Preparation and evaluation of sulfide derivatives of the antibiotic brefeldin a as potential prodrug candidates with enhanced aqueous solubilities.
Several sulfide (+)-brefeldin A (BFA) analogues were prepared through the Michael addition of various thiols. Many of the sulfides were also oxidized to the corresponding sulfoxide with m-CPBA. The sulfides were designed to act as BFA prodrugs via the metabolic oxidation to the sulfoxide and subsequent syn elimination. Kinetic experiments were used to prove that the syn elimination of the sulfoxides prepared did in fact take place. Five selenide BFA prodrugs were also prepared that are envisioned to act in the same manner as the sulfides. As expected, when oxidation of the selenide to selenoxide was attempted, in situ syn elimination was observed. All of the compounds prepared were evaluated for antiproliferative activity against human cancer cell lines in the National Cancer Institute screen. The sulfoxides were much more potent than either the sulfides or selenides. Especially notable were sulfoxide 21, which possessed a cytotoxicity mean graph midpoint value (MGM) value lower than BFA itself, and sulfoxide 22, which possessed an MGM value slightly less potent than that of BFA. The sulfide analogues were shown to possess increased aqueous solubilty with respect to BFA.
Fox
B M
BM
Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana 47907, USA.
Vroman
J A
JA
Fanwick
P E
PE
Cushman
M
M
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000903:Antibiotics, Antineoplastic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020126:Brefeldin A / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018360:Crystallography, X-Ray; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007700:Kinetics; D018942:Macrolides; D009682:Magnetic Resonance Spectroscopy; D016566:Organoselenium Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012995:Solubility; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013440:Sulfides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014407:Tumor Cells, Cultured
C439958:2,3-dihydro-(2-hydroxypropylsulfinyl)brefeldin A; C439959:2,3-dihydro-(2-hydroxypropylthio)brefeldin A; D000900:Anti-Bacterial Agents; D000903:Antibiotics, Antineoplastic; D018942:Macrolides; D016566:Organoselenium Compounds; D011355:Prodrugs; D013440:Sulfides; D020126:Brefeldin A