Skip to main content
SpringerLink
Log in

Structure–Activity Relationship Studies of Hydroxamic Acids as Matrix Metalloproteinase Inhibitors

  • Chapter
  • First Online:
Hydroxamic Acids

  • 1363 Accesses

Abstract

The chapter specifically deals with the structure–activity relationship studies on various classes of hydroxamates acting as matrix metalloproteinase (MMP) inhibitors. Among all classes of MMP inhibitors, hydroxamates are important in that their zinc-binding group CONHOH makes them a bidentate ligand to act with any metal-containing enzyme. Most of the MMP inhibitors developed by pharmaceutical companies belong to this category of compounds. The position of hydroxamate nitrogen suggests that it is protonated and forms a hydrogen bond with carbonyl oxygen of the enzyme backbone. In addition to zinc-binding affinity, several other properties of the hydroxamic acids depending upon their structures control their MMP inhibition activity. Various categories of hydroxamates such as succinyl, malonic acid, sulfonamide-based, aryl acid-based, sulfone-based, N-benzoyl aminobutyric acids, aminoproline-based, aminopyrrolidine-based, and phosphonamide/phosphinamide-based hydroxamates have been found to act as MMP inhibitors. A detailed structure–activity relationship (SAR) study of all these categories of hydroxamates has been presented.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Abbreviations

MMP:

Matrix metalloproteinase

MMPI:

Matrix metalloproteinase inhibitor

QSAR:

Quantitative structure–activity relationship

SAR:

Structure-activity relationship

TACE:

TNF-α converting enzyme

TIMP:

Tissue inhibitors of metalloproteinases

TNF:

Tumor necrosis factor-α

ZBG:

Zinc-binding group

References

  • Andrews KL, Betsuyaku T, Rogers S, Shipley JM, Senior RM, Miner JH (2000) Gelatinase B (MMP-9) is not essential in the normal kidney and does not influence progression of renal disease in a mouse model of Alport syndrome. Am J Pathol 157:303–311

    Article  CAS  Google Scholar 

  • Aranapakam V, Davis JM, Grosu GT, Baker JL, Ellingboe J, Zask A, Levin JI, Sandanayaka VP, Du M, Skotnicki JS, Di Joseph JF, Sung A, Zhao W, McDevitt J, Xu ZB (2003a) Synthesis and structure-activity relationship of N-substituted 4-arylsulfonylpiperidine-4-hydroxamic acids as novel, orally active matrix metalloproteinase inhibitors for the treatment of osteoarthritis. J Med Chem 46:2376–2396

    Article  CAS  Google Scholar 

  • Aranapakam V, Grosu GT, Davis JM, Hu B, Ellingboe J, Baker JL, Skotnicki JS, Zask A, Di Joseph JF, Sung A, Sharr MA, Killar LM, Walter T, Jin G, Cowling R (2003b) Synthesis and structure-activity relationship of a-sulfonylhydroxamic acids as novel, orally active matrix metalloproteinase inhibitors for the treatment of osteoarthritis. J Med Chem 46:2361–2375

    Article  CAS  Google Scholar 

  • Attolino E, Calderone V, Dragoni E, Fragai M, Richichi B, Luchinat C, Nativi C (2010) Structure-based approach to nanomolar, water soluble matrix metalloproteinases inhibitors (MMPIs). Eur J Med Chem 45:5919–5925

    Article  CAS  Google Scholar 

  • Babine RE, Bender SL (1997) Molecular recognition of protein-ligand complexes: applications to drug design. Chem Rev 97:1359–1472

    Article  CAS  Google Scholar 

  • Barta TE, Becker DP, Boehm TL, DeCrescenzo GA, Villamil CI, McDonald JJ, Freskos JN, Getman DP (2003) Preparation of arylsulfonyl heterocyclyl hydroxamic acids and related compounds as matrix metalloproteases inhibitors. U.S. Patent 6, 541, 489, 2003. PCT Int. Appl. WO 9925687 A1 990527 CAN 131:18929; AN 1999:350651

    Google Scholar 

  • Becker DP, Barta TE, Bedell L, DeCrescenzo G, Freskos J, Getman DP, Hockerman SL, Li M, Mehta P, Mischke B, Munie GE, Swearingen C, Villamil CI (2001a) α-amino-β-sulphone hydroxamates as potent MMP-13 inhibitors that spare MMP-1. Bioorg Med Chem Lett 11:2719–2722

    Article  CAS  Google Scholar 

  • Becker DP, Barta TE, Bedell LJ, Boehm TL, Bond BR, Carroll J, Carron CP, DeCrescenzo GA, Easton AM, Freskos JN, Funckes-Shippy CL, Heron M, Hockerman S, Howard CP, Kiefer JR, Li MH, Mathis KJ, McDonald JJ, Mehta PP, Munie GE, Sunyer T, Swearingen CA, Villamil CI, Welsch D, Williams JM, Yu Y, Yao J (2010) Orally active MMP-1 sparing α-tetrahydropyranyl and α–piperidinyl sulfone matrix metalloproteinase (MMP) inhibitors with efficacy in cancer, arthritis and cardiovascular disease. J Med Chem 53:6653–6680

    Article  CAS  Google Scholar 

  • Becker DP, DeCrescenzo G, Freskos J, Getman DP, Hockerman SL, Li M, Mehta P, Munie GE, Swearingen C (2001b) α-alkyl-α-amino-β-sulphone hydroxamates as potent MMP inhibitors that spare MMP-1. Bioorg Med Chem Lett 11:2723–2725

    Article  CAS  Google Scholar 

  • Becker DP, Villamil CI, Barta TE, Bedell LJ, Boehm TL, DeCrescenzo GA, Freskos JN, Getman DP, Hockerman S, Heintz R, Howard SC, Li MH, McDonald JJ, Carron CP, Funckes-Shippy CL, Mehta PP, Munie GE, Swearingen CA (2005) Synthesis and structure-activity relationships of β- and α-piperidine sulfone hydroxamic acid matrix metalloproteinase inhibitors with oral antitumor efficacy. J Med Chem 48:6713–6730

    Article  CAS  Google Scholar 

  • Bottomley KM, Johnson WH, Walter DS (1998) Matrix metalloproteinase inhibitors in arthritis. J Enzyme Inhib 13:79–101

    Article  CAS  Google Scholar 

  • Brown DA, Cuffe LP, Fitzpatrick NJ, Ryan AT (2004a) A DFT study of model complexes of zinc hydrolases and their inhibition by hydroxamic acids. Inorg Chem 43:297–302

    Article  CAS  Google Scholar 

  • Brown DA, Glass WK, Fitzpatrick NJ, Kemp TJ, Errington GJ, Haase W, Karsten F, Mahdy AH (2004b) Structural variations in dinuclear model hydrolases and hydroxamate inhibitor models: synthetic, spectroscopic and structural studies. Inorg Chim Acta 357:1411–1436

    Article  CAS  Google Scholar 

  • Chen D, Hackbarth C, Ni ZJ, Wu C, Wang W, Jain R, He Y, Bracken K, Weidmann B, Patel DV, Trias J, White RJ, Yuan Z (2004) Peptide deformylase inhibitors as antibacterial agents: identification of VRC3375, a proline-3-alkylsuccinyl hydroxamate derivative, by using an integrated combinatorial and medicinal chemistry approach. Antimicrob Agents Chemother 48:250–261

    Article  CAS  Google Scholar 

  • Cheng M, De B, Pikul S, Almstead NG, Natchus MG, Anastasio MV, McPhail SJ, Snider CE, Taiwo YO, Chen L, Dunaway CM, Gu F, Dowty ME, Mieling GE, Janusz MJ, Wang-Weigand S (2000) Design and synthesis of piperazine-based matrix metalloproteinase inhibitors. J Med Chem 43:369–380

    Article  CAS  Google Scholar 

  • Connolly PJ, Wetter SK, Beers KN, Hamel SC, Chen RH, Wachter MP, Ansell J, Singer MM, Steber M, Ritchie DM, Argentieri DC (1999) N-hydroxyurea and hydroxamic acid inhibitors of cyclooxygenase and 5-lipoxygenase. Bioorg Med Chem 9:979–984

    Article  CAS  Google Scholar 

  • Curtin ML, Florjancic AS, Heyman HR, Michaelides MR, Garland RB, Holms JH, Steinman DH, Dellaria JF, Gong J, Wada CK, Guo Y, Elmore IB, Tapang P, Albert DH, Magoc TJ, Marcotte PA, Bouska JJ, Goodfellow CL, Bauch JL, Marsh KC, Margon DW, Davidsen SK (2001) Discovery and characterization of the potent, selective and orally bioavailable MMP inhibitor ABT-770. Bioorg Med Chem Lett 11:1557–1560

    Article  CAS  Google Scholar 

  • Domingo JL (1998) Developmental toxicity of metal chelating agents. Reprod Toxicol 12:499–510

    Article  CAS  Google Scholar 

  • Dooley CM, Devocelle M, Mcloughlin B, Nolan KB, Fitzgerald DJ, Sharkey CT (2003) A novel family of hydroxamate-based acylating inhibitors of cyclooxygenase. Mol Pharmacol 63:450–455

    Article  CAS  Google Scholar 

  • El Yazal J, Pang Y-P (2000) Proton dissociation energies of zinc-coordinated hydroxamic acids and their relative affinities for zinc: insight into design of inhibitors of zinc-containing proteinases. J Phys Chem B 104:6499–6504

    Article  Google Scholar 

  • Fray MJ, Burslem MF, Dickinson RP (2001) Selectivity of inhibitors of matrix metalloproteinases MMP-3 and MMP-2 by succinyl hydroxamates and their carboxylic acid analogues is dependent on P3′ group chirality. Bioorg Med Chem Lett 11:567–570

    Article  CAS  Google Scholar 

  • Fray MJ, Dickinson RP (2001) Discovery of potent and selective succinyl hydroxamates inhibitors of matrix metalloproteinase-3 (stromelysin-1). Biorg Med Chem Lett 11:571–574

    Article  CAS  Google Scholar 

  • Gupta SP (2007) Quantitative structure-activity relationship studies on zinc-containing metalloproteinase inhibitors. Chem Rev 107:3042–3087

    Article  CAS  Google Scholar 

  • Gupta SP, Patil VM (2012) Specificity of binding with matrix metalloproteinases. In: Gupta SP (ed) Matrix metalloproteinase inhibitors: specificity of binding and structure-activity relationships. Springer, Basel, pp 35–56

    Chapter  Google Scholar 

  • Hannessian S, Bouzbouz S, Boudon A, Tucker GC, Peyroulan D (1999) Picking the S1, S1′ and S2′ pockets of matrix metalloproteinases: a niche for potent acyclic sulfonamide inhibitors. Bioorg Med Chem Lett 9:1691–1696

    Article  Google Scholar 

  • Heath EI, Grochow LB (2000) Clinical potential of matrix metalloproteinase inhibitors in cancer therapy. Drugs 59:1043–1055

    Article  CAS  Google Scholar 

  • Hidalgo M, Eckhardt SG (2001) Matrix metalloproteinase inhibitors: how can we optimize their development? J Natl Cancer Inst 93:178–193

    Article  CAS  Google Scholar 

  • Igeta K, Tobetto K, Saiki I, Odake S, Fujisawa T, Matsuo T, Oku T (2000) PCT Int Appl, WO 00 03,703

    Google Scholar 

  • Ikura M, Nakatani S, Yamamoto S, Habashita H, Sugiura T, Takahashi K, Ogawa K, Ohno H, Nakai H, Toda M (2006) Discovery of a new chemical lead for a matrix metalloproteinase inhibitor. Bioorg Med Chem 14:4241–4252

    Article  CAS  Google Scholar 

  • Jeng AY, Chou M, Parker DT (1998) Sulfonamide-based hydroxamic acids as potent inhibitors of mouse macrophage metalloelastase. Bioorg Med Chem Lett 8:897–902

    Article  CAS  Google Scholar 

  • Jeng AY, De Lombaert S (1997) Endothelin converting enzyme inhibitors. Curr Pharm Des 3:597–614

    CAS  Google Scholar 

  • Johnson WH, Roberts NA, Borkakoti N (1987) Collagenase inhibitors: their design and potential therapeutic use. J Enzyme Inhib 2:1–22

    Article  CAS  Google Scholar 

  • Johnstone RW (2002) Histone-deacetylase inhibitors: novel drugs for the treatment of cancer. Nat Rev Drug Discov 1:287–299

    Article  CAS  Google Scholar 

  • Jung M (2001) Inhibitors of histone deacetylase as new anticancer agents. Curr Med Chem 8:1505–1511

    Article  CAS  Google Scholar 

  • Kelly WK, O’Connor OA, Marks PA (2002) Histone deacetylase inhibitors: from target to clinical trials. Expert Opin Investig Drugs 11:1695–1713

    Article  CAS  Google Scholar 

  • Kimura T, Tamakl K, Miyazaki S, Kurakata S, Fujiwara K (2001) PCT Int. Appl. WO 0123363, 5th Apr, 2001

    Google Scholar 

  • Kolodziej SA, Hockerman SL, Boehm TL, Carroll JN, DeCrescenzo GA, McDonald JJ, Mischke DA, Munie GE, Fletcher TR, Rico JG, Stehle NW, Swearingen C, Becker DP (2010a) Orally bioavailable dual MMP-1/MMP-14 sparing, MMP-13 selective α-sulfone hydroxamates. Bioorg Med Chem Lett 20:3557–3560

    Article  CAS  Google Scholar 

  • Kolodziej SA, Hockerman SL, DeCrescenzo GA, McDonald JJ, Mischke DA, Munie GE, Fletcher TR, Stehle N, Swearingen C, Becker DP (2010b) MMP-13 selective isonipecotamide α-sulfone hydroxamates. Bioorg Med Chem Lett 20:3561–3564

    Article  CAS  Google Scholar 

  • Kontogiorgis CA, Papaioannou P, Hadjipavlou-Litina DJ (2005) Matrix metalloproteinase inhibitors: a review on pharmacophore mapping and (Q)SARs results. Curr Med Chem 12:339–355

    Article  CAS  Google Scholar 

  • Krumme D, Wenzel H, Tschesche H (1998) Hydroxamate derivatives of substrate-analogous peptides containing aminomalonic acid are potent inhibitors of matrix metalloproteinases. FEBS Lett 436:209–212

    Article  CAS  Google Scholar 

  • Leung D, Abbenante G, Fairlie DP (2000) Protease inhibitors: current status and future prospects. J Med Chem 43:305–341

    Article  CAS  Google Scholar 

  • Levin JI, Du MT, Di Joseph JF, Killar LM, Sung A, Walter T, Sharr MA, Roth CE, Moy FJ, Powers R, Jin G, Cowling R, Skotnicki JS (2001) The discovery of anthranilic acid-based MMP inhibitors. Part 1: SAR of the 3-position. Bioorg Med Chem Lett 11:235–238

    Article  CAS  Google Scholar 

  • Levin JI, Nelson FC, Delos SE, Du MT, MacEwan G, Chen JM, Ayral-Kaloustian S, Xu J, Jin G, Cummons T, Barone D (2004) Benzodiazeine inhibitors of the MMPs and TACE. Part 2. Bioorg Med Chem Lett 14:4147–4151

    Google Scholar 

  • Lipczynska-Kochany E (1988) In some new aspects of hydroxamic acid chemistry. Pr Nauk-Politech Warsz Chem 46:3–98

    Google Scholar 

  • Ma D, Wu W, Yang G, Li J, Ye Q (2004) Tetrahydroisoquinoline based sulfonamide hydroxamates as potent matrix metalloproteinase inhibitors. Bioorg Med Chem Lett 14:47–50

    Article  Google Scholar 

  • Marks PA, Richon VM, Rifkind RA (2000) Histone deacetylase inhibitors: inducers of differentiation or apoptosis of transformed cells. J Natl Cancer Inst 92:1210–1216

    Article  CAS  Google Scholar 

  • Marques SM, Chaves S, Rossello A, Tuccinardi T, Santos MA (2006) Metal ions in biology and medicine, vol 9. John Libbey Eurotext, Paris, pp 117–121

    Google Scholar 

  • Matter H, Schwab W (1999) Affinity and selectivity of matrix metalloproteinase inhibitors: a chemometrical study from the perspective of ligands and proteins. J Med Chem 42:4506–4523

    Article  CAS  Google Scholar 

  • Matter H, Schwab W, Barbier D et al (1999) Quantitative structure-activity relationship of human neutrophil collagenase (MMP-8) inhibitors using comparative molecular field analysis and X-ray structure analysis. J Med Chem 42:1908–1920

    Article  CAS  Google Scholar 

  • Miller MJ (1989) Syntheses and therapeutic potential of hydroxamic acid based siderophores and analogues. Chem Rev 89:1563–1579

    Article  CAS  Google Scholar 

  • Mishra H, Parrill AL, Williamsom JS (2002) Three-dimensional quantitative structure-activity relationship and comparative molecular field analysis of dipeptide hydroxamic acid Helicobacter pylori urease inhibitors. Antimicrob Agents Chemother 46:2613–2618

    Article  CAS  Google Scholar 

  • Moore WM, Spilburg CA (1986a) Peptide hydroxamic acids inhibit skin collagenase. Biochem Biophys Res Commun 136:390–399

    Article  CAS  Google Scholar 

  • Moore WM, Spilburg CA (1986b) Purification of human collagenase with a hydroxamic acid affinity column. Biochemistry 25:5189–5195

    Article  CAS  Google Scholar 

  • Muri EM, Nieto MJ, Sindelar RD, Williamson JS (2002) Hydroxamic acids as pharmacological agents. Curr Med Chem 9:1631–1653

    Article  CAS  Google Scholar 

  • Nakatani S, Ikura M, Yamamoto S, Nishita Y, Itadani S, Habashita H, Sugiura T, Ogawa K, Ohno H, Takahashi K, Nakai H, Toda M (2006) Design and synthesis of novel metalloproteinase inhibitors. Bioorg Med Chem 14:5402–5422

    Article  CAS  Google Scholar 

  • Natchus MG, Bookland RG, De B, Almstead NG, Pikul S, Janusz MJ, Heitmeyer SA, Hookfin EB, Hsies LC, Dowty ME, Dietsch CR, Patel VS, Garver SM, Gu F, Pokross ME, Mieling GE, Baker TR, Foltz DJ, Peng SX, Bornes DM, Strojnowski MJ, Taiwo YO (2000) Development of new hydroxamates matrix metalloproteinase inhibitors derived from functionalized 4-aminoprolines. J Med Chem 43:4948–4963

    Article  CAS  Google Scholar 

  • Nishino N, Powers JC (1978) Peptide hydroxamic acids as inhibitors of thermolysin. Biochemistry 17:2846–2850

    Article  CAS  Google Scholar 

  • Noe MC, Snow SL, Wolf-Gouveia LA, Mitchell PG, Lopresti-Morrow L, Reeves LM, Yocum SA, Liras JL, Vaughn M (2004) 3-hydroxy-4-arylsulfonyltetra hydrohydropyranyl-3-hydroxamic acids are novel inhibitors of MMP-13 and aggrecanase. Bioorg Med Chem Lett 14:4727–4730

    Article  CAS  Google Scholar 

  • Nuti E, Casalini F, Avramova SI, Santamaria S, Cercignani G, Marinelli L, Pietra VL, Novellino E, Orlandini E, Nencetti S, Tuccinardi T, Martinelli A, Lim NH, Visse R, Nagase H, Rossello A (2009) N-O-isopropyl sulfonamide-based hydroxamates: design, synthesis and biological evaluation of selective matrix metalloproteinase-13 inhibitors as potential therapeutic agents for osteoarthritis. J Med Chem 52:4757–4773

    Article  CAS  Google Scholar 

  • Nuti E, Casalini F, Santamaria S, Gabelloni P, Bendinelli S, Pozzo ED, Costa B, Marinelli L, Pietra VL, Novellino E, Bernardo MM, Fridman R, Settimo FD, Martini C, Rossello A (2011) Synthesis and biological evaluation of U87MG glioma cells of (ethynylthiophene) sulfonamide-based hydroxamates as matrix metalloproteinase inhibitors. Eur J Med Chem 46:2617–2629

    Article  CAS  Google Scholar 

  • Parvathy S, Hussain I, Karran EH, Turner AJ, Hooper NM (1998) Alzheimer’s amyloid precursor protein alpha-secretase is inhibited by hydroxamic acid-based zinc metalloprotease inhibitors: similarities to the angiotensin converting enzyme secretase. Biochemistry 37:1680–1685

    Article  CAS  Google Scholar 

  • Pikul S, McDow Dunham KL, Almstead NG, De B, Natchus MG, Anastasio MV, McPhail SJ, Snider CE, Taiwo YO, Chen L, Dunaway CM, Gu F, Mieling CE (1999) Desgin and synthesis of phosphinamide-based hydroxamic acids as inhibitors of matrix metalloproteinases. J Med Chem 42:87–94

    Google Scholar 

  • Robinson RP, Laird ER, Blake JF, Bordner J, Donahue KM, Lopresti-Morrow LL, Mitchell PG, Reese MR, Reeve LM, Stam EJ, Yocum SA (2000) Structure-based design and synthesis of a potent matrix metalloproteinase-13 inhibitor based on a pyrrolidinone scaffold. J Med Chem 43:2293–2296

    Article  CAS  Google Scholar 

  • Robinson RP, Laird ER, Donahue KM, Lopresti-Morrow LL, Mitchell PG, Reese MR, Reeves LM, Rouch AI, Stam EJ, Yocum SA (2001) Design and synthesis of 2-ooxo-imidazolidine-4-carboxylic acid hydroxamides as potent matrix metalloproteinase-13 inhibitors. J Med Chem 119:1211–1213

    Google Scholar 

  • Roedern GE, Brandstetter H, Engh RA, Bode W, Grams F, Moroder L (1998) Bis-substituted malonic acid hydroxamates derivatives as inhibitors of human neutrophil collagenase. J Med Chem 41:3041–3047

    Article  Google Scholar 

  • Rossello A, Nuti E, Carelli P, Orlandini E, Macchia M, Nencetti S, Zandomeneghi M, Balzano F, Uccello BG, Albini A, Benelli R, Cercignani G, Murphy G, Balsamo A (2005a) N-i-propoxy-N-biphenylsulfonyl aminobutylhydroxamic acids as potent and selective inhibitors of MMP-2 and MT1-MMP. Bioorg Med Chem Lett 15:1321–1326

    Article  CAS  Google Scholar 

  • Rossello A, Nuti E, Catalani MP, Carelli P, Orlandini E, Rapposelli S, Tuccinardi T, Atkinson SJ, Murphyb G, Balsamoa A (2005b) A new development of matrix metalloproteinase inhibitors: twin hydroxamic acids as potent inhibitors of MMPs. Bioorg Med Chem Lett 15:2311–2314

    Article  CAS  Google Scholar 

  • Rossello A, Nuti E, Orlandini E, Carelli P, Rapposelli S, Macchia M, Minutolo F, Carbonaro L, Albini A, Benelli R, Cercignani G, Murphy G, Balsamo A (2004) New N-arylsulfonyl-N-alkoxyaminoacetohydroxamic acids as selective inhibitors of gelatinase A (MMP-2). Bioorg Med Chem 12:2441–2450

    Article  CAS  Google Scholar 

  • Salvino JM, Mathew R, Kiesow T, Narensingh R, Mason HJ, Dodd A, Groneberg R, Burns CJ, McGeehan G, Kline J, Orton E, Tang SY, Morrisette M, Labaudininiere R (2000) Solid-phase synthesis of an arylsulfone hydroxamate library. Bioorg Med Chem Lett 10:1637–1640

    Article  CAS  Google Scholar 

  • Santos MA, Marques SM, Tuccinardi T, Carelli P, Panelli L, Rossello A (2006) Design, synthesis and molecular modeling study of iminodiacetyl monohydroxamic acid derivatives as MMP inhibitors. Bioorg Med Chem 14:7539–7550

    Article  CAS  Google Scholar 

  • Shingledecker K, Jiang S, Paulus H (2000) Reactivity of the cysteine residues in the protein splicing active center of the Mycobacterium tuberculosis RecA intein. Arch Biochem Biophys 375:138–144

    Article  CAS  Google Scholar 

  • Shuttleworth S (1998) An overview of combinatorial chemistry and its applications to the identification of matrix metalloproteinase inhibitors (MMPIs). In: Harvey AL (ed.) Advances in drug discovery techniques. Wiley, New York, p 115

    Google Scholar 

  • Sorensen MD, Blaehr LKA, Christensen MK, Hoyer T, Latini S, Hjaranaa PJV, Bjoekling F (2003) Cyclic phosphinamides and phosphonamides, novel series of potent matrix metalloproteinase inhibitors with antitumor activity. Bioorg Med Chem 11:5461–5484

    Article  CAS  Google Scholar 

  • Supuran CT, Scozzafava A (2002) Matrix Metalloproteinase (MMPs). In: Smith HJ, Simons C (eds.) Proteinase and peptidase inhibition: recent potential targets for drug development. Taylor and Francis, London, pp 35-61

    Google Scholar 

  • Szekeres T, Fritzer-Szekeres M, Elford HL (1997) The enzyme ribonucleotide reductase: target for antitumor and anti-HIV therapy. Critical Rev Clin Lab Sci 34:503–528

    Article  CAS  Google Scholar 

  • Torres G (1995) Hydroxyurea, a potential new anti-HIV agent. GMHC Treat Issues 9:7–9

    CAS  Google Scholar 

  • Tsai KC, Lin TH (2004) A ligand-based molecular modeling study on some matrix metalloproteinase-1 inhibitors using several 3D QSAR techniques. J Chem Inf Comput Sci 44:1857–1871

    Article  CAS  Google Scholar 

  • Tsukamoto K, Itakura H, Sato K, Fukuyama K, Miura S, Takahashi S, Ikezawa H, Hosoya T (1999) Binding of salicylhydroxamic acid and several aromatic donor molecules to Arthromyces ramosus peroxidase, investigated by X-ray crystallography, optical difference spectroscopy, NMR relaxation, molecular dynamics, and kinetics. Biochemistry 38:12558–12568

    Article  CAS  Google Scholar 

  • Tu G, Xu W, Huang H, Li S (2008) Progress in the development of matrix metalloproteinase inhibitors. Curr Med Chem 15:1388–1395

    Article  CAS  Google Scholar 

  • Valapour M, Gou J, Schroeder JT, Keen J, Cianferoni A, Casolaro V, Georas SN (2002) Histone deacetylation nhibits IL4 gene expression in T cells. J Allergy Clin Immunol 109:238–245

    Article  CAS  Google Scholar 

  • Venkatesan AM, Davis JM, Grosu GT, Baker J, Zask A, Levin JI, Ellingboe J, Skotnicki JS, Di Joseph JF, Sung A, Jin G, Xu W, McCarthy DJ, Barone D (2004) Synthesis and structure-activity relationships of 4-alkynyloxy phenyl sulfanyl sulfinyl and sulfonyl alkyl hydroxamates as tumor necrosis factor-α converting enzyme and matrix metalloproteinase inhibitors. J Med Chem 47:6255–6269

    Article  CAS  Google Scholar 

  • Verma RP, Hansch C (2007) Matrix metalloproteinases (MMPs): chemical-biological functions and (Q)SARs. Biorg Med Chem 15:2223–2268

    Article  CAS  Google Scholar 

  • Wada CK, Holms JH, Curtin ML, Dai Y, Florjancic AS, Garland RB, Guo Y, Heyman HR, Stacey JR, Steinman DH, Albert DH, Bouska JJ, Elmore IN, Goodfellow CL, Marcotte PA, Tapang P, Morgan DW, Michaelides MR, Davidsen SK (2002) Phenoxyphenyl sulfone N-formylhydroxylamines (retrohydroxamates) as potent, selective, orally bioavailable matrix metalloproteinase inhibitors. J Med Chem 45:219–232

    Article  CAS  Google Scholar 

  • Weisburger JH, Weisburger EK (1973) Formation and pharmacological, toxicological, and pathological properties of hydroxylamines and hydroxamic acids. Pharmacol Rev 25:1–66

    CAS  Google Scholar 

  • Whittakar M (1998) Discovery of protease inhibitors using targeted libraries. Curr Opin Chem Biol 2:386–396

    Article  Google Scholar 

  • Whittaker M, Floyd CD, Brown P, Gearing JH (1999) Design and therapeutic application of matrix metalloproteinase inhibitors. Chem Rev 99:2735–2776

    Article  CAS  Google Scholar 

  • Yang SM, Scannevin RH, Wang B, Burke SL, Wilson LJ, Karnachi P, Rhodes KJ, Lagu B, Murray WV (2008) β-N-biaryl ether sulfonamide hydroxamates as potent gelatinase inhibitors: Part 1. Design, synthesis, and lead identification. Bioorg Med Chem Lett 18:1135–1139

    Article  CAS  Google Scholar 

  • Yao W, Wasserman ZR, Chao M, Reddy G, Shi E, Liu RQ, Covington MB, Arner EC, Pratta MA, Tortorella M, Magolda RL, Newton R, Qian M, Ribadeneira MD, Christ D, Wexler RR, Decicco CP (2001) Design and synthesis of a series of (2R)-N(4)-hydroxy-2-(3-hydroxybenzyl)-N(1)-[(1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl] butanediamide derivatives as potent, selective, and orally bioavailable aggrecanase inhibitors. J Med Chem 44:3347–3350

    Article  CAS  Google Scholar 

  • Zhang X, Gonnella NC, Koehn J, Pathak N, Ganu V, Melton R, Parker D, Hu SI, Nam KY (2000) Solution structure of the catalytic domain of human collagenase-3 (MMP-13) complexed to a potent non-peptidic sulfonamide inhibitor: binding comparison with stromelysin-1 and collagenase-1. J Mol Biol 301:513–524

    Article  CAS  Google Scholar 

  • Zhang Y, Li D, Houtman JC, Witiak DT, Seltzer J, Bertics PJ, Lauhon CT (1999) Design, combinatorial chemical synthesis and in vitro characterization of novel urea based gelatinase inhibitors. Bioorg Med Chem Lett 9:2823–2826

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. School of Pharmacy, Bharat Institute of Technology, Meerut, 250103, India

    Vaishali M. Patil

  2. Meerut Institute of Engineering and Technology, Meerut, 250005, India

    Satya P. Gupta

Authors
  1. Vaishali M. Patil
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Satya P. Gupta
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Satya P. Gupta .

Editor information

Editors and Affiliations

  1. Department of Pharmaceutical Technology Department of Applied Sciences, Meerut Institute of Engineering and Technology, Meerut, India

    Satya P. Gupta

Rights and permissions

Reprints and permissions

Copyright information

© 2013 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Patil, V.M., Gupta, S.P. (2013). Structure–Activity Relationship Studies of Hydroxamic Acids as Matrix Metalloproteinase Inhibitors. In: Gupta, S. (eds) Hydroxamic Acids. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-38111-9_4

Download citation

Publish with us

Policies and ethics

Search

Navigation