Papuamides A−D, HIV-Inhibitory and Cytotoxic Depsipeptides from the Sponges <i>Theonella </i><i>m</i><i>irabilis</i> and <i>Theonella </i><i>s</i><i>winhoei</i> Collected in Papua New Guinea

The novel cyclic depsipeptides papuamides A (<b>1</b>), B (<b>2</b>), C (<b>3</b>), and D (<b>4</b>) have been isolated from Papua New Guinea collections of the sponges <i>Theonella mirabilis</i> and <i>Theonella swinhoei</i>. Their structures were determined by a combination of spectroscopic analysis and chemical degradation and derivatization studies. In addition to glycine, alanine, and threonine, these peptides contain a number of unusual amino acids including 3,4-dimethylglutamine, β-methoxytyrosine, 3-methoxyalanine, and 2,3-diaminobutanoic acid or 2-amino-2-butenoic acid residues. Papuamides A−D (<b>1</b><b>−</b><b>4</b>) are also the first marine-derived peptides reported to contain 3-hydroxyleucine and homoproline residues. These peptides also contain a previously undescribed 2,3-dihydroxy-2,6,8-trimethyldeca-(4<i>Z</i>,6<i>E</i>)-dienoic acid moiety N-linked to a terminal glycine residue. Papuamides A (<b>1</b>) and B (<b>2</b>) inhibited the infection of human T-lymphoblastoid cells by HIV-1<sub>RF</sub> in vitro with an EC<sub>50</sub> of approximately 4 ng/mL. Compound <b>1</b> was also cytotoxic against a panel of human cancer cell lines with a mean IC<sub>50</sub> of 75 ng/mL.