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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.
AuthorsMaria Chatzopoulou, Ioannis D Bonovolias, Ioannis Nicolaou, Vassilis J Demopoulos, Ioannis S Vizirianakis, Asterios S Tsiftsoglou
JournalEuropean journal of medicinal chemistry (Eur J Med Chem) Vol. 50 Pg. 75-80 (Apr 2012) ISSN: 1768-3254 [Electronic] France
PMID22341896 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2012 Elsevier Masson SAS. All rights reserved.
Chemical References
  • Acetamides
  • Antineoplastic Agents
  • Hemoglobins
  • RNA, Messenger
  • Globins
  • hexamethylene bisacetamide
Topics
  • Acetamides (chemistry, pharmacology)
  • Animals
  • Antineoplastic Agents (chemical synthesis, pharmacology)
  • Cell Cycle (drug effects)
  • Cell Differentiation (drug effects)
  • Cell Proliferation (drug effects)
  • Globins (genetics, metabolism)
  • Hemoglobins (metabolism)
  • Leukemia, Erythroblastic, Acute (drug therapy)
  • Mice
  • Molecular Structure
  • RNA, Messenger (genetics)
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tumor Cells, Cultured

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