ABSTRACT
Pancratistatin is a potent anticancer natural product, whose clinical evaluation is hampered by the limited natural abundance and the stereochemically complex structure undermining practical chemical preparation. Fifteen aromatic analogues of conduritol F, l-chiro-inositol, and dihydroconduritol F that possess four of the six pancratistatin stereocenters have been synthesized and evaluated for anticancer activity. These compounds serve as truncated pancratistatin analogues lacking the lactam ring B, but retaining the crucial C10a-C10b bond with the correct stereochemistry. The lack of activity of these compounds provides further insight into pancratistatin's minimum structural requirements for cytotoxicity, particularly the criticality of the intact phenanthridone skeleton. Significantly, these series provide rare examples of simple aromatic conduritol and inositol analogues and, therefore, this study expands the chemistry and biology of these important classes of compounds.
Subject(s)
Amaryllidaceae Alkaloids/chemical synthesis , Antineoplastic Agents/pharmacology , Glucosides/chemical synthesis , Inositol/chemical synthesis , Liliaceae/chemistry , Amaryllidaceae Alkaloids/chemistry , Amaryllidaceae Alkaloids/pharmacology , Annexin A5/metabolism , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Apoptosis/drug effects , Catalysis , Cyclization , Flow Cytometry , Glucosides/chemistry , Glucosides/pharmacology , Humans , Inositol/chemistry , Inositol/pharmacology , Isoquinolines/chemistry , Jurkat Cells/drug effects , Molecular Structure , Rhodamines/metabolism , Structure-Activity RelationshipABSTRACT
Formal synthesis of (+)- and (-)-cyclophellitol from d-xylose has been accomplished through utilization of the latent plane of chirality present in the starting carbohydrate. The synthetic pathway is suitable for preparation and biological evaluation of cyclophellitol analogues in both enantiomeric series.
Subject(s)
Cyclohexanols/chemical synthesis , Xylose/chemistry , Cyclohexanols/chemistry , Molecular Structure , StereoisomerismABSTRACT
Structurally novel cyclitols, 1-aryl-1-deoxyconduritols F, were efficiently prepared from d-xylose, utilizing RCM as a key step. Various aromatic residues were incorporated in the cyclitol skeleton with total stereochemical control, utilizing a diastereoselective aryl cuprate addition to a gamma-alkoxy enoate. The synthetic route establishes a firm foundation for a practical synthesis of the antitumor alkaloid pancratistatin and its aryl analogues. [structure: see text]
