Radiotherapy is the treatment of cancer and other diseases with ionizing radiation. Radiotherapy is used in curative therapy, palliative therapy, adjuvant therapy after or before surgery, simultaneous radio-chemotherapy, etc. Radiotherapy is successful because ionizing radiation kills dividing cells and is thus slightly more toxic to fast growing cancer cells. Radiotherapy may be used to treat localized solid tumors, such as cancers of the skin, tongue, larynx, brain, breast, or uterine cervix. Agents which are used to potentiate the effectiveness of radiation therapy in destroying unwanted cells are radiation sensitizing agents. Various attempts have been made to develop a radiation sensitizer that reduces the radiation dose and adverse drug reactions without compromising the therapeutic effect of radiotherapy.
For example, 7-Hydroxystaurosporine (UCN-01) is used as a radiosensitizing agent (Zhouguang et al., 2003) in radiotherapy to increase the radiosensitivity of tumor cells. The sulfonamide-substituted indolinones have been invented as radiation sensitizing agents (Anthony et al., U.S. Pat. Appl. Publ. 2004, 46 pp), which are capable of enhancing radiotherapy by inhibiting DNA-protein kinase (DNA-PK).
Radiotherapy is often performed for various types of cancers such as gastric cancer, colorectal cancer, pancreatic cancer, head and neck cancer, esophageal cancer, lung cancer, and breast cancer that are advanced to stage III or IV.
Radiation therapy combined with adjuvant hyperthermia has the potential to provide outstanding local-regional control for refractory disease. Hyperthermia is an extremely effective radiation sensitizer, yielding thermal enhancement factors of up to 5.0 (Kampinga and Dikomey, 2001; Raaphorst and Azzam, 1983). However, hyperthermia is limited clinically as a result of the technical problems of heat delivery (Nielsen et al., 2001). Hence there is an urgent need to develop pharmacological agents that can be used to replace hyperthermia. Previous work has established that indomethacin can act as a radiation sensitizer (Bradbury et al., 2001; Locke et al., 2002) and enhancer of thermal radiosensitization, and also it has been shown from other independent work that indomethacin lowers the temperature necessary for the heat-induced protein aggregation and lowers the temperature necessary for Hsf-1 activation, such that a complete heat shock response can be attained at temperatures that are by themselves, insufficient for activation. Although indomethacin is used as a radiation sensitizer in radiotherapy, it is highly toxic at high concentrations. Hence there is a need to invent pharmacological agents with lower toxicity.
The present inventors previously discovered novel indole as potent thermal radiosensitizers capable of lowering the threshold for Hsf1 activation and thermal sensitivity. Additionally, the present inventors previously discovered (Z)-2-(N-benzylindol-3-ylmethylidene)quinuclidin-3-ol and Z-(±)-2-[N-(4-chlorobenzyl)indole-3-ylmethylidene]quinuclidin-3-ol as potent thermal radiosensitizers capable of lowering the threshold for Hsf1 activation and thermal sensitivity (Sekhar et al. 2007; Sonar et al. 2007). These compounds needed 41° C. temperature to produce radiosensitization. It is difficult to achieve such temperatures in tumors. In order to lower the temperatures, the above compounds were modified and tested for their ability to induce heat shock effect and finally radiosensitization.
The indole derived Aplysinopsin analogs have been reported as potent and selective cytotoxic agents against cancer cells. These observations prompted us to design and synthesize a series of novel indole derivatives, including substituted 5((N-Benzyl-1H-indol-3-yl)methylene)pyrimidine-2,4,6(1H,3H,5H)-triones & (Z)-5((N-benzyl-1H-indol-3-yl)methylene)imidazolidine-2,4-diones and their related compounds with various substitutions on both the indolic ring and the N-benzyl group that are radiation sensitizers by eliminating the necessity of heat.