"Maltol more effective"

An Efficient Synthesis of 5-Amido-3-Hydroxy-4-Pyrones as
Inhibitors of Matrix Metalloproteinases
Yi-Long Yan and Seth M. Cohen*
Department of Chemistry and Biochemistry, University of California,
San Diego, La Jolla, California 92093-0358
E-mail: Email: scohen@ucsd.edu

Abstract
3-Hydroxy-4-pyrones are a class of important metal chelators with
versatile medicinal applications.
An efficient pathway for the preparation of new 5-amido-3-hydroxy-4-
pyrone
derivatives has been developed.
The synthesized 5-amido-3-hydroxy-4-pyrones have been evaluated as
inhibitors of matrix metalloproteinases.

PMID: 17521196

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http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2531216

We have found that maltol and thiomaltol are more effective chelating
inhibitors
for MMP-3 (stromelysin) than the widely reported hydroxamate ligands.

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http://books.google.com/books?isbn=9067643084

"On the basis of the data obtained in this investigation , the
mechanism of the maltol action was stated.
It includes the chelating of Fe(II) and Fe(III) ions by maltol
in the system of iron /NADPH-dependent LPO.
Chelating properties of 3-hydroxy-4-pyrones suggested a
role as regulators of absorption and metabolism of iron in
animals.
The antioxidant properties of hydroxypyrones allow us to
explain and apply their chemoprotective activity and
anticarcinogenic effects.
Besides their ability to inhibit formation of N-nitrosoamines,
the ability of maltol and ethylmaltol to suppress oxidative stress,
which accompanies consumption of alcohol and smoking , is to
be considered as a most valuable property.
Maltol and ethylmaltol as tobacco smoking inhibitors are introduced
in a 500 mg/day dose into the compositions of chewing gums,
caramels or other food agents, which should be present in the mouth
over 10 minutes.
The administration of these peroaral medicinal forms of maltol
displays an additional advantage, since a chewing gum with maltol is
patented as a dental caries inhibitor."
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Matrix metalloproteinase inhibitors as therapy for inflammatory and
vascular diseases
Nature Reviews Drug Discovery 6, 480-498 (June 2007)
Jialiang Hu1,3, Philippe E. Van den Steen1,3, Qing-Xiang A. Sang2 &
Ghislain Opdenakker1  About the authors

Top of page
Abstract
Matrix metalloproteinases (MMPs) have outgrown the field
of extracellular-matrix biology and have progressed towards
being important regulatory molecules in cancer and inflammation.
This rise in status was accompanied by the development of various
classes of inhibitors.
Although clinical trials with synthetic inhibitors for the treatment
of cancer were disappointing, recent data indicate that the use of
selective inhibitors might lead to new therapies for acute and
chronic
inflammatory and vascular diseases.
In this Review, we compare the major classes of MMP inhibitors
and advocate that future drug discovery should be based on crucial
insights into the differential roles of specific MMPs in
pathophysiology
obtained with animal models, including knockout studies.

doi:10.1038/nrd2308
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http://theoncologist.alphamedpress.org/cgi/content/full/3/4/271

New Drugs on the Horizon: Matrix Metalloproteinase Inhibitors
Mace L. Rothenberg, Amy R. Nelson, Kenneth R. Hande
The Oncologist, Vol. 3, No. 4, 271-274, August 1998
© 1998 AlphaMed Press

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Structure-based design of HIV protease inhibitors:
5,6-dihydro-4-hydroxy-2-pyrones as effective, nonpeptidic
inhibitors.
J Med Chem. 1996 Nov 8;39(23):4630-42.
Thaisrivongs S, Romero DL, Tommasi RA,
Janakiraman MN, Strohbach JW, Turner SR,
Biles C, Morge RR, Johnson PD, Aristoff PA,
Tomich PK, Lynn JC, Horng MM, Chong KT,
Hinshaw RR, Howe WJ, Finzel BC, Watenpaugh KD.
Medicinal Chemistry Research, Pharmacia & Upjohn, Inc.,
Kalamazoo, Michigan 49001, USA.

From a broad screening program, the 4-hydroxycoumarin
phenprocoumon (I) was previously identified as a lead
template with HIV protease inhibitory activity.
The crystal structure of phenprocoumon/HIV protease complex
initiated a structure-based design effort that initially identified
the
4-hydroxy-2-pyrone U-96988 (II) as a first-generation clinical
candidate for the potential treatment of HIV infection.
Based upon the crystal structure of the 4-hydroxy-2-pyrone III/HIV
protease complex, a series of analogues incorporating a
5,6-dihydro-4-hydroxy-2-pyrone template were studied.
It was recognized that in addition to having the required
pharmacophore (the 4-hydroxy group with hydrogen-bonding
interaction with the two catalytic aspartic acid residues and the
lactone moiety replacing the ubiquitous water molecule in the
active site), these 5,6-dihydro-4-hydroxy-2-pyrones incorporated
side chains at the C-6 position that appropriately extended into
the S1' and S2' subsites of the enzyme active site.
The crystal structures of a number of representative
5,6-dihydro-4-hydroxy-2-pyrones complexed with the HIV
protease were also determined to provide better understanding
of the interaction between the enzyme and these inhibitors to
aid the structure-based drug design effort.
The crystal structures of the ligands in the enzyme active site
did not always agree with the conformations expected from
experience with previous pyrone inhibitors.
This is likely due to the increased flexibility of the dihydropyrone
ring.
From this study, compound XIX exhibited reasonably high enzyme
inhibitory activity (Ki = 15 nM) and showed antiviral activity
(IC50 = 5 microM) in the cell-culture assay.
This result provided a research direction which led to the discovery
of active 5,6-dihydro-4-hydroxy-2-pyrones as potential agents for the
treatment of HIV infection.

PMID: 8917652
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Matrix metalloproteinase inhibitors: new challenges
in the era of post broad-spectrum inhibitors.Nuti E,
Tuccinardi T, Rossello A.
Curr Pharm Des. 2007;13(20):2087-100.
Dipartimento di Scienze Farmaceutiche,
Università di Pisa, Pisa, Italy.

More than two decades have been spent to develop
many families of synthetic matrix metalloproteinases
inhibitors (MMPI) as therapeutical agents for serious
pathologies.
Unfortunately, clinical trials conducted on broad-spectrum
inhibitors have yielded disappointing results, especially in
the cancer pathology area.
Despite these outcomes, some small synthetic MMPI are
in advanced trials or launched in clinical ones for cancer,
arthritis, periodontal diseases.
Today many groups are developing intensive efforts to find
new classes of inhibitors characterized by improved potency
and, above all, high selectivity against the specific MMP
involved in each targeted pathology.
The new challenges include the development of new MMPI
bearing more effective ZBGs and the development of new
allosteric non-zinc binding inhibitors, devoid of ZBGs.
An analysis of more recent results in this field reported on
journals and patents will be developed, to consider some of
the more interesting new highly selective synthetic MMPI,
their SARs, the new theoretical approaches used for modelling
and the results of their biological evaluations.

PMID: 17627541

Who loves ya.
Tom

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