Halomethyl ketones

If excess of acid chloride is employed, e.g., by adding the diazometliane solution slowly to the acid chloride, some halomethyl ketone is produced ... 

Alkyl-2-arylthiazoles and 4,5-disubstituted-2-(p-aminophenyl thiazoles were simflarly prepared from arylamides and a-halomethyl-ketones in alcoholic (239, 392, 641, 792) or acetonic solution (638, 651). 

Poulos, T.L., et al. Polypeptide halomethyl ketones bind to serine proteases as analogs of the tetrahedral intermediate. J. Biol. Chem. 251 1097-1103, 1976. 

R = Ar) and cyclized tricyclic compound 240 (R = Ar) was obtained when 2-bromoacetophenones were reacted with 8-hydroxyquinolin-2(l//)-one under the above conditions. Presence of a 4-methoxy substituent shifted the equilibrium to the ring-opened product 241 (R = 4-MeOPh), while that of 4-nitro group gave only cyclized product 240 (R = N02). Similarly, mixtures of ring-opened and 2,3,6,7-tetrahydro-5//-pyrido[l,2,3- /e]-l,4-benzoxazin-5-one derivatives were formed in the reaction of 8-hydroxy-l,2,3,4-tetrahydroquinolin-2-one and halomethyl ketones (00HCA349). 

Serine and threonine Halomethyl ketones, peptidic aldehydes... 

Enzymes Reaction of serine proteases with halomethyl ketones,... 

These methods are limited in scope. Direct thiation has been reported for the transformation of vicinal diketones to [3,4]-annelated thiophenes <1996CHEC-II(7)49>. Thionations and selenations of vicinal halomethyl ketones with thioacetamide or iV,iV-diethylselenopropionamide as sulfur and selenium donors, respectively, have also been reported <1996CHEC-II(7)49>. In a recent example, thieno[3,4-f]pyrazoles 160 were readily prepared from aryl 5-bromomethyl-l//-l-phenylpyrazole-4-yl ketones 159 by reaction with thioacetamide (Equation 35) <1998JHC71>. Additionally, an example of an amination cyclization by reaction of 161 with benzylamine to afford pyrrolo[3,4-i/ thiazole 162 has been described (Equation 36) <1998JHC71>. 

Scheme 33 Synthesis of 1-Oxoethylene Peptides using a Halomethyl Ketone and a Malonatef78-80 ...

Halomethyl ketones and acids are known to react with thiols and imidazoles. TPCK reacts far more rapidly with chymotrypsin than it does with normal histidine-containing peptides because of its high reactivity as an affinity label. This can be seen in Table 9.2 for an analogous chloromethyl ketone. In addition to this important diagnostic feature, the irreversible inhibition of chymotrypsin by TPCK has four other characteristic features 1,4... 

Many hundreds of affinity labels have been synthesized, the majority based on halomethyl ketones or epoxides (Table 9.3). They are listed each year in the Specialist Periodical Reports Amino-Acids, Peptides, and Proteins, published by the Royal Society of Chemistry (U.K.). 

Enantioselective reductions. The neat reagent (1), prepared from ( + )-< -pinene, reduces aryl a-halomethyl ketones slowly but in high chemical yield to (R)-halohydrins in 90-96% ee, but optical induction is mediocre in the case of aliphatic a-halo ketones (35-66% ee). The chiral halohydrins are useful precursors to chiral epoxides. 

C-Terminal ketone derivatives of peptides have been used as effective inhibitors for a variety of proteases including serine, cysteine, and aspartyl proteases. 271 This class of peptides includes diazomethyl ketones (Section 15.1.2), halomethyl ketones (Section 15.1.3), and fluoromethyl ketones (Section 15.1.4). In general, the A -amino group and side chain must be protected. The diazomethyl ketones serve as good intermediates for conversion into chloromethyl and bromomethyl ketones. Fluoromethyl ketones, the most widely known class of peptide haloketones, can also be prepared from diazomethyl ketones or by halogen-exchange reactions. Other methods for the synthesis of fluoromethyl ketones are described in Section 15.1.4. 

Peptide Halomethyl Ketones (Excluding Fluoromethyl Ketones)... 

Although iodomethyl ketones are more reactive than the corresponding bromomethyl and chloromethyl ketones, they are very rarely used because increasing the reactivity of the halomethyl ketone also accelerates the possible competing side reactions. Due to this limitation, most researchers avoid working with iodomethyl ketones, choosing instead to use chloromethyl ketones, and therefore only few iodomethyl ketones of amino acids, and, to date, no peptidyl iodomethyl ketones, have been synthesized (Table 3).[191... 

Peptidyl fluoromethyl ketones are widely used as fairly potent inhibitors for a variety of proteases, including serine, cysteine, and aspartyl proteases. Unlike other halomethyl ketones (Section 15.1.3), fluoromethyl ketones are reversible transition-state mimics. The electron-withdrawing fluorine(s) next to the carbonyl group enhances the electrophilicity of the a-fluoroalkyl ketone functionality, thereby making the carbonyl more susceptible to nucleophilic attack. a-Fluoroalkyl ketones are good mimics of peptide bonds due to the small size of the fluorine and the stability of C F bonds. There are three general classes of peptidyl fluoromethyl ketones fluoromethyl ketones (irreversible inhibitors of cysteine proteases), difluoromethyl ketones (reversible inhibitors of both serine and aspartyl proteases), and trifluoromethyl/perfluoroalkyl ketones, which typically exist in hydrated forms and are excellent inhibitors of both serine and cysteine proteasesJ1 ... 

The synthesis of N, /V-disubstituted 2-amino-5-acylthiazoles has been reported. Starting from the thiourea 71 reaction with a-halomethyl ketones 72 furnished the thiazoles 73 in good yields. This method is useful for preparing AfN-bisaryl derivatives <02T2137>. 

These reagents react with aldehydes and ketones to form epoxides or halohydrins, and with esters to form a-halomethyl ketones. ... 

Peptide Halomethyl Ketones While TPCK and TLCK represented a major advance in modifying active site residues in serine proteases, slow and relatively nonspecific reaction was a problem. The development of tripeptide halomethyl ketones provided a major advance in the value of such derivatives as presented in some specific examples below. However, even with these derivatives, reactions occur with unexpected enzymes. More general information can be obtained from the following references Poulos, XL., Alden, R.A., Rreer, S.X. et al.. Polypeptide halomethyl ketones bind to serine proteases as analogs of the tetrahedral intermediate. X-ray crystallographic comparison of lysine- and... 

Benzyloxycarbonyl-Val-Ala-Asp(OMe) fluoromethyl ketone (z-VAD-FMK) is a peptide halomethyl ketone used for the inhibition of caspases and related enzymes. Because z-VAD-FMK is neutral, it passes the cell membrane and can inhibit intracellular proteolysis and is useful in understanding the role of caspases and related enzymes in cellular function. See Zhu, H., Fearnhead, H.O., and Cohen, G.M., An ICE-like protease is a common mediator of apoptosis induced by diverse stimuli in human monocytes THP.l cells, FEBS Lett. 374, 303—308, 1995 Mirzoeva, O.K., Yaqoob, P., Knox,... 

Tyrosine Tryptophan Serine Aspartic Acid Glutamic Acid T etranitromethane Chloramine T iV-Bromosuccinimide 2-Hydroxy-5-nitrobenzyl bromide Diisopropylfluorophosphate Halomethyl ketones Carbodiimides Trimethyl oxonium fluoroborate Isoxazolium salts Chloramine T also modifies histidines and methionines... 

In addition to mimicking a substrate, it contains the halomethyl ketone moiety, to... 

Various compounds were obtained from the corresponding halomethyl-ketones. Yields are generally better than in the case of a-chloroaldehydes... 

An alternate approach, which also uses enzyme-catalyzed ring-opening of a lactone to generate a mechanism-activated inhibitor, was developed by Katzenellenbogen and his co-workers [183], who found enol lactones, exemplified by (13-8) and (13-9), to be potent, selective inhibitors of HLE. The haloenol lactone (13-9) was an irreversible inactivator of HLE and chymotrypsin, and after exposure to (13-9), active enzyme could not be regenerated even upon treatment with hydrazine. Enol lactone (13-8), on the other hand, was an alternate-substrate inhibitor, which produced only transient inhibition of HLE and chymotrypsin. These results have been interpreted to mean that, with the halo-substituted compounds, ring opening results in formation of an acyl-enzyme that contains a reactive halomethyl ketone, which then alkylates His-57. That these compounds... 

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