Hydroxamic replacements

Metal alkoxides undergo alkoxide exchange with alcoholic compounds such as alcohols, hydro-xamic acids, and alkyl hydroperoxides. Alkyl hydroperoxides themselves do not epoxidize olefins. However, hydroperoxides coordinated to a metal ion are activated by coordination of the distal oxygen (O2) and undergo epoxidation (Scheme 1). When the olefin is an allylic alcohol, both hydroperoxide and olefin are coordinated to the metal ion and the epoxidation occurs swiftly in an intramolecular manner.22 Thus, the epoxidation of an allylic alcohol proceeds selectively in the presence of an isolated olefin.23,24 In this metal-mediated epoxidation of allylic alcohols, some alkoxide(s) (—OR) do not participate in the epoxidation. Therefore, if such bystander alkoxide(s) are replaced with optically active ones, the epoxidation is expected to be enantioselective. Indeed, Yamada et al.25 and Sharp less et al.26 independently reported the epoxidation of allylic alcohols using Mo02(acac)2 modified with V-methyl-ephedrine and VO (acac)2 modified with an optically active hydroxamic acid as the catalyst, respectively, albeit with modest enantioselectivity. 

There are only a few collectors suitable for tin flotation that have been introduced into operating plants in the 1970s, but today they have been replaced (i.e. arsonic acid, phospho-nic acid) due to toxicity and high prices. Other collectors that have been extensively studied include oleic acid, sodium oleate, alkyl phosphoric acid and hydroxamates [2—4],... 

A number of other scissile bond replacements have been explored in an attempt to produce inhibitors of the bacterial collagenases, but all have exhibited relatively low potency Table 8.6). These include a compound with an A-methylamide residue in subsite P l (46), two carboxylates (47)-(48), the hydroxamate N-terminal (49) and C-terminal analogues (50)-(51), and one A-carboxyalkyl (52) derivative. 

The hydroxamate functionality is an effective scissile bond surrogate in collagenase inhibitors [1,186-203], probably because of its ability to serve as a bidentate ligand for the active site Zn(II). N-terminal tri- and tetrapeptide hydroxamate substrate analogues are only moderately potent inhibitors Table 8.15). An intriguing observation with respect to possible binding modes is that the residues in subsites P and P2 can be replaced with their D-stereoisomer counterparts with essentially no loss of potency, as long as both are replaced with the D-isomers (compare (151), (152) and (153), and (154) vs. (157), in Table 8.15). 

In putrebactin from Shewanella putrefaciens (201) cadaverine is replaced by pufrescine (49, R = H). For the cyclic trimer, see proferrioxamine X2 in Table 6. The arctic S. gelidimarina living in a habitat with extremely low iron supply produces a cell-associated hydroxamic acid siderophore with the mass 977 Da for of unknown structure (274). 

Researchers at Merck developed a series of benzothiophen-2-yl hydroxamic acids as HDACis [44] tvhich can be considered a hybrid of the cinnamyl and thiophenyl hydroxamic acids. Starting from simple acetyl hydroxamic acid (33a IC50 = 625 pM), they shotved that incremental boost in activity could be achieved introducing first a phenyl ring (IC50 = 20 pM), then replacing this tvith a thiophene (IC50 = 6.6 pM). 

Replacing the electrophilic epoxy ketone moiety in TPX by a reversible zinc chelator such as a hydroxamic acid was carried out by Yoshida et al. (Fig. 6) [51]. This modification led to a low nanomolar reversible inhibitor of the HDACl enzyme. Several other cyclic tetrapeptides containing the epoxyketone feature, such as chlamydocin, were converted into their hydroxamic acid coimterparts as well [52]. Additionally, the introduction of reversed hydroxamic acids (-N(OH)COR, with R = H or Me) onto the structure of Cyl-1 was reported to give potent HDAC inhibitors as illustrated in Fig. 6 [53]. Generally, the most potent inhibitors were the examples with R = H and m = 2. Apicidin, a cychc peptide more remotely related to TPX, exhibits potent antiprotozoal activity via HDAC inhibition in parasites [54]. 

Replacement of the hydroxamic acid moiety of SAHA by an alternative chelator has been the subject of several studies. Suzuki and Miyata et al. have shown that replacement of the hydroxamic acid of SAHA with a free thiol moiety does not affect the enzymatic HDAC inhibition capability of the compound [57]. Furthermore, replacement of the hydroxamic acid of SAHA by a trifluoromethyl ketone was investigated by Frey et al. (Fig. 8) [58]. The activated ketone is readily hydrated to form the vicinal diol, a structural feature known to bind to zinc-dependent proteases [59]. The in vitro evaluation was done on a partially purified HDAC preparation consisting largely of HDAC 1 and HDAC2 [60], exhibiting an IC50 of 6.7 xM. 

Fig. 8 The hydroxamic acid in SAHA replaced by a trifluoromethyl ketone - IC50S in the micromolar range (reference data for SAHA not given). (Abbott Laboratories)...

From the same laboratories, a series of heterocyclic ketones were published as HDAC inhibitors [61]. This work is a continuation and further elaboration of the concept of the use of electrophihc ketones as hydroxamic acid replacements. a-Keto oxazole derivatives appeared to act as the most potent HDAC inhibitors in the HDAC1/HDAC2 enzyme assay [60], displaying low micromolar activity (Fig. 9). 

Fig. 9 Keto oxazoles as hydroxamic acid replacements. (Abbott Laboratories)...

Finally, the Lessen rearrangement provides a practical procedure for replacing the hydroxamic group of a hydroxamic acid (12) by an amino group (14) (equation 2). The initial rearrangement product is an isocyanate (13) which readily reacts with nucleophiles, for example with OH and NH functionalities to give amines (14) and ureas (15). 

On the other hand, desmethyl-retro-hydroxamate ferrichrome 15, where the terminal methyl groups were replaced by hydrogen, showed no signihcant growth promotion activity toward Arthrobacter flavescence, and only one third of the iron(III) transport efficiency toward U. sphaerogena, which confirms the importance of the methyl groups... 

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