D2G DNG N-METHYL(5-(PYRIDIN-3-YL)FURAN-2-YL)METHANAMINE A series of
3-heteroaromatic analogues of nicotine were synthesized to delineate structural and mechanistic requirements for selectively inhibiting human cytochrome P450 (CYP) 2A6. Three furan analogues bearing methanamino side chains indicated that the amine side chain coordinated to the heme iron. The pyridyl moiety was positioned to accept a hydrogen bond from Asn297, and all three inhibitors exhibited orthogonal aromatic-aromatic interactions with protein side chains. The results suggest that inhibitors that compliment the active site features of CYP2A6 can exhibit significant selectivity for CYP2A6 relative to other human liver drug-metabolizing P450s. The axial ligand at the fifth coordination site of the heme iron(III) is provided by the sulfide S- of Cys439 in 2a6. Coordination of the heme iron by ionic donor acceptor bond Fe3+-S- plays a central role in singlet oxygen bonding scission at the sixth coordination site on the heme iron(III). Back to the tutorial.
The four pyrol rings of the porphyrine are serrounding by nitrogen atoms the central irone(III).
The four methyl groups -CH3 and two vinyl groups >C= -CH2 support hydrophobic accommodation of heme interior and active saite substrate .
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