Tumor necrosis factor alpha convertase (TACE), the enzyme responsible for the processing of pro-TNFalpha to TNFalpha, has been reported to be a metalloproteinase closely related to matrix metalloproteinases (MMPs). Current inhibitors of TACE such as succinate-based hydroxamic acids exemplified by Marimastat (TACE IC(50): 3.8 nM; blood IC(50): 7 microM) and BB1101 (TACE IC(50): 0.2 nM; blood IC(50): 2.3 microM) suffer from modest potency in blood and poor in vivo properties. The introduction of new bulky alpha-substituents into these succinate-based hydroxamic acids was studied. Substituents such as thioethers, sulfonamides, and ethers showed improved potency against TACE when compared with Marimastat. Although this improvement did not translate into better blood potency for thioether or ether substituents, the sulfonamide series exhibited improved potency both against TACE and in blood when compared with Marimastat. Optimization of this sulfonamide series has culminated in the identification of heterocyclic bicyclic sulfonamides such as 3t (TACE IC(50): 0.57 nM; blood IC(50): 0.28 microM).
(Methoxyalkyl)thiazoles are novel 5-lipoxygenase (5-LPO) inhibitors that are neither redox agents nor iron chelators. Consideration of a hypothetical model of the enzyme active site led to this series which is exemplified by 1-[3-(naphth-2-ylmethoxy)phenyl]-1-(thiazol-2-yl)propy l methyl ether (2d, ICI211965). 2d inhibits cell-free guinea pig 5-LPO activity, LTC4 synthesis in plasma free mouse macrophages, and LTB4 synthesis in rat and human blood (IC50s 0.1 microM, 8 nM, 0.5 microM, and 0.4 microM, respectively) but does not inhibit the synthesis of cyclooxygenase products at concentrations up to 50 microM in macrophages and 100 microM in blood. 2d is orally active in rat (ex vivo ED50 10 mg/kg in blood taken in 1 h after dosing). SAR studies show that high in vitro potency requires methoxy, thiazolyl, and naphthyl groups and depends critically on the substitution pattern. (Methoxyalkyl)thiazoles are chiral. Resolution of 1-methoxy-6-(naphth-2-ylmethoxy)-1-(thiazol-2-yl)indan (2j, ICI216800) shows that (+)-2j is 50-150-fold more potent than (-)-2j in in vitro assays. Thus, (methoxyalkyl)thiazoles are a new series of orally active, selective 5-LPO inhibitors and represent the first class of inhibitors in which inhibition is mediated by specific, enantioselective interactions with the enzyme.
Flav-2-enes, flavones, and 3-alkyl ethers of flavonols add alcohols and carboxylic acids in the presence of N-bromosuccinimide to give 2-alkoxy-and 2-acyloxy-3-bromoflavans which provide routes to cis-3-bromoflavans by reduction and to 3,4-diols by elimination and reaction with osmium tetraoxide. The 2-acyloxyflavans react with alcohols yielding 2-alkoxyflavans. Flavonols react with N-brornosuccinimide and alcohols to give bromine-free hemiacetals, the known 2,3-dialkoxy-3-hydroxyflavanones.Flav-2-enes and flav-2-en-4-ones (flavones) are readily available compounds which, in view of their expected reactivity, might be more widely exploited for the synthesis of other flavonoids. In this paper we describe some reactions of these compounds which we have used (see later papers) for the synthesis of polyflavonoids. ( 1 ) R' = R 2 = ,Q3= R 4 = H Flav-2-enes.-We obtained many of the flav-2-enes we required by the reduction of flavylium salts with lithium ( 2 ) R 3 = ~0 2 ,~' = R'= R4 = H aluminium hydride ' which is a quick and convenient method ( 3 ) R 3 = OMe. R'= R2= R 4 = H and appears to be of general applicability for the preparation (4) R ' = R2 = R 3 = R = OMe of flav-2enes unsubstituted at C-3 or C-2'. 3-and 2'-Substituted flavylium salts give considerable quantities of flav-3-enes on reduction with lithium aluminium hydride:3,4'-dimethoxyflavylium chloride gave 40% of the 3ene ' and we have obtained 3-methylflav-3ene (22%) and 3-methylflav-2-ene (53%) from 3-methylflavylium perchlorate and mixtures of the 2-and 3enes from 2'-benzoyloxy-and 2'-methoxyflavylium salts so that the method is less useful for the preparation of 3-and 2'-substituted flav-2enes. We have investigated the reduction of flavylium salts in acetic acid with sodium borohydride and with sodium cyanoborohydride. With sodium borohydride, flavylium perchlorate (1) gave 54% of flav-2-ene (5) containing a small proportion of a contaminant which was apparently (t.1.c.) flavan (10) (Scheme 1). With sodium cyanoborohydride, 4'-nitroflavylium perchlorate (2) gave 90% of 4'-nitroflav-2ene (6); 4'-methoxyflavylium perchlorate (3), however, gave 79% of 4'-msthoxyflavan (1 1) and the yield was similar (86%) with sodium borohydride in acetic acid. Analogously, 2'-methoxyflavylium perchlorate gave 62% of 2'-methoxyflavan with sodium cyanoborohydride. It seems probable that a flav-2-ene is always the initial product and that for further reduction to occur this enol ether must be protonated at C-3 [structure (g)], a reaction which can occur under these mild conditions only if the resulting positive charge is stabilised by a + M substituent suitably placed in the Bring. In accordance with this mechanism, we have found that flav-2-ene (5), 3-bromoflav-2-ene (12), and 4-phenylflav-2-ene (13) are not reduced by sodium cyanoborohydride in acetic acid but that 4'-methoxy-(7), 3',4',5,7-tetramethoxy-(g), and 4'-methoxy-4-phenylflav-2-ene (14) give 60-80% yields of the corresponding flavans. 4-Phenylflav-2-ene (13) and 4'-methoxy-4-phenylflav-2ene (14) were prepared b...
A series of monofluoro-and gem-difluoro-5a-androstanones and the parent ketones were incubated, under standard conditions, with the fungi named in the title. The results may be rationalised by comparing the positions of the fluorine atoms in the substrates with those of the favoured hydroxylation sites in the parent ketones. With few exceptions hydroxylation does not occur at, or adjacent to, the carbon to which a fluorine substituent is attached even though one of these centres is a favoured site (in the parent ketone). In such cases hydroxylation is usually diverted to an alternative position. Where the favoured site is more distant from the fluorine substituent(s) the behaviour of a fluoro-ketone resembles that of its parent. Hydroxylation of several fluoro-ketones by Aspergillus ochraceus gives the 1 1 a-hydroxy-derivatives cleanly and in yields which are satisfactory for preparative work.
Summary1,3-Dihydroisothianaphthen-2,2-dioxide (1) was readily converted to the I-substituted sulfones 3 by deprotonation and subsequent electrophilic attack (Scheme 3 and Table). The appropriate 1-alkenyl-and 1-alkenoyl-sulfones 3 on heating at 213" to 240" underwent SO,-extrusion to give, via the non-isolated (E)-quinodimethanes I1 (Scheme I), polycyciic products such as 4, 6 and 7 in good yields (Schemes 4 and 5 ) . On the other hand, thermolysis of the I-alkenoyl-1-thioether sulfones 9 furnished mainly the isochromenes 10 (Scheme 6).The utility of the reaction I1 -+ 111 (Scheme I) for the general, flexible and stereoselective synthesis of polycyclic systems has been amply demonstrated by work from this and other laboratories'). Although the transient dienes
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