The Anti-tumor Activity Of Natural Products And Related Compounds Synthesis

Natural stilbenoids, including Combretastatin A-4, were found to be tubulin polymerization inhibitors and display strong antimitotic activity to a broad spectrum of human cancer lines. For the purpose of searching for new antitumor agents and understanding their structure-activity relationships, we synthesized two nature dihydrostilbenes and their analogues. Furthermore, a new series of heterocyclic compounds, known as the analogues of Combretastatin A-4, had been designed and synthesized.A total synthetic route of two natural dihydrostilbenes 3'-hydroxy-3-methoxy-4,5-methylenedioxybibenzyl (2-1a) and 3',3-dihydroxy-4,5-methylenedioxybibenzyl (2-1b), which were isolated from Bulbophyllum odoratissimum Lindl. with significant cytotoxicity toward human cancer cell lines, was developed via Horner reaction etc. The natural products 2-1a and 2-1b were obtained in 22.2% and 16.0% overall yield, respectively. Additionally, nine analogues of 2-1a and 2-1b, 2-1c～2-1k, were synthesized and evaluated for their antitumor activity against human SGC-7901, KB and HT-1080 cell lines by MTT assay. The activities of 2-1c and 2-1d were in the same range as those of the natural products 2-1a and 2-1b.A new family of 4,5-disubstituted 1,2-dithiole-3-thiones has been designed and synthesized as CA-4 analogues. 5-(4-methoxyphenyl)-4-(3,4,5-trimethoxyphenyl)-3H-1,2-dithiole-3-thione (I) and 4-(4-methoxyphenyl)-5-(3,4,5-trimethoxyphenyl)-3H-1,2-dithiole-3-thione (II) were obtained by the reaction of the olefins containing anα-methyl group with sulfur in 3.1% and 5.7% overall yield, respectively. The treatment of compound I with aqueous potassium permanganate or hydroxylammonium hydrochloric acid could give 5-(4-methoxyphenyl)-4-(3, 4,5-trimethoxyphenyl)-3H-1,2-dithiole-3-one (III) and 4-(4-methoxyphenyl)-5-(3,4,5-trimethoxyphenyl)-3H-1,2-dithiole-3-one oxime (V) in good yields.Following this method, we obtained 4-(4-methoxyphenyl)-5-(3,4,5-trimethoxyphenyl)-3H-1,2-dithiole-3-one (IV) and 5-(4-methoxy phenyl)-4-(3,4,5-trimethoxyphenyl)-3H-1,2-dithiole-3-one oxime (VI) smoothly.In summary, the synthesis and evaluation for their antitumor activity in vitro of the two natural dihydrostilbenes and nine analogues had been achieved. Six heterocyclic analogues of CA-4 had also been obtained.