Novel substituted (Z)-2-(N-benzylindol-3-ylmethylene)quinuclidin-3-one and (Z)-(±)-2-(N-benzylindol-3-ylmethylene)quinuclidin-3-ol derivatives as potent thermal sensitizing agents

Abstract

Use of ionizing radiation is essential for the management of many human cancers, and therapeutic hyperthermia has been identified as a potent radiosensitizer. Radiation therapy combined with adjuvant hyperthermia represents a potential tool to provide outstanding local-regional control for refractory disease. (Z)-(±)-2-(N-Benzylindol-3-ylmethylene)quinuclidin-3-ol (2) and (Z)-(±)-2-(Nbenzenesulfoylindol-3-ylmethylene)quinuclidin-3-ol (4) were initially identified as potent thermal sensitizers that could lower the threshold needed for thermal sensitivity to radiation treatment. To define the structural requirements of the molecule that are essential for thermal sensitization, we have synthesized and evaluated a series of (Z)-2-(N-benzylindol-3-ylmethylene)quinuclidin-3-one (9), and (Z)-(±)-2-(N-benzylindol-3-ylmethylene)quinuclidin-3-ol (10) analogs that incorporate a variety of substituents in both the indole and N-benzyl moieties. These systematic structureactivity relationship (SAR) studies were designed to further the development and optimization of potential clinically useful thermal sensitizing agents. The most potent analog was compound 10 (R 1 =H, R 2 =4-Cl), which potently inhibited (93% inhibition at 50 µM) the growth of HT-29 cells after a 41°C/2hr exposure. Keywordsindolylquinuclidin-3-ones; indolylquinuclidin-3-ols; thermal sensitization Hyperthermia is one of the most potent radiosensitizers identified to date 1 . Over the last 30 years extensive experimentation using cell and animal models has demonstrated that hyperthermia can be an extremely effective radiation sensitizer, increasing the effectiveness of the radiation by up to 5-fold. 1,2 One important feature is that thermal radiosensitization does not exhibit cell type specificity nor is it limited by hypoxic conditions, suggesting that Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Heat-mediated changes in protein conformation represent the underlying biophysical/ biochemical mechanism responsible for heat-mediated cytotoxicity. 4 Westra and Dewey 5 were the first to hypothesize that cell death following hyperthermic treatment was a consequence of protein denaturation. Subsequent investigations have validated their hypothesis. 6-8 Thermal radiosensitization is also a consequence of protein unfolding and aggregation, 4 and under most conditions, is directly related to the degree of thermal sensitization. NIH Public AccessHowever, for many cancers, suboptimal thermal dosing limits radiosensitization. 6 While temperatures of 41°C can be achieved clinically, administration of higher temperatures ca...

Characterization of the intrinsic activity for a novel class of cannabinoid receptor ligands: Indole quinuclidine analogs

“…Reaction of analogue 1 , ( Z )-2-( N -benzylindol-3-ylmethylene)-quinuclidin-3-one and analogue 4 , each with hydroxyl amine hydrochloride in the presence of sodium acetate/methanol afforded their respective (2 Z ,3 E )-2-((1-benzyl-1 H -indol-3-yl)methylene)-quinuclidin-3-one oximes 9 , 10 and 11 , respectively. The structures of compounds 1–11 were confirmed by 1 H NMR, 13 C NMR and HRMS (ESI) (Madadi et al, 2013; Sonar et al, 2007). …”

Aplysinopsin analogs: Synthesis and anti-proliferative activity of substituted (Z)-5-(N-benzylindol-3-ylmethylene)imidazolidine-2,4-diones

“…1, C) was identified as a potent thermal sensitizer, capable of lowering the threshold for Hsf1 activation and increasing the thermal sensitivity of cancer cells to ionizing radiation. 8 Very recently, we have reported the synthesis and radio-sensitization activity of a small library of ( Z )-5-(( N -benzyl-1 H -indol-3-yl)methylene)imidazolidine-2,4-diones and 5-(( N -benzyl-1 H -indol-3-yl)methylene) pyrimidine-2,4,6-(1 H ,3 H ,5 H )trione derivatives 9 . In this series, 4-[(3-((2,4,6-trioxotetrahydropyrimidin-5-(6 H )-ylidene)methyl)-1 H -indol-1-yl)methyl]benzonitrile (Fig.…”

Evaluation of (Z)-2-((1-benzyl-1H-indol-3-yl)methylene)-quinuclidin-3-one analogues as novel, high affinity ligands for CB1 and CB2 cannabinoid receptors

“…16 Reduction of compounds 7 and 9 with NaBH 4 in methanol afforded the corresponding ( Z )-(±)-2-( N -benzylindol-3-yl methylene)-quinuclidin-3-ol derivatives 14 and 15 in 82–88% yield. 16 Reaction of compounds 7 and 9 with hydroxyl amine hydrochloride in the presence of sodium acetate/methanol afforded the (2 Z ,3 E )-2-((1-benzyl-1 H -indol-3-yl)methylene)-quinuclidin-3-one oximes 16 and 17 . 17 …”