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.

Sonar VN, Thirupathi Reddy Y, Sekhar KR, Sasi S, Freeman ML, Crooks PA
Bioorg Med Chem Lett. 2007 17 (24): 6821-4

PMID: 17980582 · PMCID: PMC3726020 · DOI:10.1016/j.bmcl.2007.10.035

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-(N-benzenesulfonylindol-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 structure-activity 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 microM) the growth of HT-29 cells after a 41 degrees C/2h exposure.

MeSH Terms (8)

Cell Line, Tumor Cell Survival Humans Molecular Structure Quinuclidines Radiation-Sensitizing Agents Structure-Activity Relationship Temperature

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