title: The design, synthesis and anticancer activity of new nitrogen mustard derivatives of natural indole phytoalexin 1-methoxyspirobrassinol.
abstract: Nitrogen mustards cis-1-methoxy-2-deoxy-2-[N,N-bis(2 -chloroethyl)amino]spirobrassinol (4) and trans-1-methoxy-2-deoxy-2-[N,N-bis(2 -chloroethyl)amino]spirobrassinol (5) derived from 1-methoxyspirobrassinol, an indole phytoalexin produced by the Japanese radish Raphanus sativus var. hortensis were designed as prospective dual-action compounds with DNA-alkylating effect and glutathione-depleting effects that may sensitize cancer cells to alkylating agents. Both new compounds demonstrated cytostatic/cytotoxic effects on various leukemia and ovarian cancer cell lines and dsDNA-destabilizing effects in vitro. Compound 4, the more promising of the two compounds, exerts earlier onset of anticancer effects on Jurkat cells via induction of apoptosis compared to the traditional alkylating anticancer agent melphalan. In addition, it demonstrated higher potency on ovarian cancer OVCAR-3 cell line and lower fold resistance between Jurkat and Jurkat-M cells selected for the resistance to melphalan. Therefore, compound 4 may be less affected by certain cancer drug resistance mechanisms than melphalan and it may become a prototype of a new class of anticancer active nitrogen mustards that combine DNA-damaging and DNA-damage-sensitizing properties.
authors.affiliation: Georgia Institute of technology, School of Biology, Atlanta, a 30332, USA. rmezencev3@gatech.edu
authors.forename: R
authors.initials: R
authors.lastname: Mezencev
authors.forename: P
authors.initials: P
authors.lastname: Kutschy
authors.forename: A
authors.initials: A
authors.lastname: Salayova
authors.forename: T
authors.initials: T
authors.lastname: Updegrove
authors.forename: J F
authors.initials: JF
authors.lastname: McDonald
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D020169:Caspases / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D005260:Female; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D008558:Melphalan / Q000494:pharmacology; D015394:Molecular Structure; D012717:Sesquiterpenes; D013329:Structure-Activity Relationship; D013729:Terpenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000094162:Phytoalexins
chemical_list: C542548:1-methoxy-2-deoxy-2-(N,N-bis(2'-chloroethyl)amino)spirobrassinol; D000970:Antineoplastic Agents; D007211:Indoles; D012717:Sesquiterpenes; D013729:Terpenes; D013844:Thiazoles; D020169:Caspases; D005978:Glutathione; D008558:Melphalan; D000094162:Phytoalexins