title: Bis-pyrrolyl-tetrazolyl derivatives as hybrid polar compounds: A case of lipophilic functional bioisosterism with bis-acetamides.
abstract: Based on previous studies on bis-acetamides that act as hybrid polar compounds to induce leukemia cell differentiation, an attempt was made to bioisosterically replace the amide moiety with the lipophilic non-classical bioisostere tetrazole. A pyrrole group was also included in the molecule in order to retain the hydrogen bond donor capability. Thus, by linking the two polar ring systems with a highly lipophilic methylene chain compounds 2-4 were synthesized and assessed for their anti-proliferative activity in combination with their ability to induce murine erythroleukemia (MEL) cell differentiation. Furthermore, an initial investigation of the structure-activity relation points for the active compound 3 was undertaken by synthesizing compound 5 (a p-xylene analog) and compound 8 (a methylamidopyrrolyl analog). All compounds caused a dose-dependent inhibition of MEL cell growth but to a different extent. Compound 3 (1,6-bis[5-(1H-pyrrol-1-yl)-2H-tetrazol-2-yl]hexane) promoted erythroid differentiation in a fifty-fold lower concentration than hexamethylenebisacetamide (HMBA). Though induction of differentiation was to a lesser extent than HMBA, it caused accumulation of 80% Hb-producing cells as compared to that produced by HMBA, leading to differentiation-depended cell growth inhibition equal to that of HMBA after 96 h in culture. Compound 3 represents a potent inducer of hemoglobin gene activation in leukemic cells.
authors.affiliation: Laboratory of Pharmaceutical Chemistry, Department of Pharmaceutical Sciences, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece.
authors.forename: Maria
authors.initials: M
authors.lastname: Chatzopoulou
authors.forename: Ioannis D
authors.initials: ID
authors.lastname: Bonovolias
authors.forename: Ioannis
authors.initials: I
authors.lastname: Nicolaou
authors.forename: Vassilis J
authors.initials: VJ
authors.lastname: Demopoulos
authors.forename: Ioannis S
authors.initials: IS
authors.lastname: Vizirianakis
authors.forename: Asterios S
authors.initials: AS
authors.lastname: Tsiftsoglou
mesh_terms: D000081:Acetamides / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D005914:Globins / Q000235:genetics / Q000378:metabolism; D006454:Hemoglobins / Q000378:metabolism; D004915:Leukemia, Erythroblastic, Acute / Q000188:drug therapy*; D051379:Mice; D015394:Molecular Structure; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
chemical_list: D000081:Acetamides; D000970:Antineoplastic Agents; D006454:Hemoglobins; D012333:RNA, Messenger; D005914:Globins; C014026:hexamethylene bisacetamide