S-NICS Investigation for Heterocyclic Anticancer Compounds NAYYER T . MOHAMMAdIAN , KARIM ZARE and MAJId MONAJJEMI

There are no works in theoretical of a statistical method of NICS-nucleus independent chemical shift for study of heterocyclic rings , since the asymmetry15 (h) and skew15 (k) parameter is fluctuated in small distance and are alternate in large distance in the center of heterocyclic rings . Through changing the asymmetries among 0< h< +1 skew15 could be changed in the range of -1<k<+1 , and also the parameter k will be zero when s22 = siso 15. In position of axially-symmetric tensors, ó22 equals 15 either s11 or s33, skews are k=±1. In this study, we have investigated the statistical methods through nucleus-independent chemical shifts-SNICS calculations in view point of Bq motions in the center of sphere spaces of heterocyclic rings. In our previous work15, it has been exhibited that S-NICS method is an accurate method for estimation the amount of aromaticity in the non-benzene15 rings similar heterocyclic rings which are popular molecules in organic chemical compounds as anti-cancer disease. Although NICS values for benzene and naphthalene and so on can be indicated as aromaticity criterion, for other molecules such as heterocyclic rings and their derivatives, S-NICS values are much more accurate compare to NICS index. Keyword: S-NICS, NICS, heterocyclic anticancer compounds


INTROdUCTION
Cancer is a disease dating as far back as the dinosaurs has found cancerous lesions on dinosaur bones.Egyptians also drew examples of breast cancer in their hieroglyphics on papyrus, and by the 4th century B.C. many types of tumors such as stomach and uterine cancer had been described.In 1775 Percival Pott, a London physician, linked the incidence of scrotal cancer in men to their jobs as chimney sweeps when they were young boys.It was not, however, until the 19th century that scientists began to study cancer systematically, looking at what causes cancer and how it can be cured.
Cancer is one of the important causes of death in the new century.This work is done for developing of modern anticancer drugs.Many of heterocyclic compounds are known as anticancer drugs such as alkylating agents which have targeted cell DNA causing cell death.Heterocycles 1 structures are composed by atoms other than carbon, where the most times substituents are sulfur, oxygen 1 and nitrogen 1,2 .The model size of heterocycles ring, together with the substituent group of the core scaffold 2 , impact tightly on the chemical and physical properties 3 while among the clinical applications, heterocyclic compound has an active role as anti-bacterial 4,5 , anti-viral 6 , anti-fungal 7 , antiinflammatory 8 and anti-tumor drugs [9][10][11] .
Among the heterocyclic compounds the pyridine, thiophene and Thiazole derivatives exhibited large amount cytotoxicity towards the cancer cell lines.Structure activities relationship was reduced 9 from biological results and will be used in further design 11 of new active compounds.Currently, a number of drugs are used in the treatment 11 of the cancer, but most of them were produced controlled effect on the cancer cells.The usual applications of heterocycles are as vast as it is diverse and is not extensively 9 encompassed in the scope 10 of that study.
The most drugs belong to a class of heterogenius structures.Heterocyclic structures played an important behavior in the metabolism 11 of all cells; maximum number of them is 6 (or sometimes 5) membered hetero-cycles including one to three heteroatoms 11 .Recently, imidazole fragment has been attracting much concentration because of its role as attractive scaffold for biochemical active heterocyclic 11 drugs 12 .G e n e r a l l y, c h e m i c a l -p hy s i c s a n d biochemical properties like acceptor and donor capabilities, hydrogen bond, p-p interactions, van der Waals, coordination 12 bond with a metal and in total hydrophobic force has caused much interest in anticancer studies for such compounds.These properties are important of understanding for its reactivity enable derivative for binding with various nucleic acids, enzymes and biological structures 13,14 .
A large number of the important heterocyclic compounds are used in the medical activities such as histidine and proline which are amino acids.It is notable pyridoxine, folic acid, thiamine, riboflavin, biotin, B 12 and E families of the vitamins are included of heterocyclic structures.For investigation of antifungal activity compounds, Singh et al have synthesized 1,3, 4oxadiazolo-(3,2a)-s-triazin-7-thione 13,14 and Abdle,et-al have synthesized some novel 1, 3, 4oxadiazole derivatives 12,13 .Fungi 13 are hetero-tropic micro-organisms that are distinguished 13 .Since a carcinogen is applied into a body, cancerous cell will not immediately result.This is due to the "latency effect" where certain of time elapses before there is growth of the tumor.The initial application of a carcinogen will result in the formation of the irreversible initiated cells.Time may then elapse before a second agent, known as the promoter, will act reversibly on the initiated cell giving a premalignant lesion.Changes in the premalignant lesion, such as increased growth rate, increased invasiveness and metastases, result from the 3 rd stage of the process known as progression.Those changes are usually associated with the changing in the number and arrangement of genes which encode for various proteins.

Theoretical background
Aaromaticity in point of nucleus-independent chemical shifts, with NICS (0), at the center of ring plane were compared in several studies in long distances.In small range of distance a few works have been done in theoretical and reports the statistical approach in our works 15 For anyfurther discussion of statistical methods in S-NICS especially in short range of distances, we exhibited that the asymmetry(ç) 15 and skew(ê) 15 fluctuate around the center of rings.methyl 5-(2-propenoyl)-3-thiophene carboxylatein 60% yield.The proton nmr spectrum exhibit explicitly a doublets for two hydrogens due to the de-shielding effect of the carbonyl.Infra-red spectroscopy helps to The maximum fluctuations 15 are visible around the extremums functions mathematically 15 .The fundamental of this work is based on random motions of dummy atom in de-shielding spaces of heterocyclic rings for considering the most abundant of points.The majour purpose of random data of several probes inside of de-shielding spaces is for understanding of anisotropic spin-spin interaction in short distances.
In this study, the major components [16][17][18] of Haeberlen 17 parameters [16][17][18] , has been calculated for heterocyclic rings.A large number of random points near to the center of those rings have been generated by pseudo-random numbers 15 generation, which is distributed in a Gaussian function between the interval [0, 1) 15 .
The results have been compared through the energy-decomposition-analyzation (EDA).The p bond energy and conjugation of between heteroatoms bonds of rings are signiûcantly accurate.We have optimized the geometries and calculated the carbon NMR for various heterocyclic molecules for understanding which members of rings are more stable Figs1-8.Our methods and physical chemistry approach have been done based on our previous works  .
In small distance around the center, the asymmetric-parameter 16 (h), and the skew 17 (k), exhibited.gaussian distribution based on their fluctuation behavior 15 , which is relate on its distance of molecular ring.In contrast, of that parameters, the isotropy [16][17][18] s iso Has not a fluctuating behavior and increase in around the center of the rings with a linear relationship 15 .The slopes of that line is changed for various distances of heterocyclic compounds.
The isotropy [16][17][18] in all NMR calculations are positive which indicates negative values for aromaticity 15 .It is obvious that the isotropies 15 for NICS data can explain the quantity and quality of the aromaticity for some molecules, but those are not able for expressing the mechanism as well as S-NICS 15 .
In the S-NICS method 15 the suitable shielding space near to the center of hetero rings are enables to evaluate the aromaticity 15 as a criterion data.and in this method the expectation of the (h*) 16- 18 and (k*) [16][17][18] have been estimated via the Gaussian curve.
The isotropy(s iso * ) which is related to all of (h*),(k*),(W*) and (ζ*) is suitable criterion for the aromatic molecules both hetero or regular rings through the S-NICS method.Similar to the NICS method, in S-NICS 15 , mines nucleus-independentchemical-shifts indicates the aromaticity.Therefor "+" values indicate the anti-aromaticity quantitative.In S-NICS 15 methods, the shielding& de-shielding 15 spaces are important for discussing the mechanism of the aromatic molecules in point of ring currents.
The stabilities S-NICS criterion is strongly affected on the best places in shielding spaces which is related to the composition of hetero aromatic rings.It is obvious that geometry factors cause changes in the magnetic-field 15 by the nuclei and change the resonant frequencies.Therefore the chemical shielding and several factors as the same electronegativity, magnetic anisotropy of p-systems will be changed due to the number of electrons The chemical shielding is a vector orientation function for all of the shielding parameters that can change in several places inside the shielding region .