Design, Total Synthesis And Anticancer Activity Of Novel Homocamptothecins As Topoisomerase â…  Inhibitors

Malignant tumor has been the second leading cause of death following cardiovascular disease. To improve the therapy effect of tumor, we must start with the mechanism of its emergence and progress. Studying new acting mechanism and looking for new target are necessary for great achievement of cancer therapy.DNA topoisomerase 1 (Topo I) is an enzyme essential for relaxation of DNA during a number of critical cellular processes. Investigation has indicated the overexpression of this enzyme in various types of solid tumors, so the special topo I inhibitor has good selectivity. CPT and its derivates are the most important topo I inhibitor and they are the only kind of topo I inhibitor which has been approved for cancer therapy by FDA. Now CPTs has been regarded as one of the three great discovers of anticancer drugs in 1990s. But the six-membered hydroxylactone of CPTs can hydrolyzed to its inactive carboxylate form readily at physiological pH. Toxicity and species difference are the other problems of CPTs. Homocamptothecins(hCPTs), a novel CPT analog which contain an expanded seven-membered p-hydroxylactone, have shown elevated antitumor activity and improved stability without species difference. Because of its prominent advantage, we choose hCPTs as our study object. But the yield of the two existing total synthesis approaches of hCPT (base on the synthesis strategy of ring AB+DE and ring A+DE, respectively) was lower than 1.5% and 0.5% respectively. Both approaches have some other limitation such as rigorous condition was needed, expensive and infrequent reagents were used and it was difficult to introduce some group in hCPTs. Moreover, regioisomers difficult to be separated were produced sometimes.To obtain novel potent, less toxic anticancer drugs with exclusive ownership of intellectual property right, we designed a series of novel homocamptothecins after we had searched the existing intellectual property right of hCPTs. Firstly, we designed a novel total synthesis approach of hCPTs base on the synthesis strategy of ring A+CDE. The total yield of hCPTs by this approach was about 10% from acetone. No any rigorouscondition and expensive reagent was needed. The ring A and ring B of hCPTs can be modified easily. Base on this advanced approach, we have synthesized the target compounds and tested their cytotoxicity. Some highly potent compounds were modified according to the design principle of prodrug. The in vitro cytotoxicity of all compounds and in vivo antitumor activity of some compounds were tested. The structure-activity relationship of hCPTs was first reported in this paper.I. The total synthesis of homocamptothecinsBecause of the limitation of the existing two total synthesis approaches, we have designed a novel total synthesis approach of hCPTs. The key intermediate ring CDE can be synthesized from acetone and ethyl oxalate by cyclization, condensation, hydrolyzation, protection and de-protection, alkylation, hydrogenation, nitrosation, ester interchange, reduction, oxidation, p ?hydroxylation and intramolecular cyclization. Different ring A can be aminobenzaldehyde ethylene acetals or 2-aminophenyl ke'tones (or their ethylene ketals) with different substituents. The o-aminobenzaldehyde ethylene acetals can be synthesized from corresponding nitrobenzaldehyde by reducing the nitro-group after the protection of carbonyl by ethylene. 2-Aminophenyl ketone ethylene ketal can also be prepared from 2-nitrophenyl ketones by this method. 2-Aminophenyl ketones can be synthesized from different anilines and nitriles in the presence of boron trichloride, or from anilines by Friedel-Crafts reaction. The homocamptothecins with different substituted group in ring A and ring B can be obtained by the Friedlander condensation of the ring CDE with the acetals or 2-aminophenyl ketones.The yield of ring CDE was about 16% from acetone and ethyl oxalate, and the yield of the Friedlander condensation was from 40% to 80%, so the total yield of hCPTs from the starting material was about 6.4% to 13% by this approach. Thi...