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Quantitative Structure–Activity Relationship Studies on Hydroxamic Acids Acting as Histone Deacetylase Inhibitors

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Hydroxamic Acids

Abstract

Hydroxamic acids have been found to react with both proteins and nucleic acids attracting increasing attention for their potential as highly efficacious in combating various biological targets, free radicals, and biological disorders among them cancer and inflammation. The reactivity of hydroxamic acids toward sulfhydryl groups and metal ions of proteins has been suggested to be the reason for their inhibitory effect on various enzymes. The ability of the hydroxamic acid functionality to form chelates with metals in the enzyme’s active site is considered to be an important functional feature for a metalloenzyme inhibition. Many approaches in developing hydroxamic drugs, such as trichostatin and vorinostat, that interfere with (metallo) enzymes and act as anticancer drugs have been pursued over the past few decades. We present here a brief review of the QSAR and molecular modeling studies performed on hydroxamic acid derivatives acting as histone deacetylase inhibitors that have been studied as anticancer agents. These studies have shown that the anticancer activity of these compounds is basically controlled by their hydrophobic and steric properties.

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Abbreviations

ACxDN:

Index of cohesive interactions in solids

B1 :

Sterimol parameter of Verloop for the smallest width of substituent

BMLR:

Best multilinear regression method

Clog P :

Overall calculated lipophilicity

CMR:

Molar refractivity of the whole molecule

CoMFA:

Comparative molecular field analysis

CoMSIA:

Comparative molecular similarity indices analysis

DPL:

Dipole

ES-SWR:

Elimination selection-stepwise regression method

FISA:

Hydrophilic component of the solvent-accessible surface area

GFA:

Genetic function approximation

Glob:

Globularity of the compounds

HAT:

Histone acetyl-transferase

HDAC:

Histone deacetylase

HOMO:

Highest occupied molecular orbital

L:

Verloop parameter for the length of the first atom of the substituent

LFER:

Linear free energy related

LSSVM:

Least squares support vector machine

MgVol:

MacGovan volume

MLR:

Multiple linear regression

MMPs:

Matrix metalloproteinases

MR–R :

Molar refractivity of the substituent

MSA:

Molecular shape analysis

MW:

Molecular weight

PCA:

Principal component analysis

PLS:

Partial least squares

PMIX:

Principal moment of inertia along X-axis

QSAR:

Quantitative structure-activity relationships

QTMS:

Quantum topological molecular similarity

r:

Radius

SAR:

Structure-activity relationships

SASA:

Solvent-accessible surface area

ShpC:

Shape coefficient

TopoJ:

Balaban topological index

TSAR:

Tool for structure-activity relationships

WLS:

Weighted least square

WPSA:

Weak polar component of the solvent-accessible surface area

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Authors and Affiliations

  1. Department of Pharmaceutical Chemistry, School of Pharmacy, Aristotle University of Thessaloniki, 54124, Thessaloniki, Greece

    Dimitra Hadjipavlou-Litina & Eleni Pontiki

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  1. Dimitra Hadjipavlou-Litina
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  2. Eleni Pontiki
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Correspondence to Dimitra Hadjipavlou-Litina .

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Editors and Affiliations

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

    Satya P. Gupta

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Hadjipavlou-Litina, D., Pontiki, E. (2013). Quantitative Structure–Activity Relationship Studies on Hydroxamic Acids Acting as Histone Deacetylase Inhibitors. In: Gupta, S. (eds) Hydroxamic Acids. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-38111-9_8

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