Cyclopentene (f)-dione-1 ,2-mannich Base Derivatives Of Design, Synthesis And Anticancer Activity

Terpenoids which have various biological activities exist widely in natural plants, animals and microbes. Those containing O=C-CH=CH-system have significant antitumor activities and show their antitumor activities by attacking biological nucleophiles, e.g., L-cysteine and enzymes phospho-fruclokinase and DNA polymerase, by rapid Michael addition. The therapeutic value of those natural compounds were limited because of their indiscrimi-nating toxicities, epidermic allergic reactions and instabilities. It is reported that synthetic compounds containing O=C-CH=CH-system also have significant antitumor activities. workers of Synthetic Drug Laboratory of Shenyang Pharmaceutical University have been working many years on designing, synthesizing and evaluating α,β-unsaturated cyclopentanone (cyclohexanone) derivatives based on terpenoids-antitumor activity relationship investigation results. They synthesized hundreds of cyclopentanone derivatives, some of them , e.g., WB852, WB401, had significant antitumor activities and have acquired Chinese and American patents. In the thesis, a series of 1,2-cyclopentanedione and 1,2-cyclohexanedione derivatives were designed , synthesized and evaluated their antitumor activities: 1. Based on results of terpenoids-antitumor activity relationship investigation, 1,2-cyclopentanedione and 1,2-cyclohexanedione were selected as lead compounds. (1). It had been demonstrated that Mannich bases of cyclopentanone and cyclohexanone had significant antitumor activities in vitro and in vivo. The mechanism of cytotoxicity is supposed that Mannich base can release a-methylene cyclopentanone which is a class of compounds known to have a marked affinity for thiol groups rather than hydroxy and amino groups which are present in nucleic acids. Based on the above theory (hypothesis) 1,2-cyclanediones were modified by amines having different pka and space arrangement. (2). Based on "Topliss operational schemes for analog synthesis in drug design"and results of our laboratory investigation about cyclopentanone derivatives against tumor cells, 3-position of 1,2-cyclopentanone was modified. (3). Some target compounds were further optimized according to the pharmacological results. 2. Target compounds were synthesized based on idea of modifying lead compounds: lead compounds (1,2-cyclopentanedione, 1,2-cyclohexanedione, 3-alkyl-1,2-cyclopentanedione) were synthesized by 4 synthetic methods; 31 target compounds (bis(sec-aminomethyl)-3-methyl-1,2-cyclopentanedi-ones, bis(sec-aminomethyl)-1,2-cyclopentanediones and 1,2-cyclohexanediones, 3-sec-aminomethyl-1,2-cyclopentanediones) were synthesized by Mannich reactions on different conditions, among them, 22 (RY07-26, 29, 30) have not been reported in the literature. Those compounds were identified by IR, 1H-NMR, MS spectrum and element analysis. 3. Target compounds were evaluated antitumor activities against 3 human tumor cell lines(QGY-7702 hepatic cells, SPC-A-1 lung cells, HL-60 leukemia cells) in vitro. Results revealed that most Mannich bases of 1,2-cyclopentanediones and 1,2-cyclohexanediones had significant antitumor activities and shown to have 2-10 fold more effective against 3 tumor cell lines than 5-Fu except for Mannich bases containing phenyl group and 3-morpholinomethyl-1,2-cyclopentanedione. The activity of compound RY17 against SPC-A-1 lung cells is 20 fold (mole concentration) more effective than 5-Fu, most of compounds were less than WB852 against 3 tumor cell lines. Inhibition activity of compounds RY04, 05, 17, 18 for tumor cell devision ability is greater than 5-Fu. 4. 14 compounds namely morpholine Mannich bases of 1,2-cyclopen-tanediones and Mannich bases of 3-methyl-1,2-cyclopentanedione were selected for evaluating antitumor activity against mice S-180 tumor cells in vivo. Results demonstrated that most compounds have little activities in vivo and activities of compounds RY01, 10 were fairly good but less than 5-Fu.