ABSTRACT
The tetrahydrofuran (THF) containing annonaceous acetogenins (AAs) are attractive candidates for drug development because of their potent cytotoxicity against a wide range of tumors and their relatively simple and robust structures. Replacement of the THF segment with a sugar residue may deliver analogues with improved tumor selectivity and pharmacokinetics and are therefore attractive for drug development. As a first test to the feasibility of such structures, a set of such monosaccharide analogues was synthesized and assayed against four human tumor cell lines, cervical (HeLa), breast (MDA-MB231), T-cell leukemia (Jurkat) and prostate (PC-3). Certain analogues showed low micromolar activity that was comparable to a structurally similar, naturally occurring mono-THF acetogenin. A preliminary examination of the structure-activity profile of these carbohydrate analogues suggests that they have a similar mechanism of action as their THF congeners.
Subject(s)
Acetogenins/chemistry , Antineoplastic Agents/chemical synthesis , Carbohydrates/chemistry , Furans/chemistry , Acetogenins/chemical synthesis , Acetogenins/toxicity , Antineoplastic Agents/chemistry , Antineoplastic Agents/toxicity , Cell Line, Tumor , Cell Survival/drug effects , HeLa Cells , Humans , Jurkat Cells , Light , Scattering, Radiation , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Dihydroxyalkenes or their monoprotected alcohol derivatives are transformed to 5,5- and 5,6-spiroketals through a sequence involving an initial iodocyclization, followed by a silver triflate mediated spiroketalization step on the derived hydroxy-iodoether.
Subject(s)
Cycloparaffins/chemistry , Ethers/chemistry , Furans/chemical synthesis , Hydrocarbons, Iodinated/chemistry , Spiro Compounds/chemical synthesis , Cyclization , Furans/chemistry , Halogenation , Hydrocarbons, Iodinated/chemical synthesis , Molecular Structure , Spiro Compounds/chemistryABSTRACT
A novel, efficient, and stereoselective synthesis of fragment A of cryptophycin 3 is disclosed. The key step involves the regio- and stereoselective transformation of an unsaturated ester to a bromohydrin via anchimeric assistance by the sulfinyl group.
Subject(s)
Combinatorial Chemistry Techniques , Cyanobacteria/chemistry , Depsipeptides , Peptides, Cyclic/chemical synthesis , Molecular Structure , Nuclear Magnetic Resonance, Biomolecular , Peptides, Cyclic/chemistry , Stereoisomerism , Sulfoxides/chemistryABSTRACT
Bromohydrins have been prepared from beta-methyl-gamma,delta-unsaturated sulfoxides with high regio- and stereoselectivity. The reaction proceeds via neighboring group participation of the sulfinyl moiety with inversion of sulfoxide configuration as proven by an (18)O labeling study and X-ray crystallography.