Communications - NISCAIRnopr.niscair.res.in/bitstream/123456789/49358/1/IJCA 22A... · 2019. 7....
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Indian Journal of Chemistry Vol. 22A, August 1983, pp. 639-640 Communications Wavefunction Oriented Index as Possible Link between K-Region, Bay-Region, Distal Bay-Region & Carcinogenicity of ~ethylbenz[a]anthracenes S N00R MOHAMMAD Molecular Biology and Biophysics Program, Department of Physics and Meteorology, Indian Institute of Technology, Kharagpur 721302 Received 4 April 1983; accepted 6 June 1983 A wavefunction oriented index has been devised to study the role of specific molecular regions, viz. K-, L-, bay- and distal bay-regions in the carcinogenic activity ofmethylbenz[a]anthracenes (MBAs). In contrast to experimental reports, the K-region of the compounds plays a key role, of course indirectly, in determining the carcinogenic poten y and the bay-region metabolic activation of various MBAs. Depending on the specific substitution site, a methyl substituent usually alters the biological activity+? of a polycyclic aromatic hydrocarbon (PAH). The molecular basis for this variation of biological activity is not yet properly understood. Pullman and Pullman ' have demonstrated that K- and L-region peculiarities of the electronic characteristics related to physico- chemical properties of a parent PAH dictate much of the carcinogenic behaviour of a compound. The K- region is typified by 9, lO-bond of a phenanthrene and the L-region by 7, 12-bond ofa benz[aJanthracene. In order to be carcinogenic, a compound must have a reactive K-region. If there is an L-region the latter must be reasonably unreactive. According to a recent hypothesis" PAHs are known to be metabolized by mammalian microsomal drug-metabolizing enzyme systems in a highly stereoselective manner ':". Jerina and coworkers 7 ascribe this metabolic activation to the induction of electronic changes that result in an enhanced carcinogenic activity through the bay-region of the parent compound. The metabolic transforma- tion appears to follow a pathway: PAH-+epoxide -+dihydrodiol-+ bay-region dihydrodiol-epoxide. Jerina et al. further observed that the calculated bay- region delocalization energy which forms the basis of their bay-region theory nicely correlates with the Pullmans' K-region index determined by a combi- nation of the Hiickel localization energy. In recent experiment: 8 the K-region is hardly found to mediate the binding of a carcinogen to DNA. However, the above correlation demonstrates, if not directly, that the K-region plays some indirect role in the carcinogenesis of PAH~. The present investigation is aimed at elucidating the relative role of the K- and bay- regions and of the substitution of the methyl group towards cancer inducing activities of benz[aJanthra- cene. The reactivity index, RAJ..n), defined from SCF- MO wavefunctions of quantum mechanical molecular orbital method, MINDO/3 of Bingham et al:", is employed for the purpose. The index corresponding to bond A-B is given by RAJ..n) = f C~k + C~k + 2CakCbkSab k= I Ekk where: (i)a, b = the n(z) atomic orbitals corresponding to atoms A and B. respectively; (ii)k = an occupied molecular orbital irrespective of whether it is tt- 01 a- orbital; (iii) C ak = coefficient of n(z) atomic orbital of atom A in the occupied molecular orbital k; (iv) SAB =overlap integral of n(z) atomic orbitals, a am! b of atoms A and B respectively; (v) Ekk = energy of the occupied molecular orbital k; and (vi)n = sum of all occupied n and a-molecular orbitals. The values of RAJ..n) for K-region, bay-region and distal bay-region A-B double bonds of various MBAs are presented in Table I. The values correspond to MBA geometries determined by stepwise optimization procedure described in detail in our earlier investigation I 0. The least negative values of RAJ..n) for all the three regions indicate that 7-MBA is the most carcinogenic in the series. These values for similar regions of other MBAs are in conformity with the experimental values II given in the last column of Table l . For example, on the basis of RAB(n) for the K- Table I - Comparison of Bond Reactivity with Experimental Carcinogenic Potency of Methylbenz[aJanthracenes Location - RAfin) Carcino* of the methyl group K-region (5,6-bond) Bay-region (1,2-bond) Distal bay-region (3,4-bond) 0.4414 0.4502 0.4'321 0.4537 0.4404 0.3946 0.3691 0.3952 0.4059 0.4063 0.4014 0.3820 ++ I 2 3 4 5 6 7 8 9 10 II 12 1.2421 1.2~ 12 1.2313 1.2939 1.3305 1.1378 1.0195 1.1034 1.1292 1.1552 1.1280 1.0383 0.4836 0.5139 0.5062 0.5166 0.4994 0.4373 0.4084 0.4389 0.4503 0.4529 0.4472 0.4182 ++ +++ ++ + ± "Taken from reference II. 639
Transcript of Communications - NISCAIRnopr.niscair.res.in/bitstream/123456789/49358/1/IJCA 22A... · 2019. 7....
Indian Journal of ChemistryVol. 22A, August 1983, pp. 639-640
Communications
Wavefunction Oriented Index asPossible Link between K-Region,Bay-Region, Distal Bay-Region &
Carcinogenicity of~ethylbenz[a]anthracenes
S N00R MOHAMMAD
Molecular Biology and Biophysics Program,Department of Physics and Meteorology,
Indian Institute of Technology, Kharagpur 721302
Received 4 April 1983; accepted 6 June 1983
A wavefunction oriented index has been devised to study the roleof specific molecular regions, viz. K-, L-, bay- and distal bay-regionsin the carcinogenic activity ofmethylbenz[a]anthracenes (MBAs).In contrast to experimental reports, the K-region of the compoundsplays a key role, of course indirectly, in determining the carcinogenicpoten y and the bay-region metabolic activation of various MBAs.
Depending on the specific substitution site, a methylsubstituent usually alters the biological activity+? of apolycyclic aromatic hydrocarbon (PAH). Themolecular basis for this variation of biological activityis not yet properly understood. Pullman and Pullman 'have demonstrated that K- and L-region peculiaritiesof the electronic characteristics related to physico-chemical properties of a parent PAH dictate much ofthe carcinogenic behaviour of a compound. The K-region is typified by 9, lO-bond of a phenanthrene andthe L-region by 7, 12-bond ofa benz[aJanthracene. Inorder to be carcinogenic, a compound must have areactive K-region. If there is an L-region the latter mustbe reasonably unreactive. According to a recenthypothesis" PAHs are known to be metabolized bymammalian microsomal drug-metabolizing enzymesystems in a highly stereoselective manner ':". Jerinaand coworkers 7 ascribe this metabolic activation to theinduction of electronic changes that result in anenhanced carcinogenic activity through the bay-regionof the parent compound. The metabolic transforma-tion appears to follow a pathway: PAH-+epoxide-+dihydrodiol-+ bay-region dihydrodiol-epoxide.Jerina et al. further observed that the calculated bay-region delocalization energy which forms the basis oftheir bay-region theory nicely correlates with thePullmans' K-region index determined by a combi-nation of the Hiickel localization energy. In recentexperiment: 8 the K-region is hardly found to mediatethe binding of a carcinogen to DNA. However, theabove correlation demonstrates, if not directly, thatthe K-region plays some indirect role in thecarcinogenesis of PAH~. The present investigation is
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aimed at elucidating the relative role of the K- and bay-regions and of the substitution of the methyl grouptowards cancer inducing activities of benz[aJanthra-cene. The reactivity index, RAJ..n), defined from SCF-MO wavefunctions of quantum mechanical molecularorbital method, MINDO/3 of Bingham et al:", isemployed for the purpose. The index corresponding tobond A-B is given by
RAJ..n) = f C~k + C~k + 2CakCbkSab
k= I Ekk
where: (i)a, b = the n(z) atomic orbitals correspondingto atoms A and B. respectively; (ii)k = an occupiedmolecular orbital irrespective of whether it is tt- 01 a-orbital; (iii)Cak = coefficient of n(z) atomic orbital ofatom A in the occupied molecular orbital k; (iv) SAB
=overlap integral of n(z) atomic orbitals, a am! b ofatoms A and B respectively; (v) Ekk = energy of theoccupied molecular orbital k; and (vi)n = sum of alloccupied n and a-molecular orbitals.
The values of RAJ..n) for K-region, bay-region anddistal bay-region A-B double bonds of various MBAsare presented in Table I. The values correspond toMBA geometries determined by stepwise optimizationprocedure described in detail in our earlierinvestigation I 0. The least negative values of RAJ..n) forall the three regions indicate that 7-MBA is the mostcarcinogenic in the series. These values for similarregions of other MBAs are in conformity with theexperimental values II given in the last column ofTable l . For example, on the basis of RAB(n) for the K-
Table I - Comparison of Bond Reactivity with ExperimentalCarcinogenic Potency of Methylbenz[aJanthracenes
Location - RAfin) Carcino*of themethylgroup
K-region(5,6-bond)
Bay-region(1,2-bond)
Distalbay-region(3,4-bond)
0.44140.45020.4'3210.45370.44040.39460.36910.39520.40590.40630.40140.3820 ++
I23456789
10II12
1.24211.2~ 121.23131.29391.33051.13781.01951.10341.12921.15521.12801.0383
0.48360.51390.50620.51660.49940.43730.40840.43890.45030.45290.44720.4182
++++++++±
"Taken from reference II.
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INDIAN J. CHEM., VOL. 22A. AUGUST 1983
region 12-,8-, and 6-MBAs are the most carcinogeniccompouncs next to 7-MBA of the series. The results inTable 1 indicate that K-region is as important as thebay-region or the distal bay-region in impartingcarcinogenicity to MBAs.
Both activation and detoxification pathways occurin PAHs and the biological character of the resultantproduct depends on a balance between the two. Theproducts are the metabolites of the metabolites. So it islikely that K-region metabolites which are formed inthe initial/intermediate stage undergo subsequentdetoxification due to charge delocalization presum-ably to the bay-region or the distal bay-region of acompound. This is why in the eyes of experimentaliststhe K-region is not directly involved in thecarcinogenicity of a PAH. Nevertheless it is the mostimportant factor in the phenomenon in thatelectrophilic character of the ultimate metabolitedepends on how much charge transfer from the K-region is possible in a compound.
The author thanks the CSIR, New Delhi for partlysupporting the project. He is grateful toProf'S T H Abidi for encouragement, to Dr Hasan
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Mukhtar for discussions, to Dr S P Sinha for help incomputer calculation, and to M Mainuddin Khan fora careful typing.
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