| Summary: | During a search for glycosidase inhibitors among marine natural products, we applied an integrated in vitro and in silico approach to evaluate the potency of some aaptamines and makaluvamines isolated from marine sponges on the hydrolyzing activity of α-N-acetylgalactosaminidase (α-NaGalase) from human cancer cells and the recombinant α-D-galactosidase (α-PsGal) from a marine bacterium <i>Pseudoalteromonas</i> sp. KMM 701. These alkaloids showed no direct inhibitory effect on the cancer α-NaGalase; but isoaaptamine (<b>2</b>), 9-demethylaaptamine (<b>3</b>), damirone B (<b>6</b>), and makaluvamine H (<b>7</b>) reduced the expression of the enzyme in the human colorectal adenocarcinoma cell line DLD-1 at 5 μM. Isoaaptamine (<b>2</b>), 9-demethylaaptamine (<b>3</b>), makaluvamine G (<b>6</b>), and zyzzyanone A (<b>7</b>) are slow-binding irreversible inhibitors of the bacterial α-PsGal with the inactivation rate constants (<i>k</i><sub>inact</sub>) 0.12 min<sup>−1</sup>, 0.092 min<sup>−1</sup>, 0.079 min<sup>−1</sup>, and 0.037 min<sup>−1</sup>, as well as equilibrium inhibition constants (<i>K<sub>i</sub></i>) 2.70 µM, 300 µM, 411 µM, and 105 µM, respectively. Docking analysis revealed that these alkaloids bind in a pocket close to the catalytic amino acid residues Asp451 and Asp516 and form complexes, due to π-π interactions with the Trp308 residue and hydrogen bonds with the Lys449 residue. None of the studied alkaloids formed complexes with the active site of the human α-NaGalase.
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