Low toxic and high soluble camptothecin derivative 2-47 effectively induces apoptosis of tumor cells in vitro.

The cytotoxic activity of camptothecin derivatives is so high that these compounds need to be further modified before their successful application as anti-cancer agents clinically. In this study, we reported the synthesis and biological evaluation of a novel camptothecin derivative called compound 2-47. The changes in structure did not reduce its activity to inhibit DNA topoisomerase I. Compound 2-47 induced apoptosis of many tumor cells including leukemia cells K562, Jurkat, HL-60, breast cancer cell BT-549, colon cancer cell HT-29 and liver cancer cell HepG2 with a half maximal inhibitory concentration (IC50) of 2- to 3-fold lower than HCPT as a control. In particular, 2-47 inhibited the proliferation of Jurkat cells with an IC50 of as low as 40 nM. By making use of Jurkat cell as a model, following treatment of Jurkat cells, compound 2-47 activated caspase-3 and PARP, resulting in a decreased Bcl-2/Bax ratio. These data showed that compound 2-47 induces Jurkat cell death through the mitochondrial apoptotic pathway. In addition, compound 2-47 showed a decreased cytotoxic activity against normal cells and an improved solubility in low-polar solvent. For example, compound 2-47 solutes in CHCl3 130-fold higher than HCPT. Taken together, our data demonstrated that camptothecin derivative 2-47 notably inhibits the tumor cell proliferation through mitochondrial-mediated apoptosis in vitro.

Synthesis and antitumor activity evaluation of a novel series of camptothecin analogs.

A series of novel 10-substituted camptothecin analogs (3-10) with a carbamate linker were synthesized, and their biological activities were evaluated. The amino acid-linked carbamate derivatives (8-10) of the camptothecin-type natural product not only possessed good to excellent inhibitory activity against three human tumor cell lines K562, HepG2, and HT-29, but also showed significantly less cytotoxicity against normal human cell HEK293 (half maximal inhibiting concentration >10 µM). The selectivity of compound 9 toward tumor cells relative to normal cells is at least 250 times better than that of camptothecin. The preliminary testing result indicated that the solubility of these compounds was also improved compared to that of 10-hydroxy camptothecin.

Synthesis and antitumor activity of novel podophyllotoxin derivatives against multidrug-resistant cancer cells.

Seven novel 4ß-N-substituted podophyllotoxin derivatives with indole rings were prepared and evaluated for cytotoxicity against human cancer cell lines HeLa, KB, KBV, K562, and K562/AO2. Most of them demonstrated improved antitumor activity and weak multidrug resistance compared to the drugs currently available.