The Synthesis Of Organotin Anti-cancer Compounds, Quality Standards And Preliminary Absorption Kinetics

In recent years the research of anticancer organometallic compounds attracts widespread attention in the world.As typical organometallic compounds,organotin compounds in cancer research still occupy an important position.As for this,our group put forwords a new design guideline and a series of diorganotin complexes formulated as R₂SnL₂ and[R₂Sn(L)]₂O with the the OâŒ'O type-ligands which have biological activities have been prepared.Six new dibutyltin complexes were prepared when dibutyltin dichloride reacted with the benzoyl hydroxamic acids which have different substituted group in the para-position with different electricity.These complexes were characterized by IR,¹H NMR,¹³C NMR and ¹¹⁹Sn NMR.Single crystal R-ray analysis was also been used to determined the structure for compound 2 and 5.Based on its physical and chemical properties,the quality standard of DBDCT,an antitumor compound with novel structure was established.The primilary absorption pharmacokinetics of DBDCT in rats was investigated in this study.Liquid-liquid extraction method was chosen to pretreat plasma samples before RP-HPLC analysis of DBDCT in plasma samples.In the first section the synthesis and antitumor activity study of the new complexes were described.When dibutyltin dichloride reacted with the benzoyl hydroxamic acid with different electricity,six new complexes were got which had been characterized by IR,¹H NMR,¹³C NMR and ¹¹⁹Sn NMR.Single crystal x-ray analysis was also been carried out for the compound 2 and 5.The x-ray diffraction analysis showed that tin atom is five-coordinated forming trigonal bipyramidal structure.In addition,the anti-tumor activity test in vitro showed compound 2 has strong cytotoxicity.The chemical identification,determination of general and related substance and assaying were determinated for DBDCT based on its structure,physical and chemical property,and its quality standard was established.A RP-HPLC method was developed for the deterimnation of the content of the sample and drug-related impurities.DBDCT and its related substance were separated on the Diamonsil C₁₈column(250×4.6mm,5μm)with methanol-water(40:60 with TFA to adjust pH 3.0)as the mobile phase and detected at 236nm.The calibration curve was linear(r=0.9997)within the range of 2.0-80.0μg/ml for DBDCT} the detection limit was 8ng(S/N=3),the analysis precision RSD was1.56%(n=5)the repeatability precision RSD was 1.47%(n=6),and the limit of drug-related impurities was 1.0%.This method was simple. accurate and suitable for the quality control for DBDCT.The primilary absorption pHarmacokinetics of DBDCT in rats was investigated in this study. Liquid-liquid extraction method was chosen to pretreat plasma samples before RP-HPLC analysis.DBDCT was separated on C₁₈column with(250×4.6mm 5μm)methanol-water(30:70 with TFA to adjust pH 3.0)as the mobile phase.By RP-HPLC and detect at 236nm.The calibration curve was linear(r＞0.9997)within the range of 0.1-25.0μg/ml for DBDCT.The detection limit was 9ng(S/N=3).The analytical recovery was more than 85%.Both of the intra-day and inter-day precision were less than 10.0%.The reliability of this method is high enough to perform quantitative analysis of DBDCT in plasma samples.The pharmacokinetics study of DBDCT was performed in 6 healthy rats via injection with single dosage by the established analytical method.The experimental data showed that the concentration-time curve of DBDCT in rat plasma could be fitted to two-compartment model.It was also proved that DBDCT was eliminated quickly in blood.