Hydroxamic Acids: A Unique Family of Chemicals with Multiple Biological Activities

314 Pages·2013·7.09 MB·English

by  Satya P. Gupta

Satya P. Gupta Editor
Hydroxamic Acids
A Unique Family of Chemicals with
Multiple Biological Activities
Hydroxamic Acids
Satya P. Gupta
Editor
Hydroxamic Acids
A Unique Family of Chemicals with
Multiple Biological Activities
123
Editor
SatyaP. Gupta
Department of PharmaceuticalTechnology
Meerut InstituteofEngineering and Technology
Meerut
India
ISBN 978-3-642-38110-2 ISBN 978-3-642-38111-9 (eBook)
DOI 10.1007/978-3-642-38111-9
SpringerHeidelbergNewYorkDordrechtLondon
LibraryofCongressControlNumber:2013943569
(cid:2)Springer-VerlagBerlinHeidelberg2013
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Preface
Hydroxamic acids, which can be represented by a general formula RCONR0OH,
whereR,R0maybearylorsubstitutedarylmoiety,constituteaveryuniquefamily
of chemicals that possess a wide spectrum of biological activities. They act as
selective inhibitorsofmanyenzymes,suchasmatrixmetalloproteinases(MMPs),
peroxidases, hydrolases, ureases, lipoxygenases, cyclooxygenases, histone deace-
tylase and peptide deformylases, and consequently possess hypotensive, anti-
cancer,anti-malarial,anti-tuberculosisandanti-fungalproperties.TheirCONHOH
moiety has been identified as a key functional group to develop potential thera-
peuticagentstargetingcardiovasculardiseases,HIV,Alzheimer’sdisease,allergic
diseases, metal poisoning and iron overload. Hydroxamic acids are also used
industrially as anti-oxidants, inhibitors of corrosion, for the extraction of toxic
elements, asa means offlotation of minerals and even for their abilitytoserveas
redox switches for electronic devices. They can also act as nitric oxide donors.
This versatility of hydroxamic acids depends on their ability to act as a bidentate
ligand to chelate with metal ions such as Fe2? and Zn2? at the active site of the
enzymes. Their hydroxamic acid moiety, CONHOH, is not only a strong metal-
binding group but also possesses multiple sites for potential hydrogen bond
interactions with the enzymes. Thus, the metal-chelating property and multiple
hydrogen-bond formation ability of hydroxamic acids have made them an
intriguingfamilyofcompoundswithawidespectrumoftherapeuticroles.Oneof
the first therapeutic roles of hydroxamic acids was associated with their use as
siderophores, a class of low molecular weight iron-sequestering agents. Sidero-
phores have vast therapeutic potential to deal with iron overload in transfusion-
dependent patients, such as those suffering from thalassemia. Because of these
enormous therapeutic applications, the hydroxamic acids have greatly drawn the
attention of both theoretical and experimental chemists to make studies on them
for the design and development of drugs against a number of diseases. This book
therefore presents some very interesting chapters on them, written by experts,
covering their various chemical and pharmaceutical aspects.
The book contains 11 chapters in total. Since the multi-faceted activity of hy-
droxamicacidsdependsonthechemicalaspectsofthesecompounds,theveryfirst
chapter written by Gupta and Anjana describes in detail The Chemistry of
HydroxamicAcidscoveringtheirsynthesis,structure,chelating,hydrogen-bonding
v
vi Preface
and nitric oxide releasing properties, and general mechanism of inhibition of var-
ious enzymes. The second chapter written by Kakkar on Theoretical Studies on
Hydroxamic Acids further adds to their chemistry, discussing their conformation,
tautomerism, metal ionselectivity, and complexation.
Among the various enzymes which have been found to be inhibited by
hydroxamicacids,thecarbonicanhydrases(CAs),MMPsandhistonedeacetylases
(HDACs) have been most widely studied. Therefore, the three consecutive
Chaps. 3–5, namely Hydroxamic Acids as Carbonic Anhydrase Inhibitors by
Supuran, Structure–Activity Relationships of Hydroxamic Acids as Matrix
Metalloproteinase Inhibitors by Patil and Gupta and Hydroxamic Acids
as Histone Deacetylase Inhibitors by Thaler et al. describe vividly the different
types of hydroxamic acids inhibiting these enzymes and their structure–activity
relationships. However, no less important have been hydroxamic acids acting as
inhibitors of ribonucleotide reductase, as the inhibitors of this enzyme have been
developed as potent anticancer agents. Therefore, Chap. 6 Hydroxamic Acids
as Ribonucleotide Reductase Inhibitors written by Basu and Sinha presents a few
kindsofhydroxamatesthatinhibitcarbonucleotidereductase,theirmodeofaction,
and progress in computer-aided SAR studies on them leading to the development
of anticancer drugs.
Inhibitors of MMPs, HDACs, and ribonucleotide reductase have been devel-
oped as potent anticancer drugs. Therefore, a discussion of the inhibitors of these
enzymes that belong particularly to hydroxamic acid class and have been eval-
uatedagainstcancershavebeennicelypresentedbyGuptaetal.inChap.7entitled
asHydroxamicAcidDerivativesasAnticancerAgents.Theseauthorsalsodiscuss
inthischapter the future prospectsofdesign ofpotent anticancer agents based on
hydroxamic acids.
SinceHDACinhibitorshavebeenmostattractiveasanticanceragents,detailed
quantitative structure–activity relationship (QSAR) studies have also been made
on them in order to find the physicochemical and structural properties of the
compounds governing their activity, so that the design of potent anticancer drugs
may be rationalized. Hadjipavlau-Litina and Pontiki, therefore, presented in
Chap. 8 entitled as Quantitative Structure-Activity Relatioship Studies on Hydro-
xamic Acids Acting as Histone Deacetylase Inhibitors a detailed account of
QSAR studies on hydroxamic acids acting as HDAC inhibitors. All 2D and 3D
QSAR studies pointed out that anticancer activity of these compounds are basi-
cally controlled by their hydrophobic and streric properties.
The activity of the enzyme urease, which is produced in the body by a bac-
terium called Helicobacter pylori (H. pylori), plays a critical role in the patho-
genesis of several diseases, such as urinary tract infections, urolithiasis,
pyelonephritis, hepatic encephalopathy, hepatic coma, cancer, etc. Therefore, the
inhibitorsofureasehavebeengreatlystudiedandhydroxamicacidshaveoccupied
the foremost position among the urease inhibitors. Thus Chap. 9 Hydroxamic
Acids as Inhibitors of Urease in the Treatment of Helocobactor pylori Infections
writtenbyMuriandBarrosgivesadetailedaccountofhydroxamicacidsactingas
urease inhibitors and of their structure–activity relationships. The chapter also
Preface vii
describesthenewtechnologiesforthedeliveryofeffectiveureaseinhibitorsinthe
body.
Hydroxamic acid derivatives have recently been recommended for the thera-
peutic treatment of several diseases, such as hypertension, cancer, as well as
inflammations and infectious diseases, due to their ability to chelate metals,
especially in metalloenzymes. In Chap. 10 entitled as Therapeutic Potential
ofHydroxamicAcidsforMicrobialDiseases,Rodriguesetal.thereforepresentthe
potentialuseofhydroxamatesandtheirderivativesforthetreatmentandcontrolof
such diseases, along with a general overview of their structure, synthesis and
inhibition mechanism. Application of hydroxamic acids as chelating mineral
collectors for ore beneficiation is a unique area of their use and has attracted the
attention of limited workers in this unique area. Therefore, a review of the use of
alkyl and aryl hydroxamic acids in mineral processing is finally presented by
Natarajan in Chap. 11 entitled as Hydroxamic Acids as Chelating Mineral
Collectors. In this chapter, basic information on mineral flotation chemistry is
provided for the non-expert.
Thus an attempt has been made to cover all aspects of hydroxamic acids, a
uniqueclassofchemicalshavingmultiplebiologicalactivities.Articlescoveredin
this book are not only of interest to those working in this area but also to general
readers. As an editor of this book, I have greatly enjoyed reading all the chapters
andalsohopethereaderswilldoso.Igreatlyacknowledgetheinterestandzealof
all the authors for contributing such interesting and useful chapters.
Meerut (U.P), India Satya P. Gupta
Contents
The Chemistry of Hydroxamic Acids. . . . . . . . . . . . . . . . . . . . . . . . . 1
Satya P. Gupta and Anjana Sharma
Theoretical Studies on Hydroxamic Acids . . . . . . . . . . . . . . . . . . . . . 19
Rita Kakkar
Hydroxamates as Carbonic Anhydrase Inhibitors. . . . . . . . . . . . . . . . 55
Claudiu T. Supuran
Structure–Activity Relationship Studies of Hydroxamic
Acids as Matrix Metalloproteinase Inhibitors. . . . . . . . . . . . . . . . . . . 71
Vaishali M. Patil and Satya P. Gupta
Hydroxamic Acids as Histone Deacetylase Inhibitors . . . . . . . . . . . . . 99
Florian Thaler, Vaishali M. Patil and Satya P. Gupta
Hydroxamates as Ribonucleotide Reductase Inhibitors. . . . . . . . . . . . 153
Arijit Basu and Barij Nayan Sinha
Hydroxamic Acid Derivatives as Potential Anticancer Agents. . . . . . . 173
Manish K. Gupta, Gagandip Singh and Swati Gupta
Quantitative Structure–Activity Relationship Studies on
Hydroxamic Acids Acting as Histone Deacetylase Inhibitors. . . . . . . . 205
Dimitra Hadjipavlou-Litina and Eleni Pontiki
Hydroxamic Acids as Inhibitors of Urease in the Treatment
of Helicobacter pylori Infections. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 241
E. M. F. Muri and T. G. Barros
ix
x Contents
Therapeutic Potential of Hydroxamic Acids for Microbial Diseases. . . 255
Giseli Capaci Rodrigues, Flavia Alexandra Gomes de Souza,
Whei Oh Lin and Alane Beatriz Vermelho
Hydroxamic Acids as Chelating Mineral Collectors . . . . . . . . . . . . . . 281
Ramanathan Natarajan
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 309
The Chemistry of Hydroxamic Acids
Satya P. Gupta and Anjana Sharma
Abstract This chapter presents the chemical structure of hydroxamic acids, the
routes of their synthesis, and their chemical properties. A discussion is presented
as to how their metal chelating and hydrogen bonding properties make them a
class of compounds that may have multiple biological activities. A brief
descriptionofallimportantenzymesthatcan beinhibited byhydroxamic acidsis
also presented. The most important enzymes that are inhibited by hydroxamic
acids are matrix metalloproteinases, TNF-a converting enzyme, angiotensin-
converting enzyme, lipoxygenase, LTA4 hydrolase, urease, peptide deformylase,
histone deacetylase, UDP-3-O-[R-3-hydroxymyristoyl]-GlcNAc deacetylase, pro-
collagenC-proteinase,aggrecanase,andcarbonicanhydrase.Thusthehydroxamic
acidmoietyplaysanimportantroleasapharmacophoretodevelopdrugsagainsta
variety of diseases, such as cancer, cardiovascular diseases, HIV, Alzheimer’s,
malaria, allergic diseases, tuberculosis, metal poisoning, iron overload, etc.
Besides, hydroxamic acid moiety has also been exploited to develop potential
insecticides, antimicrobials, antioxidants, anti-corrosive agents, siderophores, and
asameansofflotationsofminerals.Itisalsodiscussedthathydroxamicacidsare
also effective nitric oxide (NO) donors, because of which they produce hypoten-
sive effects.
Keywords Hydroxamic acids (cid:2) Nitric oxide donors (cid:2) Siderophores
S.P.Gupta(&)
DepartmentofAppliedSciences,MeerutInstituteofEngineeringandTechnology,
Meerut250005,India
e-mail:[email protected]
A.Sharma
DepartmentofPharmaceuticalTechnology,MeerutInstituteofEngineering
andTechnology,Meerut250005,India
S.P.Gupta(ed.),HydroxamicAcids,DOI:10.1007/978-3-642-38111-9_1, 1
(cid:2)Springer-VerlagBerlinHeidelberg2013