[Design, synthesis and antidiabetic activity of novel tetrahydrocarboline PPAR regulators].

A series of novel tetrahydrocarboline derivatives was designed and synthesized in order to discover more potent peroxisome proliferator-activated receptor (PPAR) alpha/gamma dual regulators. The structures of these compounds were confirmed by 1H NMR and HR-MS; their PPAR-regulating activities were evaluated in vitro. Compounds 6h, 6n, 6p and 6q exhibited more potent PPARalpha agonistic activities than the control drug WY14643, while compounds 60, 6g, 6i and 6q exhibited more potent PPARgamma agonistic activities than the control drug rosiglitazone. Compound 6q was discovered as a potent PPARalpha/gamma dual agonist and deserves further investigation.

Synthesis and cytotoxic activities of a series of novel N-methyl-bisindolylmaleimide amide derivatives.

A novel series of N-methyl-bisindolylmaleimides were synthesized and evaluated for their inhibitory activities against nine tumor cell lines. Some of the compounds showed an interesting activity against the tested cell lines. The most potent compounds 5e and 5j displayed antiproliferative activity with 50% inhibitory concentration values in the µM range against some tested cell lines.

[Design, synthesis, and PPARalpha/gamma agonistic activity of novel tetrahydroisoquinoline derivatives].

A series of tetrahydroisoquinoline derivatives were prepared and their peroxisome proliferator-activated receptor (PPAR) alpha/gamma agonistic activities were evaluated to obtain more potent PPAR agonist. All of them were new compounds, and their structures were confirmed by 1H NMR and HR-MS. Three compounds exhibited higher agonistic activities of PPARgamma than that of the comparison, six compounds exhibited higher agonistic activities of PPARalpha than that of the comparison, and compound 8a was discovered as a highly potent PPARalpha/gamma agonist that is much more active than that of WY14643 and rosiglitazone. The development of potent PPAR agonists may offer a new choice for the treatment of diabetes.

A novel bisindolymaleimide derivative (WK234) inhibits proliferation and induces apoptosis through the protein kinase Cß pathway, in chronic myelogenous leukemia K562 cells.

WK234, a novel bisindolymaleimide derivative, was designed as a protein kinase Cß (PKCß) inhibitor. The objective of this study was to evaluate the anti-tumor activity of WK234 in the human chronic myelogenous leukemia (CML) K562 cell line and to investigate possible mechanisms of its action. The results show that WK234 inhibited K562 cell proliferation in a time- and dose-dependent manner. WK234 increased cytochrome C release and caspase-3 cleavage, which indicates that it induced apoptosis via mitochondria- and caspase-mediated pathways. Western blotting showed that PKCß1, PKCß2, and their phosphorylation levels were effectively decreased after 2-4 h of WK234 treatment. Meanwhile the phosphorylation status of PKCß downstream proteins, glycogen synthase kinase 3α/ß (GSK3α/ß) and extracellular signal-regulated kinase (ERK), were inhibited. WK234 blocked phorbol myristate acetate (PMA)-induced Ser(660) phosphorylation of PKCß2 located at the cell membrane, and increased Ser(660) PKCß2 expression within the cytoplasm and the nucleus. These results indicate that WK234 inhibited cell proliferation and induced apoptosis through suppressing the PKCß signal pathway. WK234 might be a promising candidate for the treatment of CML.

Synthesis of N-methyl-bisindolylmaleimide amino acid methyl ester conjugates and cytotoxicity study.

A novel series of N-methylbisindolylmaleimides derivatives bearing 2-acetamino acid moieties were synthesized. The cytotoxic activities of these compounds were tested in six tumor cell lines. The most potent compound 8d displayed cytotoxicity against six human tumor cell lines in the micromolar range.

Synthesis and antitumor activity of bisindolylmaleimide and amino acid ester conjugates.

A series of novel bisindolylmaleimide and natural amino acid ester conjugates were synthesized and evaluated for their inhibitory activity against six tumor cell lines. Some compounds displayed interesting cytotoxic profiles. The most active compound 8e showed inhibitory activity against several human cancer cell lines.

Synthesis and antitumor activity of simplified ecteinascidin-saframycin analogs.

Two series of simplified analogs of the ecteinascidin-saframycin type alkaloids were prepared from l-DOPA. Their in vitro antitumor activity was tested against three human cancer cell lines (HCT-8 colon carcinoma, Bel-7402 liver carcinoma, and BGC-823 gastric carcinoma). Among these compounds, the ester analogs have stronger activities than those of amide analogs in general. Among them, 1-naphthalene carboxylate ester analog 31 has the strongest activity against BGC-823 cells.

[Progress in the studies on antitumor natural product ecteinascidin-743].

The alkaloid ecteinascidin-743, isolated from the marine tunicate Ecteinascidia turbinata, binds to DNA and induces cytotoxic effects in several tumors. The drug is being codeveloped by Pharma Mar and Ortho Biotech. In May 2001 and October 2003, it was granted orphan drug status by the European Commission for soft tissue sarcoma and ovarian cancer, respectively. This paper reviews its research progress, including chemical synthesis, in vitro studies and mechanism of action, antitumor activity in vivo, toxicity, pharmacokinetics, and clinical studies.