haouamine-a and Prostatic-Neoplasms

A total synthesis of the complex, bent aromatic ring-containing marine alkaloid haouamine A is achieved through a route in which every step (with the exception of the final deprotection) is performed on a gram-scale. This is accomplished through the development of a method for the dehydrogenation of cyclohexenones that allows for point-to-planar chirality transfer. This strategy makes it possible to program the desired atropisomeric outcome from a simple chiral cyclohexenone. By synthesizing atrop-haouamine A, this work has firmly established that natural haouamine exists as a single, nonequilibrating atropisomer. Finally, biological investigations demonstrate that the bent aromatic ring of this natural product is critical for anticancer activity against PC3 cells.

Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Survival; Crystallography, X-Ray; Heterocyclic Compounds, 4 or More Rings; Humans; Male; Microbial Sensitivity Tests; Models, Molecular; Molecular Structure; Prostatic Neoplasms; Stereoisomerism

The chemical study of the ascidian Aplidium haouarianum has led to the isolation of the new metabolites haouamines A (1) and B (2) which belong to a novel class of alkaloids. The structure of 1 was established by interpretation of its spectroscopic data and those of the N-methyl derivative 3, and confirmed by X-ray crystallographic analysis. The structure of 2 was deduced by spectroscopic study of its peracetyl derivative 2a. In solution each haouamine exists as an unseparable mixture of two interconverting isomers derived by the presence of a highly strained 3-aza-[7]-paracyclophane moiety in their structures. Compound 1 exhibits a selective cytotoxic activity against the HT-29 human colon carcinoma cell line.

Topics: Alkaloids; Animals; Colonic Neoplasms; Crystallography, X-Ray; Drug Screening Assays, Antitumor; Endothelium; Hawaii; Heterocyclic Compounds, 4 or More Rings; Humans; Inhibitory Concentration 50; Lung Neoplasms; Male; Mice; Molecular Conformation; Molecular Structure; Nuclear Magnetic Resonance, Biomolecular; Prostatic Neoplasms; Spain; Tumor Cells, Cultured; Urochordata