4-Pyridylanilinothiazoles That Selectively Target von Hippel−Lindau Deficient Renal Cell Carcinoma Cells by Inducing Autophagic Cell Death

Abstract

Renal cell carcinomas (RCC) are refractory to standard therapy with advanced RCC having a poor prognosis; consequently treatment of advanced RCC represents an unmet clinical need. The von Hippel-Lindau (VHL) tumor suppressor gene is mutated or inactivated in a majority of RCCs. We recently identified a 4-pyridyl-2-anilinothiazole (PAT) with selective cytotoxicity against VHLdeficient renal cells mediated by induction of autophagy and increased acidification of autolysosomes. We report exploration of structure-activity relationships (SAR) around this PAT lead. Analogues with substituents on each of the three rings, and various linkers between rings, were synthesized and tested in vitro using paired RCC4 cell lines. A contour map describing the relative spatial contributions of different chemical features to potency illustrate a region, adjacent to the pyridyl ring, with potential for further development. Examples probing this domain validated this approach and may provide the opportunity to develop this novel chemotype as a targeted approach to the treatment of RCC.

Identifying novel targets in renal cell carcinoma: Design and synthesis of affinity chromatography reagents

“…13 Alkylation of 3-bromopyridine 12 with ethyl iodide in DMF gave 17 in 60% yield. Sonogashira cross-coupling reaction with TMS acetylene and subsequent deprotection of the TMS group gave 3-acetylene 18 in 65% yield.…”

“…13 This handicap led us to use a comparative molecular field analysis (CoMFA) to determine possible bioactive conformations to aid our studies. We identified a positive steric contour (Fig.…”

SAR studies of 4-pyridyl heterocyclic anilines that selectively induce autophagic cell death in von Hippel-Lindau-deficient renal cell carcinoma cells

“…The imidazole analogue 3 was synthesized by condensation 22 between bromoketone 55 20 and 3-methylphenylguanidinium nitrate 56 23 using KOH as base (Scheme 1). Similarly, condensation of bromoketone 55 and 3-methylphenylurea 57 afforded oxazole 4 .…”

“…Subsequent DIAD-induced heterocyclization of amidine 58 with 3-methylphenylisothiocyanate gave thiadiazole 5 . Methylation of thiourea 59 , 20 gave thiocarbamate 60 which underwent condensation with 4-pyridinecarbohydrazide to give triazole 6 as a mixture of regioisomers. Addition of MeNH 2 to 3-methylphenylisothiocyanate gave methylated thiourea 61 which was converted to thiocarbamate 62 by alkylation with MeI, and subsequent condensation with 4-pyridinecarbohydrazide afforded triazole 7 .…”

“…20 A quantitative analysis of the SAR was used to determine a possible bioactive conformation for the PAT analogues using Comparative Molecular Field Analysis (CoMFA).…”