Bioassay-guided investigation of the sponge <i>Aaptos lobata</i> resulted in the isolation and identification of two new amphiphilic polyamines, aaptolobamines A (<b>1</b>) and B (<b>2</b>). Their structures were determined through analysis of NMR and MS data. MS analysis also indicated that <i>A. lobata</i> contained a complex mixture of aaptolobamine homologues. Both aaptolobamines A (<b>1</b>) and B (<b>2</b>) show broad bioactivity, including cytotoxicity against cancer cell lines, moderate antimicrobial activity against a methicillin-resistant strain of <i>Staphylococcus aureus</i>, and weak activity against a <i>Pseudomonas aeruginosa</i> strain. The mixtures of aaptolobamine homologues were shown to contain compounds that bind to the Parkinson's disease associated amyloid protein α-synuclein and inhibit its aggregation.