Bioactive components from Crossosoma bigelovii and studies on novel selenophene -containing heteroarene compounds as anticancer agents

The objective of the first part of the project was to discover novel and potent antitumor compounds from higher plants. The extracts of the stems of Crossosoma bigelovii showed significant cytotoxicity in human tumor cytotoxicity bioassays. Bioassay-directed isolation of Crossosoma bigelovii yielded five bioactive compounds, three of which are new natural products. CB-JZ-II-70E is a new cardiac glycoside. CB-SC-II-27A, and CB-SC-II-27C are two new 2-methylchromone derivatives. Two known chromones, eugenin and noreugenin were also isolated. All of the new compounds demonstrated moderate to high cytotoxicity (GI50 = 10−3-10 0 μg/ml) against a panel of three human solid tumor cell lines. The structure-activity relationship study showed that the glycosylation at 7-O position of 2-methylchromone is important for the cytotoxicity. The objective of the second part of the project was to synthesize novel analogs of polythiophene compounds as potent PKC inhibitors and selective cytotoxic agents. More than 16 novel selenophene- and thiophene-containing compounds were synthesized. Most of the polyselenophene derivatives were found to be good PKC inhibitors. Their potency increased with the numbers of selenophene rings in the compounds, and formylation at the α-position of the selenophene ring further increased the potency by 20 fold. Several members of this group of compounds demonstrated strong differential cytotoxicity against renal and ovarian tumor cell lines in the NCI human tumor cell panels. They also displayed very high selective cytotoxicity index (SCI \u3e1000) against human renal carcinoma A-498 cell line. Among them, 2-(5′-hydroxymethyl-2 ′selenienyl)-5-(2″-selenienyl)- N-methyl-pyrrole, demonstrated remarkable in vivo antitumor efficacy for the growth suppression of ras-transformed human bronchial epithelial (TBE) cells. In all series of compounds synthesized, it was observed that α-formylation always resulted in better PKC inhibitors while α-hydroxymethylation always resulted in stronger cytotoxic agents. In order to explain this phenomenon, the metabolism of one of the terthiophene analogues, 5-hydroxymethyl-α-terthiophene, in human renal carcinoma A-498 cell culture was investigated. It was found that no 5-hydroxymethyl-α-terthiophene was transformed into 5-formyl-α-terthiophene within twelve hours. Therefore, PKC may not be the only target for 5-hydroxymethyl-α-terthiophene to exert its cytotoxic effects on A-498 cells. Other biochemical targets may also play important roles