Marine Natural Product Et-743 Structural Analogues Synthesis And Antitumor Activity Of Research

The synthesis and the antitumor activities of the analogs of the marine natural product Et-743 were studied. The project was carried out through three steps: the first step is to construct the core structure of Et-743-a bis-tetrahydroisoquinoline pentacyclic skeleton with a concise and efficient synthetic route and correctly to establish all of the five chiral centers; the second step is to synthesize the Et-743 analogues; the third step is to evaluate the antitumor activity of these compounds and to study their structure-activity relationship, from which we hope to discover new lead compounds with the antitumor activities as potent as Et-743. The research included in this paper went on according to this strategy, which is outlined below.A. The synthesis of the pentacyclic skeleton of Et-743 and the construction of the five chiral centers thereof.1. The core pentacyclic skeleton of phthalascidin was constructed with L-dopa as the starting material via thirteen steps. First, two basic synthons, the C-1 functionalized tetrahydroisoquinoline compounds 8 and N-protected Z-dopa derivative 9, were prepared from L-dopa. They were coupled via amide bond to form the dipeptide compounds 10, which were the first key intermediates. Then the primary hydroxyl groups were transformed into the corresponding amino aldehydes 11 via Swern oxidation. Followed by the intramolecular Pictet-Spengler cyclization, the pentacyclic compounds 12 were synthesized. Finally the two functionalized compounds 14, were synthesized by transferring the 21-positon carbonyl groups of compounds 13 to cyano groups. Thus we realized the construction of the pentacyclic skeleton of Et-743 and the establishment of five correct chiral centers of the title compound. The chiral centers of 3- and 13-position were derived from the starting material Z-dopa, and the chiral centers of 1 -, 11 - and 21 -position were constructed by asymmetric induction. However, when we tried to remove the protective groups in compounds 14, we got the cyano-cleaved compounds 26. 1-substituded-6, 7-dihydroxy-1, 2, 3, 4-tetrahydroisoquinoline compounds via 1, 3- asymmetric induction. By simply stirring L-dopa methyl ester 1 and aldehyde 2 with anhydrous sodium acetate in acetic acid at room temperature for several hours, we obtained the desired 1, 3-syn compound 3 predominantly. In some cases, its epimer 4 was also obtained. 22 compounds were synthesized, among them 18 were new.3. Using the intramolecular Pictet-Spengler reaction to form the pentacyclic skeleton of Et-743, the byproducts 25 were obtained under various conditions. The structures of them were determined to be 1, 2-dihydro-isoquinoline compounds, and the mechanism of the reaction was proposed.B. The synthesis of the analogs of Et-743Because of the failure of removing the protective groups in compounds 14, the synthetic strategy was adjusted. First removing the protective groups of compounds 13, and then transfering the 21-positon carbonyl groups of compounds 13 to cyano groups, finally 18 ester and 10 amide analogs of Et-743 were synthesized.C. The antitumor activity study of the analogs of Et-743In the preliminary in vitro antitumor screening, MTT method was used with five to eight human solid cancer cell lines. For most compounds, the IC₅₀ values are between 10^-6-10^-7M. And for some compounds, the IC₅₀ values can reach 10^-9M.