Modeling of IC 50 ( 5-LOX And COX ) Activity of Phenol Derivatives Against Leukemia Cells SAMEER DIXIT

Phenols derivatives show different inhibitory selectivities towards 5-LOX and COX and induce cell death in leukemia cell lines. For modeling of activity against Leukemia cell lines K562, HL-60, Raji, MOLT4, 32D, Leukocytes, NIH3T3 etc. of phenol derivatives we used three descriptors Mor20e, Mor04m and RDF045m. 5-LOX and COX Values of Bobels are used to build model for Predicted Activity for 5-LOX and COX.


INTRODUCTION
In the present study we shall use a series of phenol derivatives for QSAR & QSPR studies.Phenol's derivatives like Bobel-24 1 (2,4,6-Triiodophenol or AM-24) induce caspaseindependent mitochondrial cell death in leukemia cells inhibited by Mys.2,4,6-Triiodophenol was originally designed as a potential anti-inflammatory drug with inhibitory activities against COX (cyclooxygenases) and LOX (lipoxygenases).It is found that it exerts a potent cytotoxic activity against several leukemia cell lines.we predicted the antiproliferative activity of the Phenol derivatives on leukemia cell lines.Its found that it exerts a potent cytotoxic activity against several leukemia lines.There phenols derivatives show different inhibitory selectivities towards 5-LOX and COX and induce cell death in leukemia cell lines.
Prostaglandins and leukotrienes are signaling mediators generated from arachidonic acid by the action of cyclo-oxygenases (COX-1 and COX-2) and 5-lipoxygenases (5-LOX), respectively.COX is expressed in most cells, whereas 5-LOX is mainly expressed in inflammatory cells such as polymorphonuclear leukocytes 2 .Leukotrienes modulate the growth of several cell types and it has also been shown that various 5-LOX metabolites from arachidonic acid regulate murine and human hematopoiesis 3 .COX and 5-LOX inhibitors are used as anti-inflammatory drugs 4 .Cytotoxic mechanisms of phenol's derivatives do not seem to be directly related to the inhibition of these enzymatic activities.However, it is important to note that the IC 50 of these compounds for all the tested cell lines are within the concentration range clinically attainable 5 .Interestingly, many phenol's derivatives show lower cytotoxic activity on nontransformed cells (32D, NIH3T3, leukocytes) than in leukemia cell lines, either from myeloid origin (K562, HL60) or lymphoid origin (Raji, MOLT).

MATERIAL AND METHODS
To calculate the different Molecular Descriptor like constitutional, topological, geometrical, charge e.g.3D-MoRSE 6-7 (3D-Molecular Representation of Structure based on Electron diffraction), RDF 8-9 (radial distribution function); DRAGON Software used in the study.
Activities of phenol derivatives are correlated with Topological indices mention above.The correlations are than subjected to regression analysis using the method of least squares.In each case we have multiple linear regression analysis which gives linear regression models shown in equation 1.1 and 1.2.

CONCLUSION
By the study of effect of phenol derivatives on 5-LOX and COX we found that IC 50 (µmol/L) of 4-OC4H9 shows high potential for 5-LOX and 3-OH for COX.The IC 50 value of phenol derivatives for 5-LOX and COX is depend on the substitute and its the position.
As size of Leophobic groups is increased than value of IC 50 is decreased for 5-LOX e.g.2.103< 3.067< 3.1014 for respectively 4-C 5 H 11 , 4-C 4 H 9 , 4-C 3 H 7 .In case of Leophobic groups, para derivatives have low value, meta has high and ortho has higher value of IC 50 for 5-LOX inhibition e.g.3.62, 3.83, 3.88 for methyl.However for ethyl ortho derivatives have min and meta has higher value.As electro negativity is increased value of IC 50 is also increased.(4-I< 4-Br < 4-Cl <4-F).Electron withdrawing group like -NO 2 has higher value at para and min value at ortho.However in case of -CN has higher value at para-and min value at ortho-.But in case of -Cl has higher value at para-and min value at meta-.This is due to hydrogen bond n inductive n mesomeric effect.while electron releasing group like -OH has higher value at ortho-and min value at para-.
Effect of phenol derivatives on COX activity is depend on size of Leophobic groups also, as size of Leophobic groups is increased than value of IC 50 is increased for COX e. g. 7.29, 11.4, 12.3, 19.9 for respectively 4-C 2 H 5 , 4-C 3 H 7 , 4-C 4 H 9 , 4-C 5 H 11 .In case of Leophobic groups, meta-derivatives have low value, ortho-has high and para-has higher value of IC 50 for COX inhibition e.g.3.92, 3.95, 6.70 for methyl.However for ethyl ortho derivatives have higher value.As electro negativity is increased value of IC 50 is also increased.(4-I < 4-Cl ).Electron withdrawing group like -NO 2 has higher value at ortho and min value at para-.However in case of -CN has higher value at para-and min value at meta-.But in case of -Cl has higher value at meta-and min value at para-.This is due to hydrogen bond n inductive n mesomeric effect.while electron releasing group like -OH has higher value at ortho-and min value at meta-.
In conclusion, this work describes the cytotoxic effect of a new series of molecules on leukemia cells by inducing a caspase-independent cell death.