N-Oxide derivatives of 3-(3-pyridyl)-2-phosphonopropanoic acids as potential inhibitors of Rab geranylgeranylation

• Published in: Bioorganic & medicinal chemistry letters Vol. 25; no. 11; pp. 2331 - 2334
• Main Authors: Zhou, Xiang, Born, Ella J., Allen, Cheryl, Holstein, Sarah A., Wiemer, David F.
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.06.2015; Elsevier
• Subjects: Alkyl and Aryl Transferases - antagonists & inhibitors; Apoptosis; Bioassay; Cell Line, Tumor; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Drug Discovery; GGTase II; Humans; Life Sciences & Biomedicine; Molecular Structure; Multiple Myeloma; Myeloma; Pharmacology & Pharmacy; Physical Sciences; Propionates - chemistry; Propionates - pharmacology; Pyridyl N-oxides; Rab GGTase; Science & Technology; Structure-Activity Relationship; GGTase II; Bioassay; Rab GGTase; Myeloma; Pyridyl N-oxides; Apoptosis; OSTEOCLASTS; ANALOGS; RABGGTASE INHIBITORS; BISPHOSPHONATES; PRENYLATION; BIOLOGICAL-ACTIVITY; TRANSFERASE
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2015.04.021

[Display omitted] The N-oxide derivatives of [2-(3-pyridinyl)-1-hydroxyethylidene-1,1-phosphonocarboxylic acid (or PEHPC) and [2-(3-pyridinyl)-1-ethylidene-1,1-phosphonocarboxylic acid (or PEPC) have been prepared and evaluated for their activity against several enzymes which utilize isoprenoids. The parent pyridines are known inhibitors of GGTase II, but the N-oxide derivatives show no improvement in biological activity in assays with the isolated enzyme. However, the PEHPC N-oxide did induce significant accumulation of intracellular light chain in myeloma cells, consistent with inhibition of Rab geranylgeranylation.