Synthesis and biological activity of fluorinated combretastatin analogues.
With the aim of understanding the influence of fluorine on the double bond of the cis-stilbene moiety of combretastatin derivatives and encouraged by a preliminary molecular modeling study showing a different biological environment on the interaction site with tubulin, we prepared, through various synthetic approaches, a small library of compounds in which one or both of the olefinic hydrogens were replaced with fluorine. X-ray analysis on the difluoro-CA-4 analogue demonstrated that the spatial arrangement of the molecule was not modified, compared to its nonfluorinated counterpart. SAR analysis confirmed the importance of the cis-stereochemistry of the stilbene scaffold. Nevertheless, some unpredicted results were observed on a few trans-fluorinated derivatives. The position of a fluorine atom on the double bond may affect the inhibition of tubulin polymerization and cytotoxic activity of these compounds.
Alloatti
Domenico
D
R&D, Sigma-Tau Industrie Farmaceutiche Riunite S.p.A., Via Pontina Km 30.400, 00040 Pomezia, Italy.
Giannini
Giuseppe
G
Cabri
Walter
W
Lustrati
Isabella
I
Marzi
Mauro
M
Ciacci
Andrea
A
Gallo
Grazia
G
Tinti
M Ornella
MO
Marcellini
Marcella
M
Riccioni
Teresa
T
Guglielmi
Mario B
MB
Carminati
Paolo
P
Pisano
Claudio
C
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001632:Bibenzyls / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001704:Biopolymers; D002417:Cattle; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D018360:Crystallography, X-Ray; D004354:Drug Screening Assays, Antitumor; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects; D005461:Fluorine; D006801:Humans; D008833:Microcirculation / Q000166:cytology; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D013237:Stereoisomerism; D013267:Stilbenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000378:metabolism
D000970:Antineoplastic Agents; D001632:Bibenzyls; D001704:Biopolymers; D013267:Stilbenes; D014404:Tubulin; D005461:Fluorine; C040105:combretastatin