Protein kinase C (PKC) was implicated as an important positive regulator of angio-genesis by studies showing that tumor promoting phorbol esters, which activate PKC, stimulate angiogenesis both in vitro and in vivo. Therefore, inhibitors of PKC might be expected to block angiogenesis. MDL 27032 [4-propyl-5-(4-pyridinyl)-2(3H)-oxazolone], an inhibitor of cellular protein kinases, prevented capillary-like tube formation by human umbilical vein endothelial cells (HUVEC) on basement membrane preparations, an in vitro model for angiogenic activity. MDL 27032 had an IC50 = 50 microM, whereas MDL 27044, the 4-methyl analog of MDL 27032, was less effective (IC50 greater than 100 microM). This selectivity was reflected in the relative abilities of the two compounds to inhibit PKC and protein kinase A (PKA) activity prepared from HUVEC, and also to inhibit the basic fibroblast growth factor stimulated proliferation of HUVEC. MDL 27032 (0.3 microgram/egg) also significantly inhibited neovascularization in yolk sac membranes of developing chick embryos, whereas MDL 27044 added at concentrations up to 3 micrograms/egg was not inhibitory when compared with vehicle treated controls. Adhesion of HUVEC to individual extracellular matrix proteins, including laminin, fibronectin, and fibrinogen, but not to the mixture of matrix components or collagen type I and IV, was inhibited after treatment with MDL 27032. These studies suggest that MDL 27032, may have potential as an anti-angiogenic agent because it disrupts both formation of tube-like structures by HUVEC on Matrigel and normal neovascularization in ovo. This inhibition may in part be due to altered cellular interactions with the extracellular matrix.
the clear mother liquor, petroleum ether (100 mL, bp 30-60 °C) was added and the solution was refrigerated overnight. The solid was filtered and recrystallized from CHCl3-petroleum ether to yield the title compound (2.4 g, 36%): mp 240-243 °C (with shrinking and darkening ~200 °C); NMR (DMF-d7) 10.13 (s,
All six dimethoxyfluorenones 6a-f and dihydroxyfluorenones 7a-f , wherein substitution occurs at only one aromatic ring, were conveniently prepared by palladium(0)-catalyzed cross-coupling reactions of aryl bromides/triflates 2a-e with in situ generated arylboranes, derived from o -bromobenzamide 1a and o -bromophenyloxazoline 1b .Fluorenone derivatives are known to display a variety of biological activities. 1-3 Also, several methoxy and hydroxyfluorenone derivatives are natural products whose syntheses have recently been described. [4][5][6][7][8][9] As part of our investigation into the protein kinase inhibitory activity of substituted fluorenones, 10 we desired a convenient method for preparing all possible dihydroxy regioisomers in which substitution occurs on only one aromatic ring of the fluorenone nucleus.Some syntheses of fluorenones employ fluorene, 11 benzophenone, 12 or hexahydrofluorenone 13a precursors. Unfortunately, these procedures either give isomeric mixtures, are low yielding or offer limited access to certain isomers. Increased accessibility of substituted biphenyls through numerous cross-coupling techniques makes the intramolecular acylation reactions of biphenyl carboxylic acids 11 and biphenyl amides 14 an attractive approach to fluorenones. Of note are the recently reported in situ Suzuki cross-coupling methods which obviate the need for isolation of boronic acid intermediates. 15 Furthermore, the respective cyclization chemistries of biaryl-2-carboxylic acids and biaryl-2-carboxamides, the classical and anionic equivalent of the Friedel-Crafts reaction, are complementary and enable the preparation of a complete isomeric set. In an effort to obtain all possible dihydroxyfluorenone regioisomers 7a-f , we have employed and here report a convenient synthetic approach utilizing, 1) an efficient in situ generation and Pd(0)-catalyzed crosscoupling of aryl boranes to prepare substituted biaryls; 2) regiospecific remote aromatic metalation cyclization; and 3) a complementary Friedel-Crafts acylation cyclization.Thus, 2-bromo-N , N -diethylbenzamide (1a) (Scheme 1) undergoes lithium-halogen exchange and boronation at the 2-position. Treatment of the boronate with dimethoxyaryl bromides and aryl triflates 2a-e under modified in situ Suzuki conditions gave the biarylamides 3a-e . Intramolecular cyclization occurs when 3a-e react with LDA in a remote metalation process as described by Snieckus. 14 The five dimethoxyfluorenone regioisomers 6a-e thus formed are easily demethylated with refluxing HBr/AcOH to give dihydroxyfluorenones 7a-e in good yield.In order to obtain the sixth regioisomer 7f , we employed the same in situ coupling procedure using 2a and oxazoline 1b as a masked carboxylic acid (Scheme 2). Acid hydrolysis of the ring-opened 16 intermediate 4 gave biaryl-2-benzoic acid 5 which underwent normal Friedel-Crafts cyclization to regioselectively provide 2,3-dimethoxyfluoren-9-one (6f) in high yield. 17 Fluorenone 6f cannot be prepared by the anionic equivalent route since the more acidic o...
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