| PDTMP(propylene diamine tetramethylene phosphonic acid) and DCTMP [1,2-hexamethylenediylbis[nitrilobis(methylene)]tetra kisphosphonic acid] are synthesized undergoing Mannich reaction. The conditions of synthesis are investigated, and all products are characterized in detail. The IR, and elemental analysis are carried out to identify products, and make certain synthesis is successful. The Sm complexes of this two ligands are synthesized, The influence of incubation time, temperature and pH value on the coordinating efficiency are investigated. The coordinating conditions are optimized. Also other nine complexes was prepared on the same conditions with high product yields and stability in 24h. It gave suitable systems for partition coefficients measurement.Traditional shake-flask method was utilized to measure partition coefficient for all those 11 Sm-complexes in six oil-water systems. In the measurement process, a few precautions are taken to get reliable values. For example, buffers are made up with equal ionic strength; They should be stored in a thermostated bath at 25 ℃;Stirring in a stoppered container for at least 30min is recommended to be certain equilibrium between phase is attained; To be assured of complete phase separation, it is centrifuged for 20 min before the phase analyzed. Under strictly condition control, we generate logP values with an average deviation of less than ±0.05 for normal solutes and ±0.15 for the more difficult one(i.e. those with logP values below -5.0). The result show there are linear free-energy relationships between partitioning solvent systems. It present in the standard linear free energy format: logP2=alogP1+b, with high regression coefficient (>0.90).The molecular modeling software Material Studio 2.0 is employed to build the molecular models for the 17 bone-seeking ligands. Their structures are fist optimized with molecular mechanics and then the predominant conformations are found by using molecular dynamics. Energies of the 17 ligands in aqueous solution are calculated by the semi-empirical orbital computation software package Vamp. A series of microscopic parameters such as LUMO and HOMO energies, molecular surface areas, molecular volumes, conformation energies, delocalization energies, formation energies, etc are obtained. The result show the values in vacuum and these in water have evident distinction.Multivariate regression analysis was performed on studying the quantitativerelationship between logP and molecular properties. One method is presented for calculation of oil/water partition coefficients on the basis of summation of atomic contributions. The others methods is based on the relationship between logP and molecular properties in water calculated by semi-empirical quantum chemical software. We get one QSPR equationl, which has the highest regression coefficient(r=0.96).logP = 0.0294*MR - 0.625*HBD + 1.53*ELUMO - 2.57Where MR is molecular refractivuy, HBD is the number of the hydrobond donor, .ELUMO is the energy of the lowest unoccupied molecular orbital. The equation shows some satisfactory prediction ability.Also the relationship between the structure parameters and its bone uptake for seventeen agents has been studied with multiple regression analysis. By choosing ADME violation number X10, surface area X14, and HOMO energy X20 as descriptors, a satisfactory QSAR equation is found by using QSAR analysis software Tsar?.3 for bone uptake (BU, unit:ID% ) 2 h post injection. The relevant equation is:BU= -29.39/10 + 12455/X14 - 790.0/X20 - 82.38With n=15; r=0.9600; r2 =0.9216 ;s=5.020 ;F=2.545e-007, r2(CV)= 0.5904. the reason why the possess different property in bone uptake has be discussed. |
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