مطالعه نظري توتومري در2-آمينو-7 H– پورين- 6- تيول با استفاده از تئوري تابعي چگال

A tautomerism in 2-amino-7H-purine-6-thiol: Theoretical study using implicit/explicit salvation models

ﻣﻄﺎﻟﻌﺎت ﺗﺠﺮﺑﯽ و ﻧﻈﺮي روي اﺷﮑﺎل ﺗﻮﺗﻮﻣﺮي و ﻧﺤﻮهي اﻧﺠﺎم اﯾﻦ ﻓﺮاﯾﻨﺪ ﺑﻪ دﻟﯿﻞ ﺗﻮﺿﯿﺢ ﺧﻮاص ﺑﺴﯿﺎري از ﺗﺮﮐﯿﺒﺎت آﻟﯽ، ﺑﯿﻮﺷﯿﻤﯿﺎﯾﯽ و داروﯾﯽ ﻫﻤﻮاره ﻣﻮرد ﺗﻮﺟﻪ ﻣﺤﻘﻘﺎن ﺑﻮده اﺳﺖ. ﻋﻤﻠﮑﺮد و ﺧﻮاص ﺑﺴﯿﺎري از ﺗﺮﮐﯿﺒﺎت داروﯾﯽ و ﺑﯿﻮﻟﻮژﯾﮑﯽ ﺗﺤﺖ ﺗﺎﺛﯿر اﺷﮑﺎل ﺗﻮﺗﻮﻣﺮي آﻧﻬﺎ اﺳﺖ 1[. ﻣﺘﺪاولﺗﺮﯾﻦ ﻧﻮع ﺗﻮﺗﻮﻣﺮي، ﺗﻮﺗﻮﻣﺮي ﻫﯿﺪروژن اﺳﺖ ﮐﻪ ﻃﯽ آن ﯾﮏ اﺗﻢ ﻫﯿﺪروژن ﯾﺎ ﭘﺮوﺗﻮن ﻫﻤﺮاه ﺑﺎ ﭘﯿﻮﻧﺪ ﺳﺎده از ﮐﺮﺑﻦ ﻣﺠﺎور ﭘﯿﻮﻧﺪ دوﮔﺎﻧﻪ ﺑﻪ اﻧﺘﻬﺎي ﺳﯿﺴﺘﻢ π ﻣﻨﺘﻘﻞ ﺷﺪه و در ﻧﺘﯿﺠﻪ آن ﺗﻌﺎدل ﯾﺎ ﺗﻌﺎدﻟﻬﺎﯾﯽ ﺑﯿﻦ اﺷﮑﺎل ﻣﺘﻔﺎوت از ﯾﮏ ﻣﻮﻟﻮل ﺑﻮﺟﻮد ﻣﯽآﯾﺪ ]2-4[. ﻓﻌﺎﻟﯿﺖ ﺑﺴﯿﺎري از ﺑﺘﺎ ﮐﺘﻮ آﻣﯿﺪﻫﺎ ﮐﻪ در ﺳﻨﺘﺰ ﺑﺴﯿﺎري از آﻧﺘﯽﺑﻮﺗﯿﮏﻫﺎ ﺑﻪ ﺻﻮرت ﺣﺪواﺳﻂ ﻋﻤﻞ ﻣﯽﮐﻨﻨﺪ ]5[، ﺗﺸﮑﯿﻞ زوج ﺑﺎزﻫﺎي آﻟﯽ ﺷﺮﮐﺖ ﮐﻨﻨﺪه در ﺳﺎﺧﺘﺎر DNA ]6[، ﻋﻤﻠﮑﺮد آﻧﺘﯽ اﮐﺴﯿﺪانﻫﺎ 7 و ﺗﺸﮑﯿﻞ ﮐﻤﭙﻠﮑﺲﻫﺎي آﻟﯽ- ﻓﻠﺰي 8 ﻫﻤﻪ ﺗﺤﺖ ﺗﺎﺛﯿﺮ ﺗﻌﺎدﻻت ﺗﻮﺗﻮﻣﺮي ﻫﺴﺘﻨﺪ. ﺑﺴﯿﺎري از داروﻫﺎي ﻣﻮرد اﺳﺘﻔﺎده در درﻣﺎنHIV ]11- 9[، ﺻﺮع]12 و ﺳﺮﻃﺎن ﻫﺎي ﭘﻮﺳﺖ ]13-14[، رﯾﻪ و ﭘﺎﻧﮑﺮاس] 15-16 داراي اﺷﮑﺎل ﺗﻮﺗﻮﻣﺮي ﻫﺴﺘﻨﺪ. ﭘﻮرﯾﻦﻫﺎي اﺳﺘﺨﻼف ﺷﺪه در ﻣﻮﻗﻌﯿﺖ 2و6 ﺗﺮﮐﯿﺒﺎت ﻣﻔﯿﺪي ﺑﺮاي ﻣﻄﺎﻟﻌﺎت ﺷﯿﻤﯽ درﻣﺎﻧﯽ ﺳﺮﻃﺎن و ﻣﻄﺎﻟﻌﺎت ﺷﻨﺎﺧﺖ آﺳﯿﺐ ﺑﻪ DNA ﻫﺴﺘﻨﺪ ]15-16[. ﺑﻪوﯾﮋه ﺳﺎﺧﺘﺎرﻫﺎي ﻧﻮﮐﻠﺌﯿﮏ اﺳﯿﺪي اﺳﺘﺨﻼف ﺷﺪه ﺑﺎ ﮔﻮﮔﺮد ﺑﻪ ﻋﻨﻮان دارو ﺑﻪﮐﺎر ﻣﯽروﻧد

A theoretical study at the B3LYP/6-31++G(d,p) level was performed on the tatumerization of 2-amino-7H-purine-6-thiol into 2-amino-9H-purine-6-thiol. Such a tautomerism can take place via three different pathways namely A, B, and C. The energetic results associated with the gas phase reveal that pathways A, B, and C display a very high activation Gibbs free energy of 47.6, 69.4, and 52.1 kcal/mol, respectively, indicating this process cannot take place in the gas phase. When solvent effects of water are taken into account through a continuum of a uniform dielectric constant, the gas phase activation Gibbs free energies increase to 51.1, 71.9, and 55.4 kcal/mol along pathway A, B, and C, respectively, emphasizing long range solute-solvent interactions do not play a key role in the considered tautomerization. The studied process can easily take place by inclusion of three molecules of water in which a significantly reduced activation Gibbs free energy of 24.8 kcal/mol indicates the predominance of short range solute-solvent interactions over the long range ones. Combination of short range and long range solute-solvent interactions lead to an activation Gibbs free energy of 23.6 kcal/mol for tatumerization of 2-amino-7H-purine-6-thiol into 2-amino-9H-purine-6-thiol. This value clearly points out that employing a polar and protic solvent is able to noticeably reduce the barrier of tatomerization.