【精选】Antineoplastic Agents. 487. Synthesis and Biological Evaluation of the.pdfVIP

J. Med. Chem. 2003, 46, 525531 525 Antineoplastic Agents. 487. Synthesis and Biological Evaluation of the Antineoplastic Agent 3,4-Methylenedioxy-5,4′-dimethoxy-3′-amino-Z-stilbene and Derived Amino Acid Amides George R. Pettit,*,† Collin R. Anderson,† Delbert L. Herald,† M. Katherine Jung,‡ Debbie J. Lee,§ Ernest Hamel,§ and Robin K. Pettit† Cancer Research Institute and Department of Chemistry and Biochemistry, Arizona State University, P.O. Box 872404, Tempe, Arizona 85287-2404, Science Applications International Corp.Frederick, National Cancer Institute at Frederick, National Institutes of Health, Frederick, Maryland 21702-1201, and Screening Technologies Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute at Frederick, National Institutes of Health, Frederick, Maryland 21702-1201 Received May 13, 2002 An efficient synthesis of 3,4-methylenedioxy-5,4′-dimethoxy-3′-amino-Z-stilbene ( 1c) and hydrochloride ( 1d) is reported. The nitrostilbene intermediate 6a was obtained via a Wittig reaction using phosphonium salt 4 and 3-nitro-4-methoxybenzaldehyde 5. A one-step reduction using zinc in acetic acid produced the synthetic objective amine 1c. The coupling of this amine with various Fmoc amino acids, followed by cleavage of the -amine protecting group, resulted in a series of new cancer cell growth inhibitory amides. Amine 1c, hydrochloride 1d, glycine amide 3b, and tyrosine amide 3f had the highest level (GI 2 3 50 10 10 g/mL) of activity against a panel of six human and one animal (P388) cancer cell lines. Amine 1c and its