title: S-allyl derivatives of 6-mercaptopurine are highly potent drugs against human B-CLL through synergism between 6-mercaptopurine and allicin.
abstract: S-allylthio-6-mercaptopurine and its ribose derivative were tested for anti-leukemic activity, using a human- mouse B-CLL model. The novel prodrugs contain two components, a purine analog, which interferes with DNA synthesis, and an S-allylthio, readily engaging in thiol-disulfide exchange reactions. The latter component targets the redox homeostasis which is more sensitive in leukemic cells, than in normal B-cells. Upon administration, the prodrug permeates cells, instantly reacts with free thiol, forming S-allyl mixed disulfides and releasing purine. Several cycles of thiol-disulfide exchange reactions occur, thus extending the duration of the prodrug effects. The concerted action of 2 components, as compared with purine alone, boosted in vitro apoptotis in B-CLL cells from 10% to 38%, and decreased in vivo engraftment of B-CLL from 30% to 0.7%.
authors.affiliation: Departments of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel. Talia.Miron@weizmann.ac.il
authors.forename: Talia
authors.initials: T
authors.lastname: Miron
authors.forename: Meir
authors.initials: M
authors.lastname: Wilchek
authors.forename: Lev
authors.initials: L
authors.lastname: Shvidel
authors.forename: Alain
authors.initials: A
authors.lastname: Berrebi
authors.forename: Fabian D
authors.initials: FD
authors.lastname: Arditti
mesh_terms: D000498:Allyl Compounds; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001402:B-Lymphocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D002463:Cell Membrane Permeability; D004247:DNA / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D004195:Disease Models, Animal; D004220:Disulfides / Q000737:chemistry / Q000378:metabolism; D004357:Drug Synergism; D005260:Female; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015122:Mercaptopurine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D008813:Mice, Inbred ICR; D010084:Oxidation-Reduction; D011355:Prodrugs / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D013438:Sulfhydryl Compounds / Q000737:chemistry / Q000378:metabolism; D013441:Sulfinic Acids / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D000498:Allyl Compounds; D000972:Antineoplastic Agents, Phytogenic; D004220:Disulfides; D011355:Prodrugs; D013438:Sulfhydryl Compounds; D013441:Sulfinic Acids; C006452:allicin; C028009:diallyl disulfide; D004247:DNA; D015122:Mercaptopurine