title: Synthesis, SAR and biological evaluation of a novel series of 1-(2-chloroethyl)-1-nitroso-3-(2-(3-oxobenzoelenazol-2(3H)-yl)ethyl) urea: Organoselenium compounds for cancer therapy.
abstract: Thioredoxin reductase 1 (TrxR1) is an important potential anticancer drug target and closely related to both carcinogenesis and cancer progression. Ethaselen (BBSKE), a novel organoselenium compound inhibiting TrxR1 with selective antitumor effect, while its symmetrical structure results in poor solubility. Carmustine (BCNU), a DNA cross-link agent and also a deactivator of TrxR, is with high toxicity and low selectivity which limit its clinical application to some extents. Herein, a novel compound, 1-(2-chloroethyl)-1-nitroso-3-(2-(3-oxobenzoelenazol-2(3H)-yl)ethyl)urea(4a-1), which was designed through the combination of Ethaselen and Carmustine, showed good solubility, good tagetability, low toxicity and excellent antitumor activity by synergism. Using the structure of 4a-1 as a key active scaffold, a series of novel 1-(2-chloroethyl)-1-nitroso-3-(2-(3-oxobenzoelenazol-2(3H)-yl)ethyl)urea was designed, synthesized and evaluated to explore the structure-activity relationships (SARs) of these inhibitors and to improve their antitumor activities. Notably, 1-(2-chloroethyl)-3-(2-(6-fluoro-3-oxobenzoselenazol-2(3H)-yl)ethyl)-1-nitrosourea(4b-1) was found to exhibit more potent antitumor activities comparable to 4a-1 against all the four cancer cell lines, including Mia PaCa-2, PANC-1, RKO, LoVo. These results have highlighted compound 4b-1 as a new potential lead candidate for future development of novel potent broad-spectrum antitumor agents. In addition, a SAR model was established to conduct further structural modification.
authors.affiliation: Peking University State Key Laboratory of Natural and Biomimetic Drugs Beijing China.
authors.forename: S
authors.initials: S
authors.lastname: Ye
authors.affiliation: Peking University State Key Laboratory of Natural and Biomimetic Drugs Beijing China.
authors.forename: X
authors.initials: X
authors.lastname: Zheng
authors.affiliation: Peking University State Key Laboratory of Natural and Biomimetic Drugs Beijing China.
authors.forename: T
authors.initials: T
authors.lastname: Hu
authors.affiliation: Peking University State Key Laboratory of Natural and Biomimetic Drugs Beijing China zenghh@bjmu.edu.cn.
authors.forename: H
authors.initials: H
authors.lastname: Zeng
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001835:Body Weight / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D008024:Ligands; D062105:Molecular Docking Simulation; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D009607:Nitrosourea Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use* / Q000633:toxicity; D016566:Organoselenium Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use* / Q000633:toxicity; D051381:Rats; D012995:Solubility; D013329:Structure-Activity Relationship; D013880:Thioredoxin-Disulfide Reductase / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: C000613750:1-(2-chloroethyl)-3-(2-(5-fluoro-3-oxobenzoselenazol-2(3H)-yl)ethyl)-1-nitrosourea; D000970:Antineoplastic Agents; D008024:Ligands; D009607:Nitrosourea Compounds; D016566:Organoselenium Compounds; D013880:Thioredoxin-Disulfide Reductase