title: SAR studies of 4-pyridyl heterocyclic anilines that selectively induce autophagic cell death in von Hippel-Lindau-deficient renal cell carcinoma cells.
abstract: We recently identified a class of pyridyl aniline thiazoles (PAT) that displayed selective cytotoxicity for von Hippel-Lindau (VHL) deficient renal cell carcinoma (RCC) cells in vitro and in vivo. Structure-activity relationship (SAR) studies were used to develop a comparative molecular field analysis (CoMFA) model that related VHL-selective potency to the three-dimensional arrangement of chemical features of the chemotype. We now report the further molecular alignment-guided exploration of the chemotype to discover potent and selective PAT analogues. The contribution of the central thiazole ring was explored using a series of five- and six-membered ring heterocyclic replacements to vary the electronic and steric interactions in the central unit. We also explored a positive steric CoMFA contour adjacent to the pyridyl ring using Pd-catalysed cross-coupling Suzuki-Miyaura, Sonogashira and nucleophilic displacement reactions to prepare of a series of aryl-, alkynyl-, alkoxy- and alkylamino-substituted pyridines, respectively. In vitro potency and selectivity were determined using paired RCC cell lines: the VHL-null cell line RCC4 and the VHL-positive cell line RCC4-VHL. Active analogues selectively induced autophagy in RCC4 cells. We have used the new SAR data to further develop the CoMFA model, and compared this to a 2D-QSAR method. Our progress towards realising the therapeutic potential of this chemotype as a targeted cytotoxic therapy for the treatment of RCC by exploiting the absence of the VHL tumour suppressor gene is reported.
authors.affiliation: Auckland Cancer Society Research Centre, The University of Auckland, Auckland, New Zealand.
authors.forename: Muriel
authors.initials: M
authors.lastname: Bonnet
authors.forename: Jack U
authors.initials: JU
authors.lastname: Flanagan
authors.forename: Denise A
authors.initials: DA
authors.lastname: Chan
authors.forename: Edwin W
authors.initials: EW
authors.lastname: Lai
authors.forename: Phuong
authors.initials: P
authors.lastname: Nguyen
authors.forename: Amato J
authors.initials: AJ
authors.lastname: Giaccia
authors.forename: Michael P
authors.initials: MP
authors.lastname: Hay
mesh_terms: D000814:Aniline Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D001343:Autophagy; D002292:Carcinoma, Renal Cell / Q000188:drug therapy*; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy*; D008958:Models, Molecular; D011725:Pyridines / Q000737:chemistry; D021281:Quantitative Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics* / Q000378:metabolism
chemical_list: D000814:Aniline Compounds; D011725:Pyridines; D013844:Thiazoles; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C023666:pyridine; C023650:aniline