title: Analogues of orphan nuclear receptor small heterodimer partner ligand and apoptosis inducer (E)-4-[3-(1-adamantyl)-4-hydroxyphenyl]-3-chlorocinnamic acid. 2. Impact of 3-chloro group replacement on inhibition of proliferation and induction of apoptosis of leukemia and cancer cell lines.
abstract: The parent phenol of adapalene and its (E)-cinnamic acid analogue were found to induce cancer cell apoptosis but cause adverse systemic effects when administered to mice. In contrast, their respective 5-Cl- and 3-Cl-substituted analogues had their adverse effects mitigated without a comparable loss of cancer cell inhibitory activity. As a result, pharmacologic space in this region of the cinnamic phenyl ring scaffold was explored. Various substituents were introduced, and their effects on cancer cell proliferation and viability were evaluated. Cinnamic acids having 3-Br, CN, NO(2), NH(2), OMe, and N(3) groups had activity comparable to that of 4-[3'-(1-adamantyl)-4'-hydroxyphenyl]-3-chlorocinnamic acid. A comparative molecular field analysis study indicated that introduction of an H-bond acceptor at position 3 of the central phenyl ring would favor inhibition of leukemia cell viability, and docking suggested its hydrogen bonding with a polar group in a small heterodimer partner homology model. The 3-CN, NO(2), NH(2), and OH analogues also inhibited MMTV-Wnt1 murine mammary stem cell viability.
authors.affiliation: Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, California 92037, United States.
authors.forename: Zebin
authors.initials: Z
authors.lastname: Xia
authors.forename: Ricardo G
authors.initials: RG
authors.lastname: Correa
authors.forename: Jayanta K
authors.initials: JK
authors.lastname: Das
authors.forename: Lulu
authors.initials: L
authors.lastname: Farhana
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: Joseph A
authors.initials: JA
authors.lastname: Fontana
authors.forename: John C
authors.initials: JC
authors.lastname: Reed
authors.forename: Marcia I
authors.initials: MI
authors.lastname: Dawson
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002934:Cinnamates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D007938:Leukemia; D008024:Ligands; D051379:Mice; D008958:Models, Molecular; D014411:Neoplastic Stem Cells / Q000166:cytology / Q000187:drug effects; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D051155:Wnt1 Protein / Q000378:metabolism
chemical_list: C480030:4-(3-(1-adamantyl)-4-hydroxyphenyl)-3-chlorocinnamic acid; D000970:Antineoplastic Agents; D002934:Cinnamates; D008024:Ligands; D018160:Receptors, Cytoplasmic and Nuclear; D051155:Wnt1 Protein; C099713:nuclear receptor subfamily 0, group B, member 2; D000218:Adamantane