Galanthamine derivatives as acetylcholinesterase (AChE) inhibitors. Synthetic and structural investigations of the novel biologically active cyclodepsipeptides: The didemnins

The mnemonic and cognitive impairments associated with patients suffering from Alzheimer\u27s Disease (AD), the fourth leading cause of death among the elderly, are directly related to the deficiency of acetylcholine in the brain. Galanthamine (1), an Amaryllidaceae alkaloid, has recently been evaluated as a palliative treatment of this disease. Carbamate and ester derivatives of this centrally acting competitive inhibitor have been synthesized and tested to determine structural requirements for bioactivity. In vivo testing of all derivatives is currently being conducted elsewhere. The didemnins (50a-50j), an interesting class of cyclodepsipeptides isolated from a marine tunicate of the family Didemnidae, have offered the chemical community an exciting synthetic challenge. These compounds along with their structural appeal have also been shown to possess a varied degree of bioactivity: antiviral, antitumor, and immunosuppressive activity. After devising an asymmetric synthesis to the common macrocycle in which several steps were optimized to create gram quantities of important intermediates, efforts were directed towards the determination of the structural features responsible for the bioactivity. To achieve this goal and a better understanding of this class of biologically active natural products, several investigations were carried out. New side chain analogs (50k-50n) of the most active natural product (50b) were synthesized and shown to have cytotoxic and immunosuppressive activities comparable to those of natural compound, didemnin B. A conformationally restricted isostatine analog, predicted by molecular modeling to be superimposable to 50b, was prepared to investigate the effect of introducing more rigidity in the macrocycle. An X-ray analysis and biological testing of the macrocycle backbone core (50e) confirmed the importance of the side chain (linear portion of molecule) for bioactivity