Synthesis and Biological Evaluation of Aromatic Analogues of Conduritol F, l-chiro-Inositol, and Dihydroconduritol F Structurally Related to the Amaryllidaceae Anticancer Constituents

• Published in: Journal of organic chemistry 2006-07, Vol.71 (15), p.5694-5707
• Main Authors: KIREEV, Artem S., NADEIN, Oleg N., AGUSTIN, Vincent J., BUSH, Nancy E., EVIDENTE, Antonio, MANPADI, Madhuri, OGASAWARA, Marcia A., RASTOGI, Shiva K., ROGELJ, Snezna, SHORS, Scott T., KORNIENKO, Alexander
• Format: Article
• Language: English
• Subjects: Amaryllidaceae Alkaloids - chemical synthesis; Amaryllidaceae Alkaloids - chemistry; Amaryllidaceae Alkaloids - pharmacology; Annexin A5 - metabolism; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Carbohydrates with 4, 5, 6, ... C atoms, dissacharides and oligosaccharides; Carbohydrates. Nucleosides and nucleotides; Catalysis; Chemistry; Cyclization; Exact sciences and technology; Flow Cytometry; Glucosides - chemical synthesis; Glucosides - chemistry; Glucosides - pharmacology; Heterocyclic compounds; Heterocyclic compounds with only one n hetero atom and condensed derivatives; Humans; Inositol - chemical synthesis; Inositol - chemistry; Inositol - pharmacology; Isoquinolines - chemistry; Jurkat Cells - drug effects; Liliaceae - chemistry; Molecular Structure; Organic chemistry; Preparations and properties; Rhodamines - metabolism; Structure-Activity Relationship
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo0607562

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.