on both flanks of the carbonyl group. Deacetylation of 694 followed by epoxidation completed the synthesis. 

Anti-cancer drugs such as cyclophosphamide (15), aniline mustard, and nitrosoureas are transformed to reactive metabolites which are the toxic species required for their anti-cancer activity. Experiments with selectively deuterated analogs of these drugs has distinguished which pathway, among several alternative pathways of metabolism, is responsible for antitumor activity. For example, a deuterium isotope effect was observed for the formation of 4-ketocyclophosphamide (16), formed by the oxidation of the carbon alpha to the phosphoramide nitrogen, but there was no Isotope effect on the anti-tumor activity. However, there was a marked effect on the subsequent -elimination reaction and consequent decrease in anti-tumor activity by deuterium substitution at C-5. Thus, the formation of acrolein and phosphoramide mustard is rate determining for the anti-tumor activity of cyclophosphamide. 

Synthetic approaches and anti-tumor activity of microtubule-stabilizing marine metabolite laulimalide and its derivatives 03CRV3753. 

Signal transduction enzyme inhibition assays guided the isolation of two novel hybrid polyketide-terpenoid metabolites from a Penicillium sp. growing in the deepest waters (>750 ft) of Berkeley Pit Lake [9], Their structures were deduced by spectroscopic analysis and confirmed by single crystal x-ray analysis on berkeleydione (13). Both compounds inhibited signal transduction enzymes caspase-1 and matrix metalloproteinase-3. Berkeleydione (13) was also active against non-small cell lung cancer in NCI s 60 cell line anti-tumor screen. 

Hirayama T, Fujikawa F, Yosiokaletal (1974) Anew depsidone oxyphysodic acid isolated from a lichen Parmelia enteromorphia Ach. Chem Pharm Bull (Tokyo) 22 1678-1680 Hirayama T, Fujikawa F, Kasahara T et al (1980) Anti-tumor activities of some lichen products and their degradation products. Yakugaku Zasshi 100 755-759 Huneck S (1999) The significance of lichens and their metabolites. Naturwissenschaften 86 559-570... 

Currently, there has been no study of the secondary metabolites of Cephalochordata. Studies of Urochordata have been considerable but have focused on the class Ascidiacea (ascidians or sea squirts), which contain entire series of alkaloids, often with antiviral and anti-tumor properties. The ascidians share with sharks, which are primitive cartilaginous fish, the absence of liability to tumor development. In many species there is no epibio-sis, which often indicates the presence of cytotoxic and/or antibacterial substances, but antiviral substances were discovered among ascidians with epibionts (Eudistoma sp. and eudistomins (see below). 

Chrysene is a weak tumor initiator and is inactive as a complete carcinogen (38). The 1,2-dihydrodiol is more active as a mutagen than the 3,4- or the 5,6-dihydrodiols. The biological data support the hypothesis that the principal active metabolite of chrysene is the bay region anti-1,2-diol-3,4-epoxide (58). 

The answer is a. (Hardman, p 1302.) Cyclophosphamide, an alkylating agent, reacts with purine and pyrimidine bases of DNA to form bridges and dimers. These products interfere with DNA replication. 5-FU, methotrexate, and 6-thioguanine are anti metabolites, and the steroid prednisone has some tumor-suppressive effects. 

These novel tetrameric bromotyrosine metabolites display a range of biological activities, including effects on calcium channels (1900), lipoxygenase inhibition (1772), tumor angiogenesis inhibition (1901), and endothelial cell anti-proliferation (1902). Syntheses of several bastadins have been accomplished (1903,1904). 

Inflammation is now recognized as a key process in atherogenesis [Libby, 2002]. The potential for dietary flavonoids to inhibit inflammatory activities is of particular interest. A potential anti-inflammatory feature of the flavonoids is the ability to inhibit the biosynthesis of eicosanoids. Selected phenolic acids and some flavonoids have been shown to inhibit both cyclooxygenase (COX) and 5-lipoxygenase (5-LO) pathways [Nijveldt et al., 2001 Takano-Ishikawa et al., 2006], Epicatechin and related flavonoids have been shown to inhibit the synthesis of pro-inflammatory cytokines in vitro [Sanbongi et al., 1997], and plasma metabolites of catechin and quercetin inhibit the adhesion of monocytes to cultured endothelial cells [Koga and Meydani, 2001]. Silymarin has been shown to inhibit the production of inflammatory cytokines, such as interleukin-1, interferon-, and tumor necrosis factor-a (TNFa), from macrophages and T-cells [Matsuda et al., 2005], Some flavonoids can inhibit neutrophil... 

The same group showed that e-allylselenocysteine (98), which is expected to yield allylselenol, a fairly hydrophobic metabolite, has more anti-carcinogenic power than 77 and propylselenocysteine (99) in rat methylnitrosourea model [233]. The diallyl selenide (106) has significant anti-carcinogenic activity using DMB-induced mammary tumor model and is 300 times more active than the diallyl sulfide, a flavor component of garlic [234]. 

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