Structure Optimization Of The Antitumor Diorganotin Lead Compound DBDPT

Organometallic Compounds have become one of the most important types among the new developing antitumor complexes. Organotin compound is a representative one.The rational drug design is based on the detailed knowledge of the action mechanism. In recent years we have made researches armed at this problem and have found the basic qualifications which the antitumor drug should meet. A design guideline of the new type antitumor organotin compounds was put forword and a series of diorganotin(IV) arylhydroxamates formulated as R2Sn(L)2 or [R2Sn(L)]2O with the ligands (O-O) which have biologic activities have been prepared. Most of them exhibited very promising activity against a series of human tumor cell lines in vitro. Now the key problem is that the water-solubility of the lead compound is very low. So it is difficult to develop the new drug and to study the mechanism of the antitumor action. Therefore the lead compound must be reconstructed and introducing a hydrophilic group is our strategy. In this paper a series of diorganotin compounds have been prepared, characterized and screened. All the work is summed up as follows:(1)The antitumor tests of SN1 and SN2 against H22 liver cancer and SN1 against BGC-823 gastric carcinoma in vivo have been investigated. The acute toxicity test also has been done. The results show that the LD50 of the two compounds are all up 230 mg/kg. It illuminates that the treat exponent is up 10 and the acute toxicility is low. But the value of LD50 is unknown. The reason is that the water - hydrophilic is too small that it should be reconstructed from two aspect: 1. improve the dosage form of the material drug. 2. introduce the hydrophilic group.(2) According to the theory of electron equatability array a series of diorganotin (IV) arylhydroxamates formulated as R2Sn(L)2 or [R2Sn(L)]2O with the ligand (PFBHA) have been prepared. They are characterized by melting points, elemental analysis, MS, FT-IR, 1H, 13C, 19F, 119Sn NMR spectra. Their solubility has been improved compared to the lead compound. The di(n-butyl)tin and diphenyltin compounds have strong antitumor activity in vitro.(3)A series of diorganotin (IV) heterocyclichydroxamates formulated as R2Sn(L)2 or [R2Sn(L)]2O with the ligand (FuHA) have been prepared. They are characterized by melting points, elemental analysis, FT-IR, 1H, 13C NMR spectra. Their solubility has been improved compared to the lead compound. The di(n-butyl)tin and diphenyltin compounds have strong antitumor activity agaist K562 leucocythemia cell in vitro and The di(n-butyl)tin and dimethyltin compounds have strong antitumor activity agaist EP - 20 marrow tumor cell in vitro. The di(n-butyl)tin derivative is the strongest one.By above study, we think that the solubility of the series of diorganotin (IV) formulated as R2Sn(L)2 or [R2Sn(L)]2O with the ligands (FuHA and PFBHA) have been unproved, and they are worthy further study.