Hydroxamic acids, alternative

Benzamides e.g. MS-275 8 are one of the more common hydroxamic acid alternatives but are often less potent. Recent exceptions to this pattern include substituted pyridyl [29] and thiazolyl [30] benzamides, such as 9 and 10 with HDAC1 enzyme IC50s of 19nM and 29 nM, respectively and series of benzamides substituted with other heterocycles, such as indazoles [31] and benzo [l,2,4]thiadiazines [32], many with HDAC2 IC50s of <50 nM. The addition of... 

Quinazoline hydroxamic acids (26) can be prepared by acylation of an o-aminobenzohydroxamic acid (25). An alternative procedure... 

Hydroxamic acids are an important class of compounds targeted as potential therapeutic agents. A-Fmoc-aminooxy-2-chlorotrityl polystyrene resin 61 allowed the synthesis and subsequent cleavage under mild conditions of both peptidyl and small molecule hydroxamic acids (Fig. 14) [70]. An alternative hydroxylamine linkage 62 was prepared from trityl chloride resin and tV-hydroxyphthalimide followed by treatment with hydrazine at room temperature (Scheme 30) [71]. A series of hydroxamic acids were prepared by the addition of substituted succinic anhydrides to the resin followed by coupling with a variety of amines, and cleavage with HCOOH-THF(l 3). 

Acyl nitroso compounds (3, Scheme 7.2) contain a nitroso group (-N=0) directly attached to a carbonyl carbon. Oxidation of an N-acyl hydroxylamine derivative provides the most direct method for the preparation of acyl C-nitroso compounds [10]. Treatment of hydroxamic acids, N-hydroxy carbamates or N-hydroxyureas with sodium periodate or tetra-alkyl ammonium periodate salts results in the formation of the corresponding acyl nitroso species (Scheme 7.2) [11-14]. Other oxidants including the Dess-Martin periodinane and both ruthenium (II) and iridium (I) based species efficiently convert N-acyl hydroxylamines to the corresponding acyl nitroso compounds [15-18]. The Swern oxidation also provides a useful alternative procedure for the oxidative preparation of acyl nitroso species [19]. Horseradish peroxidase (HRP) catalyzed oxidation of N-hydroxyurea with hydrogen peroxide forms an acyl nitroso species, which can be trapped with 1, 3-cyclohexanone, giving evidence of the formation of these species with enzymatic oxidants [20]. 

In 1984, Corey and co-workers reported that A -hydroxyarachidonamides (111) were potent reversible inhibitors of cRBL (0.03-0.2 juM) [284]. Alkylation on nitrogen increased the inhibitory potency significantly, and truncation to (112) still gave activity (1.9 juM). An alternative approach at Abbott placed the hydroxamic acid moiety in the 5-position, giving analogues of 5-HPETE such as (113) which also inhibited cRBL [285]. 

Further work by the same group resulted in the identification of indole amides as an alternative capping group for aliphatic hydroxamic acids [31]. Starting from... 

In an attempt to move away from the hydroxamic acid zinc binding group, which is known to causes poor pharmacokinetics as a result of hydrolysis or glucuronidation, the group at Abbott searched for alternative zinc chelators culminating in the development of a series of electrophilic ketone HDACis (Figure 9.12) [64—66]. Subsequently, a group at IRBM developed a related series of thiophene trifluor-omethyl ketones and showed these to be selective class II HDACis [12]. 

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. 

Intermolecular reactions of hydroxylamines with secondary alkyl halides and mesylates proceed slower than with alkyl triflates and may not provide sufficiently good yield and/or stereoselectivity. A nseful alternative for these reactions is application of more reactive anions of 0-alkylhydroxamic acids or 0-alkoxysulfonamides ° like 12 (equation 8) as nucleophiles. The resulting Af,0-disubstituted hydroxamic acids or their sulfamide analogs of type 13 can be readily hydrolyzed to the corresponding hydroxylamines. The same strategy is also helpful for synthesis of hydroxylamines from sterically hindered triflates and from chiral alcohols (e.g. 14) through a Mitsunobu reaction (equation 9). 

An alternative procedure that generates stable, storable nitrone intermediates 175 from 170, mediated by dry m-CPBA as oxidating reagent, is shown in Scheme 77 ". Conversion of the nitrone 175 to the hydroxylamine by an exchange reaction with hydroxylamine hydrochloride was followed by EDC/HOAt-mediated cyclization to hydroxamic acid 174 (HOAt l-hydroxy-7-azabenzotriazole). 

To improve the product yields in Lossen rearrangement, mesyloxycarbamates have been used as alternative reagents . The use of A-acyl-O-mesylhydroxamic acids (558) avoids the competing formation of self-condensation by-products (560). These are obtained from the accumulation of isocyanate (559) before complete consumption of the hydroxamic acid (557) as observed in the classical Lossen rearrangement (equation 249). 

It may be mentioned that an alternative name for hydroxamic acids, treating them as derivatives of hydroxylamine, continues to be used. For example A-phenylbenzohydroxamic acid [PhCON(Ph)OH] has also been named alternatively as A-benzoyl-A-phenylhydroxylamine even in recent literature. 

As an alternative to polymers bearing pendant catechols, Winston and his colleagues have prepared hydroxamic acid polymers in which hydroxamate side-chains were linked by oligomethacroyl units216"218. From experiments on iron-overloaded mice four polymers were found to be as good as, or better, than DFOA in removing iron. Several of the polymers had quite low toxicity. A polymeric form of (25) of around 106 Daltons was particularly effective. 

In search for potent and systemically available inhibitors of the matrix metalloproteinase MMP-8 (Matter et al. 1999 Matter et al. 2002) following oral administration, a local ADME model was derived to support lead optimization. For an internal series of inhibitors on the tetrahydroisoquinoline scaffold, hydroxamic acids for zinc ion binding in 3-position are essential for MMP affinity in first generation inhibitors. However, those compounds are characterized by insufficient pharmacokinetic properties and low systemic exposure following oral administration. Driven by X-ray and 3D-QSAR studies (CoMFA), alternative Zn2+ binding groups like carboxylates were... 

The use of acyl nitroso compounds as dienophiles was first described by Kirby. The primary method for generating these highly reactive, unstable species is by periodate oxidation of hydroxamic acids. The acyl nitroso compounds can be trapped in a Diels-Alder reaction with 9,10-dimethylanthracene to give adduct (95) (equation 36) which can act as an alternative source of the dienophile, since retro [4 + 2] cycloaddition occurs under mild thermal conditions. 

In one of our alternative approaches the lactol unit of the 2,4-dihydroxy-2i/-l,4-benzoxazin-3(4//)-one skeleton was developed by oxidation of the unsubstituted methylene function (Fig. (9)) [114]. The starting cyclic hydroxamic acids have been prepared by catalytic transfer hydrogenation of appropriate 2-nitrophenoxyacetate precursors with the sodium borohydride/Pt-C method. The oxidative transformation intended caused a need for protection of the hydroxamic acid moiety. From several... 

Alternatively, DIBOA and DIMBOA in a THF solution have been methylated witii a solution of diazomethane in diethyl ether at their more acidic hydroxamic acid unit, regioselectively. 

An alternative activation mechanism for glucxironldes that may occur with hydroxamic acids is the de-acetylation of N-acetyl-N-0-glucuronldes, as has been demonstrated for 2AAF ( ). Deacetylation of the N-O-glucuronlde of N-hydroxy-2AAF yields the N-O-glucuronlde of 2-aminofluorene, which is very reactive and binds spontaneously to DNA. Whether such a mechanism operates in vivo is still unclear. 

As an alternative to Ti-based systems for allylic oxidation, the groups of Bregeault [81] and Yamamoto [178] have reported V-based catalysts. Bregeault uses a O=V(OC3H7)3 catalyst which achieves high TOP. Yamamoto employs V catalysts with chiral Zzz s-hydroxamic acid (foz s-hydroxam) ligands of C2 symmetry which allow use of lower catalyst concentrations and the use of aqueous TBHP rather than the use of anhydrous reagent (Table 1.7). 

The THP-based hnker can be modified in such a way as to allow fhe synthesis of hydroxamic acids 49, as outlined in Scheme 24. Linker 48 has played a role in the solid-phase synfhesis of matrix metalloproteinase inhibitors [52], Alternative linkers that yield hydroxamic acids after release have been used in connection with peptide chemistry, as well as for the preparation of combinatorial compounds [53-58]. 

Alternatively (Fig. 2, route B), a nitrile group in principle could serve as a precursor of the final hydroxamic acid function via oxidation to the nitrileoxide and its hydrolysis. This strategy would be based on the nitrile ester 10 as a key intermediate and its racemic resolution. While the resolution step could be achieved enzymatically, the oxidation experiments failed and this approach was finally abandoned. 

The attachment of iron chelating ligands to polymers is an alternative means of modifying bioavailability. DFB has been covalently bonded to poly(acrolein) and other synthetic polymers and shown to have some potential for use in extracorporeal detoxification of acute iron overloaded plasma (57). Poly(N-methacryl-oyl-6-alanine hydroxamic acid), a polydentate polymer obtained by derivatization of poly(acrylic acid) with pendant hydroxamic acid groups, has shown significant iron chelation activity in vivo (58), a result which is possibly related to the longer retention of polymeric species in the circulatory system. 

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