Catechol Tetrahydroisoquinolines: Synthesis, Biological Activity, and Natural Occurrence in <i>Portulaca oleracea</i> as Analyzed by UPLC-Q-TOF-ESI-MS/MS

Catechol tetrahydroisoquinolines (THIQs) with structural novelty have been sporadically reported in <i>Portulaca oleracea</i> L., an edible vegetable and also a medicinal plant. However, their natural occurrence and biological activities are largely unknown. Using dopamine hydrochloride and aliphatic or aromatic aldehydes as substrates, 20 catechol THIQs with varied C1 side chains (<b>A1</b>-<b>A20</b>) were synthesized via an optimized mild phosphate-mediated Pictet-Spengler (P-S) reaction. Besides our previously developed AB-8 macroporous resin for the purification of hydrophilic THIQs, silica gel column chromatography employing ethyl acetate-methanol-ammonia or dichloromethane-methanol-85% formic acid as the eluent was optimized for the purification of lipophilic THIQs. Except for <b>A1</b>, <b>A3</b>, and <b>A11</b>, all compounds were synthesized for the first time using a mild phosphate-mediated P-S reaction, and <b>A5</b>, <b>A10</b>, <b>A19</b>, and <b>A20</b> were novel compounds. Using UPLC-Q-TOF-ESI-MS/MS analysis and some synthesized compounds as reference, real-virtual-combined target screening of catechol THIQs was performed. A total of 29 catechol THIQs were simultaneously detected in <i>P</i>. <i>oleracea</i> for the first time, including 11 fatty alkane-connected ones (containing 3 new natural products and 5 new compounds), 9 fatty acid-connected ones (containing 7 new compounds), 1 amide-connected one, and 8 aryl ring-connected ones (containing 1 new compound and 1 new natural product). <i>In vitro</i> assay indicated that two catechol THIQs (6,7-dihydroxy-1-<i>n</i>-undecyl-1,2,3,4-tetrahydroisoquinoline and ethyl 5-(6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline)-<i>n</i>-valerate) exhibited antibacterial activity, and most of them displayed potent antioxidant, Fe²⁺-chelation, and α-glucosidase inhibition activities. This study demonstrated that catechol THIQs made up a group of bioactive alkaloids in <i>P</i>. <i>oleracea</i>.