Study On Design Synthesis And Antitumor Activity Of CA - 4 Analogues

Combretastatin A-4 (CA-4) was isolated from the bark of the South African tree combretum caffrum. This cis-stilbene strongly inhibits tubulin polymerization by binding to the colchicine site and is found to be a cytotoxic agent against a wide ariety of tumor cell lines.Their excellent antitumor and antivascular activities, have attracted considerable interest of medicinal chemists.In this article, a docking simulation was used to identify molecules having the same binding mode as the lead compound, and 3D-QSAR models had been built by using CoMFA based on docking. As a result, these studies indicated that the QSAR models were statistically significant with high predict abilities (CoMFA model, q2= 0.786, r2= 0.988).3D-QSAR models revealed: influence of the steric field was more important than that of the electrostatic field; bulky groups at C-4 of the A-ring was helpful to enhance biological activity; the larger groups at C-3 substituent of the B-ring were favorable to promote inhibitory ability; bulky groups above the C-2 position of the B-ring and the two-atom chain would decrease the ability to inhibit the tubulin polymerization; higher electropositive moiety below the para-substituent of the A-ring is favorable to enhance the ability to inhibit the tubulin polymerization.Thiazolinone and pyrazole structure had a wide range of biological activity, their anti-tumor effects also were reported. Thiazolinone and the pyrazole ring as the two atom bridges between CA-4 A ring and B ring, we designed and synthesized 36 pyrazole analogues,24 thiazolinones. As plants secondary metabolites, the structure of dihydro-aurones has high similarity with CA-4.12 dihyro-aurones were designed and synthesized as analogs of CA-4. In this thesis, a total of 72 compounds was synthesized, their structures were confirmed by 1H-NMR and ESI-MS.Cytotoxic activity of three kinds of compound was evaluated against human gastric cancer cell line SGC-7901, Human fibrosarcoma cell line HT-1080 and Human oral squamous carcinoma cell Lines KB in vitro according to the MTT-based assay. The result showed that pyrazole analogues had significant antiproliferative activity comparable with that of CA-4 in vitro, compounds 1-1-2, 1-2-1,1-2-5,1-2-9,1-3-2,1-4-1,1-4-5,1-4-6,1-4-10,1-5-2,1-6-2 showed excellent activity, the value of IC50 is better than that of the positive control drug adriamycin 1-2 orders of magnitude. Good activity of pyrazole compounds proved again the necessary of cis-connect between the ring A and ring B, pyrazole ring is a good electronic isostere of the double bond. Activity of thiazolidinone analogs was not very strong, may be due to the influence of ring carbonyl, only compounds 2-1-7, 2-2-2 had similar activity with cisplatin. The structure of dihydro-aurone compound is far away from CA-4, the activity was not very ideal.With the aim of better understanding the binding mode of the target compounds to the biological target, the molecular modeling study was performed by the MVD program. Compounds 1-1-1,1-3-1,1-4-7,2-1-7,3-2-3,3-2-6 were docked to the colchicine binding site of tubulin.The results showed that three kinds of CA-4 analogues interacted with tubulin.