In 1984, the structure of (+)-pancratistatin (1a), the principal anticancer constituent of the Amaryllidaceae tropical spider lily Pancratium littorale, which was later reidentified as Hymenocallis littoralis, first isolated and elucidated (by x-ray employing the 7-methoxy derivative) (Pettit, G. R., et al., G. M. Antineoplastic Agents 105, Zephyranthes grandiflora, J. Nat. Prod. 1984, 47, 1018-1020, Pettit, G. R., et al., Isolation and Structure of Pancratistatin, J. Chem. Soc., Chem. Commun. 1984, 1693-1694; Pettit, G. R., et al., Antineoplastic Agents, 120. Pancratium Littorale, J. Nat. Prod. 1986, 49, 995-1002; Pettit, G. R., et al., Antineoplastic Agents, 301. An Investigation of the Amaryllidaceae Genus Hymenocallis, J. Nat. Prod. 1995, 58, 756-759.) Because of the early promise of pancratistatin (1a) as a new type of anticancer and antiviral (RNA viruses) drug, various phases of preclinical development have been underway for over seventeen years. (Pettit, G. R., et al., Isolation and Structure of Pancratistatin, J. Chem. Soc., Chem. Commun. 1984, 1693-1694; Gabrielsen, B., et al., Antiviral (RNA) Activity of Selected Amaryllidaceae Isoquinoline Constituents and Synthesis of Related Substances, J. Nat. Prod. 1992, 55, 1569-1581; Pettit, G. R., et al., Antineoplastic Agents 320: Synthesis of a Practical Pancratistatin Prodrug, Anti-Cancer Drug Design 1995, 10, 243-250; Pettit, G. R., et al., Antineoplastic Agents 453. Synthesis of Pancratistatin Prodrugs, Anti-Cancer Drug Design 2000, 15, 389-395; Toki, B., et al., Protease-Mediated Fragmentation of p-Amidobenzyl Ethers: A New Strategy for the Activation of Anticancer Prodrugs. J. Org. Chem. 2002, 67, 1866-1872.)
Meanwhile, there has been increasing success in developing the availability of pancratistatin (1a) by horticultural and synthetic approaches as well as further defining SAR requirements. (Pettit, G. R., et al., Antineoplastic Agents, 301, An Investigation of the Amaryllidaceae Genus Hymenocallis, J. Nat. Prod. 1995, 58, 756-759; Pettit, G. R., et al., Antineoplastic Agents 450. Synthesis of (+)-Pancratistatin from (+)-Narciclasine as Relay, J. Org. Chem. 2001, 66, 2583-2587; Hudlicky, T., et al., Total Synthesis and Biological Evaluation of Amaryllidaceae Alkaloids: Narciclasine, ent-7-deoxypancratistatin, 7-deoxypancratistatin, its 10b-Epimer, and Truncated Derivatives, J. Org. Chem., 2002, 67, 8726-8743; McNulty, J., et al., Studies Directed Towards the Refinement of the Pancratistatin Cytotoxic Pharmacophore. Bioorg. Med. Chem. Lett. 2001, 11, 169-172; Pettit, G. R., et al., Synthesis of 10b-R-Hydroxy-Pancratistatin via Narciclasine, J. Chem. Soc., Chem. Commun. 1994, 2725-2726.) When the preclinical drug formulation of pancratistatin (1a) began to present another challenge owing to the sparing (53 μg/ml in water) solubility behavior of this isocarbostyril (1a) investigation began into structural modifications that were expected to greatly increase aqueous solubility while serving as a successful delivery-type prodrug. (Pettit, G. R., et al., Antineoplastic Agents 320: Synthesis of a Practical Pancratistatin Prodrug, Anti-Cancer Drug Design 1995, 10, 243-250; Toki, B., et al., Protease-Mediated Fragmentation of p-Amidobenzyl Ethers: A New Strategy for the Activation of Anticancer Prodrugs, J. Org. Chem. 2002, 67, 1866-1872.) Those studies led to useful syntheses (4 steps) of sodium pancratistatin 7-O-phosphate (1b) with considerably improved aqueous solubility (20 mg/ml). (Pettit, G. R., et al., Antineoplastic Agents 320: Synthesis of a Practical Pancratistatin Prodrug, Anti-Cancer Drug Design 1995, 10, 243-250; Pettit, G. R., et al., Antineoplastic Agents 453. Synthesis of Pancratistatin Prodrugs, Anti-Cancer Drug Design 2000, 15, 389-395.)
While the 7-O-phosphate (1b) proved to have attractive aqueous solubility properties, the yield penalizing synthetic steps from pancratistatin (1a) required continuation of parallel efforts to directly, but selectively, phosphorylate pancratistatin (1a). The necessity of discovering more efficient techniques for converting pancratistatin (1a) to very effective phosphate prodrugs has been accelerating with the recent realization that the long elusive key mechanism of action by isocarbostyril 1a against in vivo neoplastic disease is cancer antiangiogenesis/vascular targeting. (Bibby, M. C., et al., Anti-Vascular and Anti-Tumour Effects of the Novel Agent Pancratistatin Phosphate. Biological Basis for Antiangiogenic Therapy Conference, Milan, Italy, Nov. 8-10, 1999.) Furthermore, pancratistatin (1a) has also recently been found to display remarkable activity against microspirochesis, another potentially lethal challenge for some cancer patients. (Ouarzane-Amara, M., et al., In Vitro Activities of Two Antimitotic Compounds, Pancratistatin and 7-Deoxynarciclasine, against Encephalitozoon intestinalis, a Microsporidium Causing Infections in Humans, Antimicrob. Agents Chemother. 2002, 45, 3409-3415.)