Phenolic thio- and selenosemicarbazones as multi-target drugs.
A series of isosteric phenolic thio- and selenosemicarbazones have been obtained by condensation of naturally-occurring phenolic aldehydes and thio(seleno)semicarbazides. Title compounds were designed as potential multi-target drugs, and a series of structure-activity relationships could be established upon their in vitro assays: antioxidant activity, α-glucosidase inhibition and antiproliferative activity against six human tumor cell lines: A549 (non-small cell lung), HBL-100 (breast), HeLa (cervix), SW1573 (non-small cell lung), T-47D (breast) and WiDr (colon). For the antiradical activity, selenium atom and 2 or 3 phenolic hydroxyl groups proved to be essential motifs; remarkably, the compound with the most potent activity, with a trihydroxyphenyl scaffold (EC50 = 4.87 ± 1.57 μM) was found to be stronger than natural hydroxytyrosol, a potent antioxidant present in olive oil (EC50 = 13.80 ± 1.41 μM). Furthermore, one of the thiosemicarbazones was found to be a strong non-competitive inhibitor of α-glucosidase (Ki = 9.6 ± 1.6 μM), with an 8-fold increase in activity compared to acarbose (Ki = 77.9 ± 11.4 μM), marketed for the treatment of type-2 diabetes. Most of the synthesized compounds also exhibited relevant antiproliferative activities; in particular, seleno derivatives showed GI50 values lower than 6.0 μM for all the tested cell lines; N-naphthyl mono- and dihydroxylated derivatives behaved as more potent antiproliferative agents than 5-fluorouracil or cisplatin.
Departamento de Química Orgánica, Facultad de Química, Universidad de Sevilla, Apartado 1203, E-41071 Seville, Spain.
Verónica
V
Calcatierra
Departamento de Química Orgánica, Facultad de Química, Universidad de Sevilla, Apartado 1203, E-41071 Seville, Spain. Electronic address: osc-lopez@us.es.
Óscar
Ó
López
Departamento de Química Orgánica, Facultad de Química, Universidad de Sevilla, Apartado 1203, E-41071 Seville, Spain.
José G
JG
Fernández-Bolaños
BioLab, Instituto Universitario de Bio-Orgánica "Antonio González" (IUBO-AG), Centro de Investigaciones Biomédicas de Canarias (CIBICAN), Universidad de La Laguna, c/ Astrofísico Francisco Sánchez 2, E-38206 La Laguna, Spain.
Gabriela B
GB
Plata
BioLab, Instituto Universitario de Bio-Orgánica "Antonio González" (IUBO-AG), Centro de Investigaciones Biomédicas de Canarias (CIBICAN), Universidad de La Laguna, c/ Astrofísico Francisco Sánchez 2, E-38206 La Laguna, Spain.
José M
JM
Padrón
D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D000975:Antioxidants / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor / Q000187:drug effects; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004354:Drug Screening Assays, Antitumor; D065089:Glycoside Hydrolase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D010636:Phenols / Q000737:chemistry / Q000494:pharmacology; D012664:Semicarbazones / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013457:Sulfur Compounds / Q000737:chemistry / Q000494:pharmacology; D000520:alpha-Glucosidases
D000970:Antineoplastic Agents; D000975:Antioxidants; D065089:Glycoside Hydrolase Inhibitors; D010636:Phenols; D012664:Semicarbazones; D013457:Sulfur Compounds; D006861:Hydrogen Peroxide; D000520:alpha-Glucosidases
Antioxidants; Antiproliferative agents; Glycosidase inhibitors; Phenolic compounds; ROS scavengers; Thio(seleno)semicarbazones