Synthesis and cytostatic properties of structure-simplified analogs of dolastatin 15.
The linear peptide dolastatin 15 (1), a potent antineoplastic constituent from the shell-less mollusk Dolabella auricularia, has been selected as the lead compound for developing novel antitumor drugs. Recently LU103793 (2), a synthetic and structure-simplified analog of dolastatin 15, has been demonstrated to be highly cytotoxic [IC50 = 0.1 nM; M. De Arruda, C.A. Cocchiaro, C.M. Nelson, C. M. Grinnel, B. Janssen, A. Haupt & T. Barlozzari (1995) Cancer Res. 55, 3085-3092]. Both compounds have been undergoing human cancer clinical trials in Europe and North America. Based on the novel structure of LU103793, a series of analogs modified at the N-terminal dolavalyl moiety and -Pro-Pro-benzylamide unit was developed. These synthesized analogs were tested using a sulforhodamine B (SRB) assay for the drug-screening program at NCI on a variety of human cancer cell lines. As expected, most analogs exhibited potent and selective growth inhibition against leukemia. Analog 18 was specifically active against HL-60 and K-562 cell lines (GI50s: 0.05 microM and 0.07 microM, respectively) while analogs 14 and 17 were selectively potent against prostate and breast cancer cell lines (GI50s at micromolar levels). However, all analogs were less potent than 2 as growth inhibitors of some breast and colon cancer cell lines (e.g. MDA-MB-435 and HT-29). We believe that modification of novel marine natural products as synthetic analogs might show particular promise for developing novel anticancer candidates with moderate specificity.
Hu
M K
MK
School of Pharmacy, National Defense Medical Center, Taipei, Taiwan, China. hmk@ndmc1.ndmctsgh.edu.tw
Huang
W S
WS
D000595:Amino Acid Sequence; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D016339:Spectrometry, Mass, Fast Atom Bombardment; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D009842:Oligopeptides; C094621:cemadotin