A comparative QSAR study on carbonic anhydrase and matrix metalloproteinase inhibition by sulfonylated amino acid hydroxamates

A quantitative structure-activity relationship (QSAR) study is made on the inhibition of a few isozymes of carbonic anhydrase (CA) and some matrix metalloproteinases (MMPs), both zinc containing families of enzymes, by sulfonylated amino acid hydroxamates. For both enzymes, the inhibition potency of the hydroxamates is found to be well correlated with Kier's first-order valence molecular connectivity index 1chi(v) of the molecule and electrotopological state indices of some atoms. From the results, it is suggested that while hydroxamate-CA binding may involve mostly polar interactions, hydroxamate-MMP and hydroxamate-ChC (ChC: Clostridium histolyticum collagenase, another zinc enzyme related to MMPs) bindings may involve some hydrophobic interactions. Both MMPs and ChC also possess some electronic sites of exactly opposite nature to the corresponding sites in CAs. A group such as C6F5 present in the sulfonyl moiety is shown to be advantageous in both CA and MMP (also ChC) inhibitions, which is supposed to be due to the interaction of this group with Zn2+ ion present in the catalytic site of both families of enzymes.     

A quantitative structure-activity relationship study on some matrix metalloproteinase and collagenase inhibitors

A quantitative structure-activity relationship (QSAR) study is made on some hydroxamic acid-based inhibitors of matrix metalloproteinases (MMPs) and a bacterial collagenase, namely Clostridium histolyticum collagenase (ChC), that also belongs to an MMP family, M-31, using Kier's valence molecular connectivity index (1)chi(v) of the substituents and electrotopological state (E-state) indices of some atoms. The results indicate that out of the four MMPs (MMP-1, MMP-2, MMP-8, and MMP-9) studied, MMP-2 and MMP-9 can be structurally quite similar, but widely differing from MMP-1 and MMP-8 and ChC. For MMP-2 and MMP-9, the inhibition activity of compounds is shown to depend on both (1)chi(v )and E-state indices, while for MMP-1 and MMP-8 it is shown to depend only on E-state indices and for ChC only on (1)chi(v). However, in all the cases, an aromatic group like C(6)F(5) or 3-CF(3)-C(6)H(4) attached to SO(2) moiety in the compounds is indicated to be equally beneficial, due to probably the involvement of fluorine atom(s) in charge-charge interactions with the Zn(2+) ion of the enzymes or in the formation of the hydrogen bonds with some sites of the receptors.     

A Comparative QSAR Study on Carbonic Anhydrase and Matrix Metalloproteinase Inhibition by Sulfonylated Amino Acid Hydroxamates

A quantitative structure-activity relationship (QSAR) study is made on the inhibition of a few isozymes of carbonic anhydrase (CA) and some matrix metalloproteinases (MMPs), both zinc containing families of enzymes, by sulfonylated amino acid hydroxamates. For both enzymes, the inhibition potency of the hydroxamates is found to be well correlated with Kier's first-order valence molecular connectivity index ¹χ^v of the molecule and electrotopological state indices of some atoms. From the results, it is suggested that while hydroxamate-CA binding may involve mostly polar interactions, hydroxamate-MMP and hydroxamate-ChC (ChC: Clostridium histolyticum collagenase, another zinc enzyme related to MMPs) bindings may involve some hydrophobic interactions. Both MMPs and ChC also possess some electronic sites of exactly opposite nature to the corresponding sites in CAs. A group such as C 6 F 5 present in the sulfonyl moiety is shown to be advantageous in both CA and MMP (also ChC) inhibitions, which is supposed to be due to the interaction of this group with Zn 2+ ion present in the catalytic site of both families of enzymes.     

alpha-Amino-beta-sulphone hydroxamates as potent MMP-13 inhibitors that spare MMP-1

A series of alpha-amino-beta-sulphone hydroxamates was prepared and evaluated for potency versus MMP-13 and selectivity versus MMP-1. Various substituents were employed on the alpha-amino group (P(1) position), as well as different groups attached to the sulphone group extending into P(1)'. Low nanomolar potency was obtained for MMP-13 with selectivity versus MMP-1 of >1000x for a number of analogues.     

Novel bis-(arylsulfonamide) hydroxamate-based selective MMP inhibitors

A series of bis-(arylsulfonamide) hydroxamate inhibitors were synthesized. These compounds exhibit good potency against MMP-7 and MMP-9 depending on the nature, steric bulk, and substitution pattern of the substituents in the benzene ring. In general, the preliminary structure-activity relationships (SAR) suggest that among the DAPA hydroxamates (i) electron-rich benzene rings of the sulfonamides may produce better inhibitors than electron-poor analogs. However, potential H-bond acceptors can reverse the trend depending on the isozyme; (ii) isozyme selectivity between MMP-7 and -9 can be conferred through steric bulk and substitution pattern of the substituents in the benzene ring, and (iii) the MMP-10 inhibition pattern of the compounds paralleled that for MMP-9.     

A quantitative structure-activity relationship study on some series of anthranilic acid-based matrix metalloproteinase inhibitors

A quantitative structure-activity relationship (QSAR) study has been made on four different series of anthranilic acid-based matrix metalloproteinase (MMP) inhibitors, in which two substituted aryl rings, one bearing the hydroxamic acid moiety that binds with the zinc atom of MMPs, are joined through a bridge group of sulfonamide. The QSAR results indicate that the sulfonamide group plays a very important role in the inhibition activity of the inhibitors and that the effectiveness of this sulfonamide group can be increased by the presence at the aryl rings or at the sulfonamide nitrogen itself of nitrogen-containing or some such substituents that can increase the electronic character of the sulfonamide group. The hydrophobic character of the molecules is not found to be of any advantage; rather in most of the cases it is shown to have detrimental effect, suggesting that MMPs provide little opportunity to the inhibitors to have a any hydrophobic interactions with them. On the other hand, polarizability of the molecules has been found to be conducive to activity in some cases. Thus the inhibition mechanism seems to predominantly involve the electronic interactions between the inhibitors and the enzymes.     

Indole amide hydroxamic acids as potent inhibitors of histone deacetylases

A series of hydroxamic acid-based HDAC inhibitors with an indole amide residue at the terminus have been synthesized and evaluated. Compounds with a 2-indole amide moiety have been found as the most active inhibitors among the different regioisomers. Introduction of substituents on the indole ring further improved the potency and generated a series of very potent inhibitors with significant antiproliferative activity. A representative compound in the series, 7b, has been found to be orally active in tumor growth inhibition model.     

Protease inhibitors: synthesis of bacterial collagenase and matrix metalloproteinase inhibitors incorporating arylsulfonylureido and 5-dibenzo-suberenyl/suberyl moieties

Novel matrix metalloproteinase (MMP)/bacterial collagenase inhibitors are reported, considering the sulfonylated amino acid hydroxamates as lead molecules. A series of compounds was prepared by reaction of arylsulfonyl isocyanates with N-(5H-dibenzo[a,d]cyclohepten-5-yl)- and N-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl) methyl glycocolate, respectively, followed by the conversion of the COOMe to the carboxylate/hydroxamate moieties. The corresponding derivatives with methylene and ethylene spacers between the polycyclic moiety and the amino acid functionality were also obtained by related synthetic strategies. These new compounds were assayed as inhibitors of MMP-1, MMP-2, MMP-8 and MMP-9, and of the collagenase isolated from Clostridium histolyticum (ChC). Some of the new derivatives reported here proved to be powerful inhibitors of the four MMPs mentioned above and of ChC, with activities in the low nanomolar range for some of the target enzymes, depending on the substitution pattern at the sulfonylureido moiety and on the length of the spacer through which the dibenzosuberenyl/suberyl group is connected with the rest of the molecule. Several of these inhibitors also showed selectivity for the deep pocket enzymes (MMP-2, MMP-8 and MMP-9) over the shallow pocket ones MMP-1 and ChC.     

beta-N-Biaryl ether sulfonamide hydroxamates as potent gelatinase inhibitors: part 1. Design, synthesis, and lead identification

A new series of beta-N-biaryl ether sulfonamide hydroxamates as novel gelatinase inhibitors is described. These compounds exhibit good potency for MMP-2 and MMP-9 without inhibiting MMP-1. The structure-activity relationships (SAR) reveal the biaryl ether type P1' moiety together with methanesulfonamide is the optimal combination that provides inhibitory activity of MMP-9 in the single-digit nanomolar range.     

A quantitative structure-activity relationship study on a series of Na+, K+-ATPase inhibitors

A quantitative structure-activity relationship (QSAR) study has been made on a new series of digitalis-like Na+,K+-ATPase inhibitors in which the guanylhydrazone group has been replaced by an aminoalkyloxime group. The correlations obtained have shown that the oxime moiety, primary amine group, overall size, and polarizability of the new type of substituents are higly beneficial to the Na+,K+-ATPase inhibition potency of the compounds and that their effect can be quantitatively assessed. The study also showed that the inotropic activity of the compounds is very well correlated with their Na+,K+-ATPase inhibition potency.     

Tetrahydroisoquinoline based sulfonamide hydroxamates as potent matrix metalloproteinase inhibitors

The synthesis and MMP inhibitory activity of a series of tetrahydroisoquinoline based sulfonamide hydroxamates are described. In nine MMPs tested, most of the compounds display potent inhibition activity except for MMP-7. Some subtle isozyme selectivity is observed by varying the substituents at the 6- and 7-positions and aromatic ring of arylsulfonyl groups.     

Protease inhibitors: synthesis of bacterial collagenase and matrix metalloproteinase inhibitors incorporating succinyl hydroxamate and iminodiacetic acid hydroxamate moieties

A series of succinyl hydroxamates/bishydroxamates as well as a new structural type of matrix metalloproteinase (MMP)/bacterial protease (BP) inhibitors, incorporating iminodiacetic (IDA) hydroxamate/bishydroxamate moieties, has been synthesized and tested for interaction with four vertebrate proteases, MMP-1, MMP-2, MMP-8 and MMP-9, and a BP, the collagenase isolated from Clostridium histolyticum (ChC). The new derivatives generally showed inhibition constants in the range of 8-62 nM against the five proteases mentioned above.     

Protease Inhibitors: Synthesis of Bacterial Collagenase and Matrix Metalloproteinase Inhibitors Incorporating Succinyl Hydroxamate and Iminodiacetic Acid Hydroxamate Moieties

A series of succinyl hydroxamates/bishydroxamates as well as a new structural type of matrix metalloproteinase (MMP)/bacterial protease (BP) inhibitors, incorporating iminodiacetic (IDA) hydroxamate/bishydroxamate moieties, has been synthesized and tested for interaction with four vertebrate proteases, MMP-1, MMP-2, MMP-8 and MMP-9, and a BP, the collagenase isolated from Clostridium histolyticum (ChC). The new derivatives generally showed inhibition constants in the range of 8-62 nM against the five proteases mentioned above.     

Hydroxamate-based peptide inhibitors of matrix metalloprotease 2

There is major interest in designing inhibitors for matrix metalloproteinase 2 (MMP-2, gelatinase A) since this enzyme is known to be involved in pathological processes such as tumor invasion or rheumatoid arthritis. The majority of MMP-2 inhibitor candidate drugs block the active site of MMP-2 by binding to its catalytic Zn2+ ion through a chelating (hydroxamate, sulphonate etc.) group. Despite the general interest in designing MMP-2 inhibitors, the results with many of the drug candidates were disappointing, their failure was usually explained by cross-reactions with other MMPs. One way to enhance MMP-2 selectivity is to design inhibitors that interact with both the active site and exosites such as the fibronectin type II (FN2) domains of the enzyme. In the present work, we have examined the inhibitory potential and MMP-2 selectivity of hydroxamates of three groups of peptides known to bind to the collagen-binding FN2 domains of MMP-2. The first type of peptides consisted of collagen-like (Pro-Pro-Gly)(n) repeats, peptides of the second group were identified from a random 15-mer phage display library based on their binding to immobilized FN2 domains of MMP-2. A hydroxamate of peptide p33-42, known to bind to the third FN2 domain of MMP-2 has also been tested. Our studies have shown that these compounds inhibited MMP-2 with IC50 values of 10-100 microM. The fact that their inhibitory potential was nearly identical for MMP-2del, a recombinant version of MMP-2 that lacks the FN2 domains, suggests that inhibition is not mediated by their binding to FN2 domains. It seems likely that the failure to exploit interaction with the FN2 domains is due to the fact that the FN2 domains and the catalytic domain of MMP-2 tumble independently, therefore only a tiny fraction of the conformational isomers can bind peptide hydroxamates via both the active site and the FN2 domain(s).     

Quantitative structure-activity relationship study of benzylsulfanyl imidazoles as cytokine release inhibitors

Benzylsulfanyl imidazole derivatives (Figure 1) have shown their ability to inhibit the release of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) from peripheral blood mononuclear cells or human whole blood. Such anticytokine actions of these congeners are quantitatively studied using Fujita-Ban and Hansch type analyses. The Fujita-Ban study resulted in the contributions of different substituents and the parent moiety for the inhibitions of cytokines TNF-alpha and IL-1beta. The substituents that have a higher positive contribution to the given activity, relative to substituents of the parent moiety at different positions were then used to obtain a trend for the active analogues. None of the substituents present at X, Y, 2-R and 3-R, appears to be advantageous over the substituents of the parent moiety for inhibition of both the cytokines. However, the substituents at 4-R, 5-R and 6-R help to improve the inhibitory actions of the compounds for both cytokines. The optimal activities seem to be manifested by compounds in which 4-R, 5-R and 6-R are substituted respectively by OH (or SOCH3 and SO2CH3), Cl and OH for inhibition of TNF-alpha, whereas by SOCH3 (or SO2CH3 and OH), H and OH for inhibition of IL-1beta. The Hansch type analysis, on the other hand, revealed that the F-substituents of the X-position and a less bulky structural moiety such as--S(CH2)2--at the Y-incision are advantageous in improving the inhibitory action towards TNF-alpha. Similarly, a less bulky/polar substituent present at 2-R and not having a hydrogen-bond donor property, while a more hydrophobic substituent at 3-R and hydrogen-bond acceptor substituent at 4-R are helpful in augmenting inhibitory activity of a compound. However, for inhibition of cytokine IL-1beta, it emerged that the X-substituents that transmits a higher negative resonance effect, the Y-substituent that offers less molecular bulk are beneficial. The R-substituents, being more electron donors at the meta-position, less hydrophobic at the para-position and offering smaller refractivity (less bulky and or polar) at the ortho-position are likewise helpful in improving the activity of a compound.     

Approaches to the simultaneous inactivation of metallo- and serine-β-lactamases

A series of cephalosporin-derived reverse hydroxamates and oximes were prepared and evaluated as inhibitors of representative metallo- and serine-β-lactamases. The reverse hydroxamates showed submicromolar inhibition of the GIM-1 metallo-β-lactamase. With respect to interactions with the classes A, C, and D serine β-lactamases, as judged by their correspondingly low K_m values, the reverse hydroxamates were recognized in a manner similar to the non-hydroxylated N–H amide side chains of the natural substrates of these enzymes. This indicates that, with respect to recognition in the active site of the serine β-lactamases, the OC–NR–OH functionality can function as a structural isostere of the OC–NR–H group, with the N–O–H group presumably replacing the amide N–H group as a hydrogen bond donor to the appropriate backbone carbonyl oxygen of the protein. The reverse hydroxamates, however, displayed k_cat values up to three orders of magnitude lower than the natural substrates, thus indicating substantial slowing of the hydrolytic action of these serine β-lactamases. Although the degree of inactivation is not yet enough to be clinically useful, these initial results are promising. The substitution of the amide N–H bond by N–OH may represent a useful strategy for the inhibition of other serine hydrolases.     

Synthesis and biological activity of selective pipecolic acid-based TNF-alpha converting enzyme (TACE) inhibitors

A series of novel, selective TNF-alpha converting enzyme inhibitors based on 4-hydroxy and 5-hydroxy pipecolate hydroxamic acid scaffolds is described. The potency and selectivity of TACE inhibition is dramatically influenced by the nature of the sulfonamide group which interacts with the S1' site of the enzyme. Substituted 4-benzyloxybenzenesulfonamides exhibit excellent TACE potency with >100x selectivity over inhibition of matrix metalloprotease-1 (MMP-1). Alkyl substituents on the ortho position of the benzyl ether moiety give the most potent inhibition of TNF-alpha release in LPS-treated human whole blood.     

Phosphinic acid-based MMP-13 inhibitors that spare MMP-1 and MMP-3

Phosphinic acid-based inhibitors of MMP-13 have been investigated with the aim of identifying potent inhibitors with high selectivity versus MMP-1. Independent variation of the substituents on a P(1)' phenethyl group and a P(2) benzyl group improved potencies in both cases around 3-fold over the unsubstituted parent. Combining improved P(1)' and P(2) groups into a single molecule gave an inhibitor with a 4.5 nM IC(50) against MMP-13 and which is 270-fold selective over MMP-1.     

Pyrimidine-2,4,6-Triones: a new effective and selective class of matrix metalloproteinase inhibitors

Matrix metalloproteinases (MMPs) are a family of zinc endopeptidases that have been implicated in various disease processes. Different classes of MMP inhibitors, including hydroxamic acids, phosphinic acids and thiols, have been previously described. Most of these mimic peptides and most likely bind in a similar way to the corresponding peptide substrates. Here we describe pyrimidine-triones as a completely new class of metalloprotease inhibitors. While the pyrimidine-trione template is used as the zinc-chelating moiety, the substituents have been optimized to yield inhibitors comparable in their inhibition efficiency of matrix metalloproteinases to hydroxamic acid derivatives such as batimastat. However, they are much more specific for a small subgroup of MMPs, namely the gelatinases (MMP-2 and MMP-9).     

A Quantitative Structure–Activity Relationship Study on a Series of Na+, K+-ATPase Inhibitors

A quantitative structure–activity relationship (QSAR) study has been made on a new series of digitalis-like Na⁺,K⁺-ATPase inhibitors in which the guanylhydrazone group has been replaced by an aminoalkyloxime group. The correlations obtained have shown that the oxime moiety, primary amine group, overall size, and polarizability of the new type of substituents are higly beneficial to the Na⁺,K⁺-ATPase inhibition potency of the compounds and that their effect can be quantitatively assessed. The study also showed that the inotropic activity of the compounds is very well correlated with their Na⁺,K⁺-ATPase inhibition potency.