Abstract
A high-yield regioselective synthesis of (E)-combretastatin A-1 2b was completed using methoxymethyl (MOM) protection and a Wadsworth-Emmons reaction as key steps. In turn, (E)-stilbene 11 was converted by convenient syntheses to both (S,S)- and (R,R)-1, 3-dioxolanes 5a and 6a. A Sharpless asymmetric dihydroxylation reaction was employed for preparation of intermediates (S,S)-12 and (R,R)-13. The (4S,5S)-4-(2′,3′-dihydroxy-4′-methoxyphenyl)-5- (3″,4″,5″-trimethoxyphenyl)-1, 3-dioxolane 5a was found to be a highly potent inhibitor of microtubule assembly (IC50 = 0.59 μM) and was designated dioxostatin. Conversion to sodium phosphate 17 (P388 lymphocytic leukemia cell line: ED50 = 0.2 μg/ml) provided a very useful water-soluble prodrug.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 361-371 |
| Number of pages | 11 |
| Journal | Anti-Cancer Drug Design |
| Volume | 15 |
| Issue number | 5 |
| State | Published - 2000 |
Keywords
- Asymmetric dihydroxylation
- Dioxostatin
- Dioxostatin prodrug
- Tubulin binding agent
ASJC Scopus subject areas
- Biochemistry
- Oncology
- Biochemistry, Genetics and Molecular Biology(all)
- Pharmacology
- Drug Discovery
- Organic Chemistry