紫杉醇类似物C13侧链手性构型与活性关系的从头算研究

应用从头算RHF/STO-3G方法优化了四个紫杉醚异构体,在RHF/6-31G*水平进行单点计算,并计算了四个分子的静电势。分子立体构型表明:C13侧链上2 R构型的2-OH和3 S构型的3-NH均处于分子外侧,有利于与受体极性基团结合;2 S构型的2-OH和3 R构型的3-NH在分子的内侧,不利于与受体极性基团结合。静电势的结果表明,R构型的2-OH和S构型的3-NH可以产生相应的负电势区域。当C13侧链为天然构型(2 R,3 S)时,分子可能以双基结合的方式通过负静电势区域与受体作用,活性较高。

Ab initio study on the relationship between chiral conformation of C13 side chain and anti-tumor activity in taxol analogues

Geometric structures of four taxol analogues were optimized by using ab initio RHF method at STO-3G level,and their electrostatic potentials were calculated with the same method at 6-31G~* level.Calculational results show the 2'-OH and 3'-NH group are positioned out of the molecule in 1 with 2'R 3'S conformation,which has the best anti-tumor activity among four analogues.However,the corresponding 2'-OH and 3'-NH are positioned inner in 2 molecule with 2'S 3'R conformation and this analogue has the lowest anti-tumor activity among them.Only one 2'-OH or 3'-NH group is positioned out of the molecules in 3 and 4,and the anti-tumor activity of 3 and 4 are lover than that of 1.Electrostatic potential calculation indecates the 2'R-OH and 3'S-NH group exhibited a negative electrostatic potential.These results suggest 2'R-OH and 3'S-NH group in C_(13) side chain display negative electrostatic potentials and could interact with the receptor via hydrogen bonding.Thus,the 2'R 3'S conformation of taxol analogues possess the best anti-tumor activity.