title: Heteroatom-substituted analogues of orphan nuclear receptor small heterodimer partner ligand and apoptosis inducer (E)-4-[3-(1-Adamantyl)-4-hydroxyphenyl]-3-chlorocinnamic acid.
abstract: (E)-4-[3'-(1-Adamantyl)-4'-hydroxyphenyl]-3-chlorocinnamic acid (3-Cl-AHPC) induces the cell cycle arrest and apoptosis of cancer cells. Because its pharmacologic properties-solubility, bioavailability, and toxicity-required improvement for translation, structural modifications were made by introducing nitrogen atoms into the cinnamyl ring and replacing its E-double bond with XCH(2) (X = O, N, and S) with the objective of enhancing these properties without impacting apoptosis-inducing activity. Analogues having nitrogen atoms in heterocyclic rings corresponding to the cinnamyl phenyl ring displayed equal or higher biological activities. The pyrimidine and pyridine analogues were more soluble in both phosphate-buffered saline and water. While the 2,5-disubstituted pyridine analogue was the most potent inducer of KG-1 acute myeloid leukemia cell apoptosis, on the basis of apoptotic activity in KG-1 cells and solubility, the 2,5-disubstituted pyrimidine proved to be the more promising candidate for treatment of acute myeloid leukemia.
authors.affiliation: Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.
authors.forename: Zebin
authors.initials: Z
authors.lastname: Xia
authors.forename: Lulu
authors.initials: L
authors.lastname: Farhana
authors.forename: Ricardo G
authors.initials: RG
authors.lastname: Correa
authors.forename: Jayanta K
authors.initials: JK
authors.lastname: Das
authors.forename: David J
authors.initials: DJ
authors.lastname: Castro
authors.forename: Jinghua
authors.initials: J
authors.lastname: Yu
authors.forename: Robert G
authors.initials: RG
authors.lastname: Oshima
authors.forename: John C
authors.initials: JC
authors.lastname: Reed
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Fontana
authors.forename: Marcia I
authors.initials: MI
authors.lastname: Dawson
mesh_terms: D000179:Acrylates / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D000218:Adamantane / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D002934:Cinnamates / Q000737:chemistry* / Q000494:pharmacology; D015195:Drug Design; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*; D008024:Ligands; D051379:Mice; D057093:Orphan Nuclear Receptors / Q000378:metabolism*
chemical_list: C556168:3-(2-(3-(1-adamantyl)-4-hydroxyphenyl)-5-pyrimidinyl)-2-propenoic acid; C480030:4-(3-(1-adamantyl)-4-hydroxyphenyl)-3-chlorocinnamic acid; D000179:Acrylates; D000970:Antineoplastic Agents; D002934:Cinnamates; D008024:Ligands; D057093:Orphan Nuclear Receptors; D000218:Adamantane