Antineoplastic agents 440. Asymmetric synthesis and evaluation of the combretastatin A-1 SAR probes (1S,2S)- and (1R,2R)-1, 2-dihydroxy- 1-(2',3'-dihydroxy-4'-methoxyphenyl)-2-(3' ',4' ',5' '-trimethoxyphenyl)-ethane.
The synthetic (E)-isomer (3b) of natural combretastatin A-1 (1a) isolated from the African bushwillow Combretum caffrum was the focus of chiral hydroxylation (Sharpless) reactions as part of a structure-activity relationship study. The resulting (R,R)- and (S,S, )-diols (6 and 7) and synthetic intermediates were evaluated against a series of cancer cell lines, microorganisms, and tubulin. Chiral diols 6 and 7 showed increased activity against the P-388 murine lymphocytic leukemia cell line with ED(50) values of 3.9 and 2.9 microg/mL, respectively, when compared to the precursor (E)-stilbene 3b. In contrast, (E)-stilbene 3b exhibited more potent antibiotic activity than the chiral diols (6 and 7). Both diols, (R,R)-6 and (S, S)-7, displayed less cancer cell growth inhibition and less antibiotic activity than did natural combretastatin A-1 (1a) (P-388 ED(50) 0.25 microg/mL).
Cancer Research Institute and Department of Chemistry Arizona State University, Tempe, Arizona 85287-2404, USA.
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D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D005026:Ethylene Glycols / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006139:Guaiacol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D051379:Mice; D008826:Microbial Sensitivity Tests; D015335:Molecular Probes; D013237:Stereoisomerism; D013267:Stilbenes / Q000737:chemistry*; D013329:Structure-Activity Relationship; D014197:Trees / Q000737:chemistry; D014407:Tumor Cells, Cultured
C413036:1,2-dihydroxy-1-(2',3'-dihydroxy-4'-methoxyphenyl)-2-(3'',4'',5''-trimethoxyphenyl)ethane; D000972:Antineoplastic Agents, Phytogenic; D005026:Ethylene Glycols; D015335:Molecular Probes; D013267:Stilbenes; C063690:combretastatin A-1; D006139:Guaiacol