A series of (Z)-5-((N-benzyl-1H-indol-3-yl)methylene)imidazolidine-2,4-dione (9a–9m) and 5-((N-benzyl-1H-indol-3-yl)methylene)pyrimidine-2,4,6(1H,3H,5H)-trione (10a–10i) derivatives that incorporate a variety of aromatic substituents in both the indole and N-benzyl moieties have been synthesized. These analogs were evaluated for their radiosensitization activity against the HT-29 cell line. Three analogs, 10a, 10b, and 10c were identified as the most potent radiosensitizing agents.
CN OH O Ar NH 2 R' R Ar-CHO R + + TiCl 4 r.t 1 2 3 4a-tThree component coupling of one pot reaction which servers as the most convenient route to the synthesis of benzopyran derivatives using the TiCl 4 catalyst (10 mol %) under solvent free conditions is described. The procedure offers a systematic method with a number of advantages including operational simplicity, neat reactions, reduced reaction time, high yields of products and applicability to large scale reactions.
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...
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