{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T18:02:46Z","timestamp":1792000966621,"version":"4.4.0"},"reference-count":72,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,14]],"date-time":"2026-04-14T00:00:00Z","timestamp":1776124800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Hyperpigmentation disorders stem from tyrosinase-catalyzed melanin overproduction, worsened by ultraviolet oxidative stress. The native Chilean species\n                      <jats:italic>Cryptocarya alba<\/jats:italic>\n                      ,\n                      <jats:italic>Laurelia sempervirens<\/jats:italic>\n                      , and\n                      <jats:italic>Peumus boldus<\/jats:italic>\n                      are sources of aporphine and benzylisoquinoline alkaloids, known for their antioxidant activity. Boldine derivatives, notably diacetylboldine (DAB, Lumiskin\u2122), demonstrate commercial depigmenting efficacy, yet structure-activity relationship data are limited.\u200b\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Purpose<\/jats:title>\n                    <jats:p>\n                      Systematically evaluate pure alkaloids and boldine derivatives for tyrosinase inhibition\n                      <jats:italic>via<\/jats:italic>\n                      mushroom enzyme assays, molecular docking, human melanocyte (HEMn-DP), and 3D epidermal (MelanoDerm\u2122) models to elucidate depigmenting mechanisms.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Material and Methods<\/jats:title>\n                    <jats:p>\n                      Boldine (BOL),\n                      <jats:italic>N<\/jats:italic>\n                      -methyllaurotetanine (NMLT), laurolitsine (LTS), laurotetanine (LTT), and reticuline (RET) alkaloids were isolated from authenticated plant material\n                      <jats:italic>via<\/jats:italic>\n                      acid\u2013base partitioning\/silica gel chromatography; structures were confirmed by\n                      <jats:sup>1<\/jats:sup>\n                      H-NMR\/UHPLC\u2013MS\/MS (98% HPLC purity). Coclaurine (CC),\n                      <jats:italic>N<\/jats:italic>\n                      -methylcoclaurine (NMCC), and BOL derivatives: 3-bromoboldine (3BrBOL) and DAB were synthesized. Isocorydine (ISO) was obtained commercially. Mushroom tyrosinase (EC 1.14.18.1) inhibition measured spectrophotometrically (475\u00a0nm, L-DOPA; IC\n                      <jats:sub>50<\/jats:sub>\n                      interpolation). Docking performed on\n                      <jats:italic>A. bisporus<\/jats:italic>\n                      tyrosinase (PDB:2Y9X) with AutoDock Vina (30 \u00d7 30 \u00d7 30\u00a0\u00c5 grid). HEMn-DP cells treated (40\/250\u00a0ppm, 24\u00a0h) for MTS viability and alkali-solubilized melanin (450\u00a0nm). MelanoDerm\u2122 tissues were dosed topically (0.1% w\/v) for 14 days, followed by the Solvable\u2122 melanin assay (490\u00a0nm). Data analyzed in GraphPad Prism 8 (Dunnett\u2019s test,\n                      <jats:italic>P<\/jats:italic>\n                      &amp;lt; 0.05).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results and Discussion<\/jats:title>\n                    <jats:p>\n                      LTS (IC\n                      <jats:sub>50<\/jats:sub>\n                      = 0.96\u00a0mM), an aporphine alkaloid, followed by CC (1.29\u00a0mM), a benzylisoquinoline alkaloid, were the most potent mushroom tyrosinase inhibitors, outperforming BOL 6.8- and 5.1-fold (6.56\u00a0mM), respectively, yet trailing reference standards such as kojic acid (0.014\u00a0mM). Boldine derivatives, including DAB (2.22\u00a0mM) and 3BrBOL (1.96\u00a0mM), exhibited superior potency relative to the parent compound. Docking revealed LTS\u2019s highest affinity (\u22127.3\u00a0kcal\/mol; H-bonds: His259 3.4\u00a0\u00c5, Asn260 3.2\u00a0\u00c5)\n                      <jats:italic>versus<\/jats:italic>\n                      BOL (\u22125.3\u00a0kcal\/mol; solely van der Waals), explained by NH-mediated His263 interaction absent in\n                      <jats:italic>N<\/jats:italic>\n                      -methylated boldine. In addition, hemisynthetic alkaloids (3BrBOL and DAB) show interactions and affinity energies similar to those of BOL. In HEMn-DP (40\u00a0ppm, 24\u00a0h), BOL\/3BrBOL achieved 100% tyrosinase inhibition (viability \u223c50%), exceeding DAB (62%). MelanoDerm\u2122 (0.1% w\/v, 14 days): results confirmed the efficacy of 3BrBOL (\u221233% melanin,\n                      <jats:italic>P<\/jats:italic>\n                      &amp;lt; 0.05; \u223carbutin), BOL (\u221210%), and DAB\/LTS inactivity, highlighting the superiority of C-3 halogenation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>LTS is the premier natural inhibitor; optimization of 3BrBOL validates BOL derivatization for ARB equivalent depigmentation in 3D models. These findings support the development of hydroquinone-free cosmeceuticals from Chilean flora alkaloids and advocate the use of nanoemulsions to enhance delivery and reduce cytotoxicity.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1795496","type":"journal-article","created":{"date-parts":[[2026,4,14]],"date-time":"2026-04-14T05:39:14Z","timestamp":1776145154000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Molecular docking and experimental evaluation of natural alkaloids from Chilean flora (Cryptocarya alba, Peumus boldus, and Laurelia sempervirens) for tyrosinase inhibition and depigmenting potential"],"prefix":"10.3389","volume":"17","author":[{"given":"Sebasti\u00e1n","family":"Castro-Saavedra","sequence":"first","affiliation":[{"name":"Departamento de Ciencias del Ambiente, Facultad de Qu\u00edmica y Biolog\u00eda, Universidad de Santiago de Chile","place":["Santiago, Chile"]},{"name":"SAPHYCHEM","place":["Santiago, Chile"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gonzalo","family":"Fuentes-Barros","sequence":"additional","affiliation":[{"name":"SAPHYCHEM","place":["Santiago, Chile"]},{"name":"Programa de Doctorado en Pol\u00edticas P\u00fablicas, Universidad Mayor","place":["Santiago, Chile"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Mellado","sequence":"additional","affiliation":[{"name":"Direcci\u00f3n de Investigaci\u00f3n, Universidad Bernardo O\u2019Higgins","place":["Santiago, Chile"]},{"name":"Laboratorio de Espectroscopia y Qu\u00edmica Aplicada, Grupo de Investigaci\u00f3n en Ciencias Biom\u00e9dicas Aplicadas, Universidad Central de Chile","place":["Santiago, Chile"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Javier","family":"Echeverr\u00eda","sequence":"additional","affiliation":[{"name":"Departamento de Ciencias del Ambiente, Facultad de Qu\u00edmica y Biolog\u00eda, Universidad de Santiago de Chile","place":["Santiago, Chile"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,4,14]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"298","DOI":"10.36849\/JDD.8899","article-title":"The multifaceted effects of berberine: potential uses in dermatology","volume":"24","author":"A Okoye","year":"2025","journal-title":"J. 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